What safety margins were accepted for approved small molecules?

“Six-month mouse 200 mg/kg/day 4.8 μg·h/mL 0.02× Nine-month dog 20 mg/kg/day 11.8 μg·h/mL (males) 3.4 μg·h/mL (females) 0.06× 0.02×”

“The Reviewer agreed with the Applicant’s interpretation that the NOAEL was the MD (20 mg/kg/day) based on the mortality, weight loss and GI toxicity observed at the HD.”

“The total AUC in the chronic repeat-dose toxicity studies at the no observed adverse effect level (NOAEL) is approximately 4% of the exposure achieved in patients at the proposed clinical dose of 500 mg in both rats and dogs.”

“Both species experienced liver toxicity following tepotinib exposure, with dose-dependent elevated liver enzymes (AST, ALT, and/or ALP), histopathologic changes, liver enlargement”

“The safety margins (total AUC ratio) derived from the GLP-compliant 13-week rat and dog study NOAELs are 0.3 and 0.05, respectively.”

“The identified target organs of fruquintinib toxicity were liver, kidney, adrenal gland, thymus, spleen, bone marrow (sternum), and femur.”

“The no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day. AUC0-24hr at 15 mg/kg/day was 2.31 ȝJ·hr/mL in males and 14.1 ȝJ·hr/mL in females, which are 0.06 and 0.36 times the human AUC0-24hr (39.1 ȝJ·hr/mL) observed with 150 mg/m2 BID, respectively.”

“The results of the 6-month oral toxicity study in rats indicated that treatment with lonafarnib (at doses of 30 and 60 mg/kg/day) produced renal toxicity, including necrosis and mineralization in the inner medulla and mononuclear cell infiltrates. The no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day.”

“NOAELs for severe haematopoietic inhibition are 3 mg/kg/day for rats (MOE: 1.42-1.51) and monkeys (MOE: 0.07- 0.10) and 5 mg/kg/day for dogs (MOE: 0.41-0.54).”

“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”

“The NOAEL in the monkeys in the 9-month study was 50 mg/kg/d. At the NOAEL, the associated Week 39 AUC0-last values were 16,700 h⋅ng/mL in males and 12,700 h⋅ng/mL in females or 0.2 and 0.1 times, respectively, the AUC0-24 in humans at 800 mg clinical dose.”

“All sparsentan-related changes were reversible or reversing at the end of the 1-or 2-month recovery periods. The NOAEL in the monkeys in the 9-month study was 50 mg/kg/d.”

“The NOAEL was set at 25 mg/kg/day resulting in exposures below human therapeutic exposures for total (approximately 0.1-times) and free unbound (approximately 0.5-times) maribavir based on AUC.”

“The major findings in the 52-week study in monkeys and 26-week study in rats were regenerative anemia and gastrointestinal effects”

“At the NOAEL, male AUC is lower than (~0.1x), and female AUC is approximately equal to (~0.8x), human AUC at the MRHD.”

“The reductions in body weight were dose-limiting in animals and would be monitorable in humans. There were no unmonitorable toxicities observed at doses below those with adverse effects on body weight.”

“In the rat 4-week study, the AUC exposure margins at NOAEL were 0.1/0.2-fold (males/females) for GS-441524, and 0.2/0.4-fold (males/females) for GS-704277.”

“Also in the 4-week study in rats clinical pathology and microscopic findings indicative of kidney injury and/or dysfunction in animals administered ≥ 3 mg/kg/day, and unscheduled deaths of 2 females and decreased body weight gain and food consumption at 10 mg/kg/day were seen. Based on the nature and severity of the kidney changes the NOAEL was 3 mg/kg/day, which corresponds to 0.4-fold (males) and 0.2-fold (females) the human AUC of GS-441524.”

“Study NOAEL was considered at 8 mg/kg/day (approximately 0.1-fold of the maximum human dose)”

“However, in the 13-week studies in the rats and marmosets at similar doses to those used in shorter term studies, convulsions and mortality were observed (≥50 mg/kg in marmosets, 0.2 times the MRHD; ≥250 mg/kg in rats, 0.94 times the MRHD, based on BSA comparisons).”

“The NOAEL was 3 mg/kg/day, a dose equivalent to 0.2 that of the clinical dose based on body surface area comparisons.”

“Histopathologic and hematologic changes were comparable to controls at the end of recovery, indicating reversibility of effects. The NOAEL was 3 mg/kg/day, a dose equivalent to 0.2 that of the clinical dose based on body surface area comparisons.”

“The human equivalent dose (HED) values for the rat and dog NOAEL values based on body surface area comparison provide only low safety margins of 0.4 for rats and 1.7 for dogs with respect to a 10 mg/kg/day clinical dose and 0.2 for rats and 0.8 for dogs with respect to a 20 mg/kg/day clinical dose.”

“The NOAEL values for nifurtimox in rats and dogs in the 13-week and 1-year toxicology studies were considered to be 25 and 30 mg/kg/day, respectively.”

“In the 91-day study in minipig, the HNSTD and NOAEL was 5 mg/kg/day (175 mg/m2/day) and exposure at this dose corresponded to approximately 0.2 to 0.3 times the human geometric mean AUC at the recommended clinical dose.”

“Minipigs were exquisitely sensitive to selpercatinib and was the most sensitive species. Major toxicological findings that occurred in the minipig were at doses that induced moribundity/lethality with exposures below therapeutic exposures in human.”

“In the rabbit embryo-foetal toxicity study, the NOAEL resulted in safety margin of 0.08, and dog 9-month repeat dose toxicity study NOAELs resulted in safety margins of 0.2 and 0.4, when compared to the expected clinical exposure.”

“In the rabbit embryo-foetal toxicity study, the NOAEL resulted in safety margin of 0.08, and dog 9-month repeat dose toxicity study NOAELs resulted in safety margins of 0.2 and 0.4, when compared to the expected clinical exposure.”

“The no observed adverse effect level (NOAEL) was considered to be 0.5 mg/kg which was associated with a maximum plasma concentration (Cmax) of 741 ng/mL and an AUC of 14,295 ngꞏhr/mL (about 0.2 times the MRHD based on AUC comparisons).”

“Oteseconazole dosing for 26 weeks in rats resulted in changes in the liver, adrenals, thyroid, kidneys, and ovaries with no significant effects at 0.15 mg/kg”

“Oral administration of TCBZ was not embryotoxic in rats and rabbits up to 200 and 20 mg/kg/day, which is 1.6 and 0.3 times the clinical dose respectively, based on a body surface area comparison.”

“The no observed adverse effect level (NOAEL) was 0.7 to 0.8 mg/kg/day dose in rats (10 ppm) and 0.35 mg/kg/day dose in dogs (10 ppm).”

“It should however be noted that the margins to clinical exposure from NOAEL (100mg/kg/day in the 3- month monkey study) is only 3-fold and 0.3-fold of the Cmax and AUC-values in humans respectively.”

“It should however be noted that the margins to clinical exposure from NOAEL (100mg/kg/day in the 3- month monkey study) is only 3-fold and 0.3-fold of the Cmax and AUC-values in humans respectively.”

“It should be taken into consideration that low margins of exposure ranging from 0.3 to 2.4 were observed in the 28-day and 13-week repeat-dose studies in rat and dog. And in general, the observed exposure at NOAEL levels were similar or below the exposure level at the maximum human recommended dose.”

“In both rats and dogs, the target organs were heart, lungs, adrenal gland, kidney, and liver.”

“The maternal NOAEL is considered 3 mg/kg/day and the developmental NOAEL is considered 10 mg/kg/day in rabbits, corresponding to exposure margins of 0.3 and 0.7, respectively.”

“Based on the liver (bile duct hyperplasia) and kidney (tubular degeneration/regeneration) findings at all doses (0, 0.3, 1, or 3 mg/kg) in the 26-week study, a NOAEL was not established in rats.”

“The no observed adverse effect level (NOAEL) of mavorixafor in female dogs was defined at 3.8 mg/kg/day based on mavorixafor-related adverse findings at higher doses and corresponds to exposures 0.3-times the exposures at the MRHD.”

“Mavorixafor (free base) target organs of toxicity included the liver, gallbladder, testes, epididymides, and eyes (based on histopathological examination only).”

“The NOAEL was identified at 0.1 mg/kg/day (0.35-fold the clinical exposure).”

“The determined NOAEL was 0.1 mg/kg/day in male rats and 0.3 mg/kg/day in female rats. Exposures at these doses are below the clinical predicted exposure at the intended posology.”

“39-week repeat dose study in monkeys Female 30 3000 0.35X Male 80 8370 1X”

“No adverse PD related reproductive findings were observed in rats up to 25 mg/kg and in monkeys up to 30 mg/kg, corresponding to a safety margin of 10 and 0.3, respectively, based on total exposure (AUC0-24).”

“However, exposure multiples compared to the NOAEL of the clinical exposure demonstrated no margins of exposure within the pivotal long-term repeat-dose toxicology studies (rats: 0.39 (M) for adults and 0.22 (M) for paediatric patients; monkeys: 0.41 (M) for adults”

“However, exposure multiples compared to the NOAEL of the clinical exposure demonstrated no margins of exposure within the pivotal long-term repeat-dose toxicology studies (rats: 0.39 (M) for adults and 0.22 (M) for paediatric patients; monkeys: 0.41 (M) for adults and 0.23 (M) for paediatric patients).”

“The no observed adverse effect level (NOAEL) for SAM in rats is 5 mg/kg/day, which is 0.4 and 5 times the MRHD in males and females, respectively based on AUC.”

“The NOAEL for SAM in dogs is 1 mg/kg/day, which is approximately equal to the clinical exposure at the MRHD of 10 mg SAM based on AUC.”

“The NOAEL by oral route were 75, 30 and 12 mg/kg/day in mice, rats and monkeys, respectively with safety margins based on AUC for male and female of 9, 1 and 0.4, respectively.”

“The NOAEL by oral route were 75, 30 and 12 mg/kg/day in mice, rats and monkeys, respectively”

“Safety margins based on the Cmax- and AUC0-last-related exposure at the respective NOAELs determined in repeat-dose toxicity studies were negligible in adult or juvenile mice or not existent in dogs when compared to corresponding levels in human DMD patients at the MRHD.”

“In the general toxicology studies, the target tissues of vamorolone were liver, adrenal glands, lymphocytes and lymphoid tissues, male and female reproductive tissues, and skeletal muscle; plasma exposures at the no effect level for the findings in these tissues were similar to or less than that in humans at the proposed clinical dose of 6 mg/kg (Table 44).”

“Major target organs for toxicity in rats comprises CNS, skin and bone marrow, with low to non-existing safety margins based on systemic exposure at NOAEL and expected human exposure at clinical intended dosing of 160 mg BID.”

“In the pivotal GLP-compliant RD-toxicity studies, the major target organs across species were the skin (rat), CNS (rat), bone marrow (rat and monkey), and GI (monkey). These findings were generally dose-dependent and were reversible or showed a trend towards reversibility.”

“In the repeat-dose toxicology studies up to 13-weeks duration in rats, myocardial degeneration and necrosis were observed at doses ≥ 0.01 mg/kg/day (below the human exposure at the recommended dose based on AUC).”

“The major target organs of toxicity in rats and monkeys included the skin and lymphoid organs. Additional organs in rats included the eye, kidney, heart, and liver, and in monkeys, gastrointestinal organs, and ovary.”

“choroid plexus edema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1 or 0.4 times the human exposure based on AUC at the 25 mg, 200 mg or 300 mg dose, respectively), but were not observed in a 9-month study at 5 mg/kg/day.”

“Repeat dose studies in dogs indicated haemorrhage and choroid plexus oedema in the brain at ≥ 0.4 times the human exposure at the clinical dose of 300 mg once daily. Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥8-fold higher than the exposure in patients at the clinical dose of 300 mg once daily.”

“For rats, the exposures at the no adverse effect level (NOAEL) for stimulant-related findings (25 mg/kg) was less than the human exposure at the MRHD.”

“For rats, the exposures at the no adverse effect level (NOAEL) for stimulant-related findings (25 mg/kg) was less than the human exposure at the MRHD. For dogs, the NOAEL for stimulant-related findings was not established because the NOAEL is less than the lowest dose tested.”

“Thus, interpretation of the observed adverse effects is difficult since the exposure multiples following repeat dose administration of erdafitinib are much lower than the AUC in humans at the intended clinical dose of 8 or 9 mg.”

“The predominant target organs were aorta (vascular/degeneration), heart (mineralisation/degeneration), bone femur and sternum (chondroid dysplasia), skin (increased hair follicles) and epithelial atrophy in the tongue, oral mucosa, parotid salivary glands, eye, teeth and lacrimal glands.”

“Plasma exposure in all toxicology studies and reproductive toxicology studies at the NOAEL is less than those in humans at the MRHD (Table 146).”

“A no-observed-adverse-effect-level (NOAEL) was determined to be 0.3 mg/kg/day and 0.06 mg/kg/day, respectively for the rat and dog, based on echocardiographic, electrocardiographic, or histological endpoints in the heart in the chronic toxicity studies.”

“NOAEL = 5 mg/kg (0.5X MRHD) [LOAEL = 15 mg/kg (1X MRHD; consistent with exaggerated pharmacologic effect)]”

“Drug-related effects in the low dose were limited to slight hematology changes and hematology changes in the 10 mg/kg/d were considered of insufficient magnitude to be adverse to the animals. Marked reductions in neutrophils (↓ 60%, mean count <600/μL) and lymphocytes ((↓ 77%, mean count <60/μL) at 25 mg/kg/d were considered adverse.”

“No adverse effects were observed. Plasma exposure (AUC) at the highest dose tested was similar to that those in pediatric patients at recommended doses.”

“These data resulted in NOAELs of 2000 mg/kg/day (1000 mg/kg BID) in juvenile rats, 1000 mg/kg/day (500 mg/kg BID) in M dogs, and 300 mg/kg/day (150 mg/kg BID) in F dogs.”

“However, no relevant Cmax- and AUC-based safety margins could be established for givinostat at the respective NOAELs in subchronic and chronic toxicity studies in mice, rats and monkeys compared to the envisaged therapeutic human doses of 25 to 70 mg bid in DMD patients.”

“Primary toxicities included transient CNS signs in rat and monkey, decreases in WBC counts and bone myeloid series in rats, and bile duct hyperplasia and thymic atrophy in monkeys.”

“At exposures approximately equal to the clinical exposure based on AUC at 225 mg/day, dogs exhibited severe skin lesions particularly on the ear, which led to dose reduction.”

“Dogs exhibited severe skin lesions particularly on the ear at 20 mg/kg, which led to dose holiday on Days 12-17 and reduced dosing at 15 mg/kg on Day 18. • The target organs of toxicity were skin, liver, and thymus.”

“the NOAEL was considered to be 1.5 mg/kg/day. At the NOAEL, systemic exposure (AUC0-24h) to risdiplam in males and females was identical to the targeted exposure in patients.”

“The NOAEL (1.5 mg/kg/day) was associated with RIS exposures of 414 / 396 ng/mL (Cmax) and 1870 / 2060 ng·hr/mL (AUC0-24 h) during Week 39 of the dosing phase for males / females.”

“6-month, Rat 150 29000 100000 1.4 9-month, Dog Male 5 4580 39300 0.5 Female 30 21000 155000 2.2”

“Target organs of toxicity included thyroid, male reproductive system, lymphoid tissues, liver and bone marrow.”

“This exposure corresponds approximately to an exposure in humans that is 2-fold below the exposure obtain at the NOAEL in the 6-month rat study and is greater than the exposure observed at the NOAEL in the 9-month monkey study (the exposure in monkeys was approximately 0.5-fold that of RCC patients).”

“The predominant toxicities in both species were associated with the following systems/organs: adrenal gland, gastrointestinal system (stomach, duodenum, and pancreas), kidney, bone (femur and tibia), liver, brain, pituitary gland, heart, incisors and reproductive system (ovaries and uterus).”

“When comparing animal exposure at the NOAELs with preliminary available clinical exposure (AUCꚍ,ss at the 120 mg dose), there are reasonable exposure multiples in rats (~ 1.5 to 3 fold) while there are low exposure multiples in dogs (approximately the clinical exposure).”

“The major target organs of zongertinib in rats and/or dogs included the gastrointestinal (GI) tract, adrenal gland, and oral mucosa.”

“In monkeys, minimal lens degeneration occurred at 5 mg/kg (0.1 times the human exposure at the recommended dose based on AUC).”

“Additional target organs in both species included the skin (wounds and scab formation; histological findings of up to moderate erosion/ulcer, atrophy, crust, hyperplasia, and inflammation), liver (up to marked fat accumulation), and pancreas (acinar cell atrophy).”

“Taletrectinib treatment resulted in increase in abortions and total pregnancy loss at doses ≥15 mg/kg/day (≥ 0.04 times the human exposure based on AUC at the recommended dose).”

“Drug-related target organs in both species included lung, lymph nodes, kidney, GI tract, and pituitary.”

“Daily oral administration of imlunestrant resulted in follicular cysts in the ovary and atrophy in the vagina, cervix, and uterus at doses ≥ 10 mg/kg/day in female rats (≥ 4 times the human AUC at the recommended dose) and ≥ 15 mg/kg/day in female cynomolgus monkeys (≥ 1 times the human AUC at the recommended dose).”

“Daily oral administration of imlunestrant resulted in follicular cysts in the ovary and atrophy in the vagina, cervix, and uterus at doses ≥ 10 mg/kg/day in female rats (≥ 4 times the human AUC at the recommended dose) and ≥ 15 mg/kg/day in female cynomolgus monkeys”

“In TK, low exposure levels were obtained in mice, rats and dogs following repeated administration, resulting in no safety margin.”

“In rats, the main target organs of toxicity included the bone marrow and liver. Effects were also observed in the lymphoid tissues, lungs and heart.”

“Based on the exposure margins recalculated by the CHMP, the observed findings in the preclinical studies are likely to be clinically relevant, as most of the exposure margins for the repeat-dose toxicity studies for elafibranor are <1”

“Microscopic changes in liver included hepatocytic hypertrophy (minimal), hepatocellular degeneration/necrosis (minimal), single cell necrosis/apoptosis (minimal to slight), and granulocytic foci (minimal) at ≥ 10 mg/kg/day (0.5 times the recommended dose based on combined AUC for elafibranor and GFT1007).”

“The AUC exposure margins NOAELs in the 4- and 13-week repeat-dose rat and dog studies, and in the preliminary EFD study in rats were generally below 1 indicating a lack of exposure margins to the adverse effects observed in the non-clinical studies.”

“Overall, the major target organs of toxicity in rats or dogs were the lymphoid tissues (thymus, gut-associated lymphoid tissue/Peyer’s patch, mesenteric and mandibular lymph nodes, spleen, bone marrow), eye, pancreas, and male and female reproductive organs.”

“Corneal lesions were only observed in 2 dogs treated for 3 months. To date, this has not been identified as a drug class toxicity and has not been identified as a significant safety finding in the human population but is nevertheless described in the product information as it was observed at 0.42-fold human exposure (at the recommended dose of 200 mg based on AUC).”

“Minimal to mild corneal lesions were observed in two high dose dogs at systemic exposure below human exposure at 200 mg QD. In addition, pirtobrutinib caused a decrease in B lymphocytes and a decrease in the TDAR following KLH immunisation. The NOAEL was 2.5 mg/kg BID, due to adverse eye effects at 5 mg/kg BID.”

“Rats had dose-dependent increased incidence and severity of decreased lymphocytes in the marginal zone of the spleen and thymus in females at ≥3 mg/kg/day (approximately 1.7-times the human exposure based on AUC) and ≥6 mg/kg/day in males (comparable to human exposure).”

“The major target organs of zidesamtinib in the 13-week studies included the pancreas and liver (rats), CNS (dogs), and gastrointestinal (GI) tract and lymphoid organs (both species).”

“Skeletal malformations were observed in all test article dose groups, notably in the ribs, skull, and vertebra. Exposures at the lowest dose were approximately 0.3 times the human exposure (AUC) at the recommended clinical dose of 600 mg once daily.”

“The liver was the primary organ of toxicity, where elevated liver enzyme levels in the blood were observed along with discoloring and microscopic findings of cholestasis and biliary hyperplasia. Other organs of toxicity included the lymph node, spleen, gall bladder, thymus, ovaries, bone marrow, adrenal glands”

“In general, low exposure margins based on systemic exposure at NOAELs or LOAELs were observed in animal studies, and corresponded to clinical exposures at or below the recommended human dose of 240 mg/kg/day.”

“Consistent with its mechanism of action as an EGFR inhibitor, lazertinib induced skin/eyelid, ocular, and gastrointestinal (GI) toxicity in rats and/or dogs. Additional target organs in animals included the liver, kidney, heart, esophagus, lung, reproductive organs, and bone marrow.”

“Additional adverse effects included skeletal variations of bipartite interparietal bone of the skull observed at doses ≥ 1 mg/kg/day (lower than the human exposure based on AUC at the recommended dose).”

“None of these changes were considered adverse. Therefore, the NOAEL was considered to be 30 mg/kg/day. The NOAEL was associated with a Week 39 relacorilant AUC0-24 of 22510.9 ng.h/mL and 22847.1 ng.h /mL respectively, in female and male monkeys.”

“The mean observed sotorasib clinical exposures from 180, 360, 720, and 960 mg once daily (QD) dosing in subjects (Study 20170543) were lower than the exposures observed at the STD10 of 180 mg/kg in rats in the 3-month GLP repeat-dose toxicology study (Study 150432), but higher than the exposures observed at the HNSTD of 1000 mg/kg/day in dogs”

“In rats, renal toxicity including minimal to marked histologic tubular degeneration/necrosis and increased kidney weight, urea nitrogen, creatinine, and urinary biomarkers of renal tubular injury were present at doses resulting in exposures approximately ≥ 0.5 times the human AUC at the clinical dose of 960 mg.”

“A severely toxic dose (STD10) was determined for QOD dosing of 10 mg/kg based on the cardiac mineralisation. There is no exposure multiple as this exposure corresponds to approximately the clinical exposure.”

“Drug‐related findings in both species were consistent with FGFR inhibition including increases in plasma phosphorus, ectopic mineralization in multiple tissues, and lesions in bone at exposure levels that are in range with human exposures at the recommended clinical dose of 20 mg.”

“No adverse effects for either species were observed with chronic dosing at clinical exposure based on free AUC and up to 3-fold based on free Cmax. No adverse findings occurred in dogs at exposures less than clinical total AUC and total Cmax.”

“The heart was identified as the primary organ of toxicity in both species with repeated aficamten administrations. Cardiac toxicities culminating in heart failure resulting from exaggerated pharmacology of the drug were observed in both rats and dogs in a dose- and duration-dependent fashion.”

“Based on the adverse findings of necrosis in the liver of males at ≥150 mg/kg/day and females at 1500 mg/kg/day, the NOAEL was considered the lowest dose of 15 mg/kg/day in males (less than the maximum clinical dose, based on HED) and the mid dose of 150 mg/kg/day in females (8.5-fold the maximum clinical dose)”

“Repeat-dose oral toxicity studies with tradipitant have been conducted in mice (13 weeks), rats (up to 6 months), and dogs (up to 3 months). Target organs were identified as liver and thyroid.”

“Toxicities in male reproductive organs occurred at doses ≥ 100 mg/kg/day in male rats (0.6 times the human exposure based on AUC) and ≥ 50 mg/kg/day in dogs (1 times the human exposure based on AUC).”

“Toxicities in male reproductive organs occurred at doses ≥ 100 mg/kg/day in male rats (0.6 times the human exposure based on AUC) and ≥ 50 mg/kg/day in dogs (1 times the human exposure based on AUC).”

“The exposures at the NOAEL or lowest observed adverse effect level in the 1 and 3‐month studies were below the human steady state exposures after administration of nirogacestat at 150 mg BID.”

“Due to oocyte mineralization at the lowest dose in the 3-month dog study, a NOAEL was not identified. The lowest dose in the dog was 2 mg/kg/day (human equivalent dose of 70 mg/day).”

“In rabbits, maternal toxicity and reduced fetal body weights occurred at sulopenem etzadroxil doses associated with sulopenem plasma exposures approximately 0.1 and 0.2 times, respectively, the clinical sulopenem exposure for the MRHD of sulopenem etzadroxil.”

“PF-03709270 administered by oral gavage to Cynomolgus monkeys at ≥400 mg/kg caused positive Coombs’ test, decreased red blood cell parameters, and GI side effects.”

“(reduced body weight gain, low food consumption, red vulvar discharge) and embryo-fetal mortality (increased resorptions, post-implantation loss, and reduced number of live fetuses) were noted at ≥3 mg/kg/day (approximately 0.1 times the human AUC at the recommended dose).”

“Female rats and monkeys displayed decreased weight and atrophy of the uterus, vagina, cervix, and mammary gland, increased weight of the ovaries correlating with the presence of follicular cysts, and atrophy of the pituitary gland (only in rats).”

“A number of adverse effects were observed in the test animals at dose levels comparable or even lower than the anticipated clinical exposure.”

“Hematologic changes included increased RBCs, reticulocytes, and haematocrit, with increased cellularity of bone marrow and extramedullary haematopoiesis in spleen consistent with exaggerated pharmacology of voxelotor in normal animals.”

“There are no safety margins for the soft tissue mineralisation in rats and monkeys and ophthalmic findings for up to 90 days.”

“Treatment with ≥0.27 mg/kg pemigatinib (approximately 0.4 times the exposure based on AUC at the human dose of 13.5 mg) induced hyperphosphatemia in rats, which correlated with firm/white areas in the aorta and vena cava and multi-organ histologic soft tissue and vascular mineralization.”

“All effects were observed at doses that resulted in total plasma exposure levels lower than those reached in patients treated with the maximum recommended dose and were reversible or showed a tendency towards reversibility after a 4- or 8-week treatment-free recovery period.”

“Administration of alpelisib to rats and dogs resulted in adverse effects in the GI tract, hemolymphoid system, skin, metabolic, and reproductive system.”

“In a 26-week study, exposures at the NOAEL were lower than predicted human exposures.”

“Pretomanid caused irreversible, late onset, cataracts at 100 mg/kg/day and testicular atrophy/degeneration at doses of 30 mg/kg/day and higher.”

“The Agency expressed concern over the lack of a safety margin between the no observed adverse effect level (NOAEL) exposures for seizures in animals and the blood levels already attained in clinical trials.”

“In all three species (rat, mouse, and dog), repeat administration of viloxazine caused dose-dependent hepatocellular hypertrophy and/or vacuolation in the liver.”

“Exposure margins between the NOAEL and patient exposures were below 1.”

“The major target organ of toxicity in both species was the skin; in the rat, the teeth, lung, and male reproductive tract were additional target organs.”

“The 845 mg/kg dose is not a limit, maximum feasible, or maximum tolerated dose, and it resulted in plasma Cmax and AUC below those in humans administered the clinical dose.”

“There was no notable toxicity in either species; however, it was unclear why the high dose in the 6- and 9-month studies was reduced to 845 mg/kg.”

“All findings occurred at exposure ≤ 0.2 times the human AUC at the recommended dose.”

“The no-observed-adverse-effect level (NOAEL) was considered to be 5 mg/kg in the 8-dose study (based on mortality, adverse body weight changes, focal skin ulcerations, and testicular tubular degeneration), and 1 mg/kg in the 4-cycle study (based on histopathologic evidence).”

“It is important to notice that no margins of exposure were observed in the 13-week dog study at NOAEL (for free and total vimseltinib) whereas in rats, margins of exposure were around 4 at NOAEL.”

“The vimseltinib toxicity profile is characterized by inflammation, hematologic, hepatic, renal, bone, and gastrointestinal toxicities, and is generally consistent with CSF1R inhibition.”

“Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the CNS (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased RBC parameters at ≥0.1 times the human exposure by AUC at the recommended dose.”

“Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the CNS (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased RBC parameters at ≥0.1 times the human exposure by AUC at the recommended dose.”

“A NOAEL could not be established in the rat studies since hepatocellular necrosis occurred already at the lowest dose tested (≥15 mg/kg/day). This exposure was equivalent or even below the intended clinical dose of 80 mg QD.”

“The general toxicology studies identified toxicities in the hematopoietic system, liver, kidney, adrenal gland, gastro-intestinal (GI) tract, and pancreas (dog only).”

“Because of the exaggerated pharmacology in healthy animal models, no safety margins were established at the palovarotene NOAEL doses of <0.03 mg/kg/day and <12 mg/kg/day in the 26-week rat and 39-week dog toxicity studies, respectively (Table 42).”

“The target organs were the skin, growth plate of stifle or knee joints and sternum, and nonglandular forestomach during the interim and terminal sacrifices at all doses.”

“The safety margins relative to the MRHD of 300 mg at the no observed adverse effect levels (NOAELs) in the pivotal general toxicology studies were approximately 1 in the dog and < 1 in the mouse and rat, based on AUC.”

“In both rats and dogs, the target organ of the drug is the lung with elevated macrophages and phospholipidosis-like inclusion bodies (without functional adversity in the lung).”

“Sixteen animals were found dead or euthanized in extremis throughout the study and recovery period and deaths occurred even at the low dose of 50 mg/kg (approximately equal to the adult human exposure at the 800 mg BID dose).”

“In total, lymphoblastic lymphoma originating from the thymus occurred in 40% of the females and 15% of the males treated at 300 mg/kg and 5% of the males treated at 600 mg/kg.”

“Most capivasertib-induced toxicities were dose-dependent and observed in rats at doses ≥ 30 mg/kg and in dogs at doses ≥ 10 mg/kg (approximately 0.4 and 0.6 times the exposure in humans at the recommended dose of 400 mg twice daily based on AUC, respectively).”

“The major target organs/systems identified in the nonclinical studies comprised insulin signaling, cardiovascular system, male reproductive organs, liver, kidneys, hypothalamic pituitary axis and hematopoietic system.”

“The safety margins at all dose levels was <1 based on a comparison of Cmax or AUC values in rat and dog toxicity studies to the human exposure (6284 ng*hr/mL; Cycle 1, Day 15) at the recommended dose of 125 mg QD”

“Targets of toxicity included bone (decreases in bone strength, decreases in total bone mineral density, and multifocal growth plate fractures) and liver (centrilobular vacuolation and mild focal necrosis in the rat).”

“Repeat-dose toxicology studies in rats and cynomolgus monkeys showed primarily effects on liver presumably as an adaptive response to enzyme induction and GI at safety margins below 1 i.e. at clinically relevant doses leading to weight loss, dehydration and emesis.”

“Administration of tucatinib to rats and monkeys resulted in body weight loss, reduced food consumption, and adverse effects in the gastrointestinal (GI) system (rat and monkey), liver (rat and monkey), hemolymphoid system (rat), skeletal muscle (rat), and reproductive system (rat).”

“In the liver, hemosiderin deposition and necrotizing inflammation with increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) occurred at doses ≥20 mg/kg (approximately 0.6 times the clinical exposure at 800 mg).”

“In the liver, hemosiderin deposition and necrotizing inflammation with increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) occurred at doses ≥20 mg/kg (approximately 0.6 times the clinical exposure at 800 mg).”

“In a repeat-dose toxicology study in dogs, adverse findings in reproductive organs were observed in males and included findings in the testis (decreased weight, tubular degeneration, tubular atrophy) and epididymis (decreased weight, luminal debris) at doses ≥100 mg/kg, which is approximately 0.1 times the human exposure (AUC) at the recommended dose of 800 mg.”

“The liver was identified as the main target organ in mice and the gastrointestinal tract in dogs.”

“Exposure in animals at the ‘no observed adverse effect level’ (NOAEL) were all below human exposure at the clinical dose of 600 mg QD”

“The predominate toxicity observed in nonclinical studies can be reasonably attributed to the exaggerated pharmacological effects of excessive erythropoiesis; the toxicity was marked by thromboses, tissue necrosis, and mortalities. Exposure in animals at the ‘no observed adverse effect level’ (NOAEL) were all below human exposure at the clinical dose of 600 mg QD”

“In repeat-dose toxicity studies, oral administration of vepdegestrant resulted in decreased corpora lutea, follicle hemorrhage and granulosa cell hyperplasia in the ovary and atrophy of the uterus, oviduct, cervix and vagina at doses ≥30 mg/kg/day (0.3 times the human AUC at the recommended dose).”

“Administration of vepdegestrant to rats and dogs resulted in dose-dependent changes in the reproductive systems of both sexes, observed as early as 1-month studies and persisting in longer-duration studies.”

“The no observed adverse effect level (NOAEL) was defined at 50 mg/kg/day based on mortality, inflammation of meninges/neuropil and hemorrhage/inflammation of stomach at higher doses with corresponding AUC0-24 2060 and 5760 ng*h/mL in males and females. Exposures at the NOAEL approximated the clinical exposures at the MRHD of 400 mg BID, based on AUC.”

“The no observed adverse effect level (NOAEL) was defined at 50 mg/kg/day based on mortality, inflammation of meninges/neuropil and hemorrhage/inflammation of stomach at higher doses”

“In all toxicology species, acute neurotoxicity was dose-limiting and resulted in minimal to no safety margins to clinical exposures (see Table 2 under section 5 below).”

“Microscopic changes in the kidney (males) and liver (males and females) were attributed to drug, but renal changes were male rat specific, and the liver finding (centrilobular hepatocellular hypertrophy) is considered adaptive. The NOAEL (12 mg/kg/day) was associated with Week 26 Cmax and AUC0-t values of 9.3 ug/mL and 113.9 ug.h/mL in males and 17.6 ug/mL and 213.7 ug.h/mL in females, respectively.”

“The exposure levels at the identified NOAEL in the 13-week study in monkeys is less than the measured exposure at the clinical dose of 80 mg.”

“Rats exhibited toxicological sequalae due to hematopoietic/lymphoid hypoplasia and male/female reproductive organ effects. Female rats also exhibited higher liver weights and/or centrilobular hepatocellular hypertrophy and/or increased mitotic figures. Monkeys exhibited gastrointestinal effects and lymphoid/hematologic depletion.”

“Ocular toxicities (hemorrhage of the anterior chamber of the eye) were observed in rats at 35 mg/kg (approximately 0.8 times the clinical AUC at the 200 mg human dose) and persisted through the recovery period.”

“Dose-limiting toxicity was gastrointestinal (GI) tract effects (including diarrhea, low food consumption and body weight loss), consistent with clinical symptoms in human. The main target organs were GI tract, eyes, skin, lungs, and immune organs, etc.”

“The highest doses used in the rat and monkey 8-cycle studies resulted in exposures approximately 8 times lower than the human exposure at the recommended dose of 3.2 mg/m2 once every 3 weeks.”

“The major toxicological findings in all three tested species were injection site findings including hemorrhage, edema, inflammation, thrombosis, and necrosis and bone marrow effects leading to transient leukopenia and mild anemia with decreased cellularity in the bone marrow.”

“renal, hepatic, and splenic histopathologic and clinical pathology changes occurred mainly at 5 mg/kg/day, but as low as 1 mg/kg/day (equivalent to the human plasma concentration at the recommended dose of CuHis [based on Cmax])”

“CuHis-related microscopic and clinical pathology in kidneys, liver, and spleen occurred as low as 1 mg/kg/day; thus, the no-observed-adverse-effect level could not be determined.”

“Based on measured or estimated exposures (AUC), at the chronic toxicity NOAEL, in rats, systemic exposures to ozanimod, the metabolites RP101124, CC112273 and CC1084037 and total active drug in humans (ozanimod+CC112273+CC1084037) were calculated to be 10.4-, 17.7-, 0.0446-, 0.0036- and 0.62-times, respectively, those expected in humans. In Cynomolgus monkeys, these multiples at the NOAEL were 3.73, 0.445, 0.316, 0.363 and 0.515, respectively.”

“In both rats and monkeys, the severity of these lung toxicities did not deteriorate in long-term toxicity studies, but they were incompletely reversible after the 6 weeks recovery period and served to determine the no observed adverse effect level (NOAEL)s (0.2 and 0.1 mg/kg/day in rats and monkeys, respectively) in these investigations.”

“The NOAEL based on mild testicular bilateral spermatocyte degeneration and renal epithelial vacuolation was 20 mg/kg/day in dogs (<0.6x the MRHD on an AUC basis for combined momelotinib + M21).”

“Based on adverse renal tubular degeneration at ≥15 mg/kg/day, the low dose of 5 mg/kg/day was considered the no observed adverse effect level (NOAEL) in rats (5x to 10x the maximum recommended human dose (MRHD) based on combined clinical momelotinib and M21 AUC).”

“The no-observed-adverse-effect level (NOAEL) was estimated to be 200 mg/kg for males (0.7 times the clinical exposure, which is approximately 7 µg*hr/mL) and 800 mg/kg for females (similar to the clinical exposure).”

“The liver and thymus were identified as the target organs of toxicity in repeat-dose toxicity studies in rats and dogs at doses of 50, 200, and 800 mg/kg/day for 28 days.”

“Based on the AUC at the NOAEL, the exposure multiples in animals compared to humans ranged from 0.7 to 1.5-fold (compared to fasted healthy humans, AUC0-24h = 14827 ng.h/mL from clinical study BLI400-101) to approximately 3.7 to 1.8-fold (compared to fed healthy humans, AUC0-24h = 5842 ng.h/mL from clinical study BLI400-101).”

“Target organs could not be identified in the absence of significant treatment-related histopathological changes in any organ or tissue in either species. The No Observed Adverse Effect Level (NOAEL) was 2000 mg/kg/day for both mice and rats.”

“The safety margins for lung toxicity based on plasma exposure were 12- and 2.4-fold in M and F mice, respectively, 0.7-fold in rats, and 4.4-fold in dogs.”

“The NOAELs for lung toxicity were 90 and 30 mg/kg in M and F mice, respectively, 4 mg/kg in rats, and 3 mg/kg in dogs.”

“Shorter half-lives in nonclinical species compared to humans resulted in AUC plasma concentrations at these doses that were 75% and 70% clinical AUCs in rat and dogs, respectively.”

“The Cmax plasma concentrations measured in rats (NOAEL; 125 mg/kg once weekly as the highest dose administered) and dogs (LOAEL; 60 mg/kg once weekly exhibiting adverse but reversible clinical signs) exceeded plasma concentrations observed in humans administered 625 mg dordaviprone by 1.9 and 3.9-fold, respectively.”

“There was no evidence of embryo-fetal loss at doses up to 5 mg/kg (approximately 0.8 times the clinical AUC at the 160 mg human dose)”

“Findings in one or both species consistent with clinical experience included effects on the pancreas (increased amylase), liver (elevated alanine aminotransferase [ALT], aspartate transaminase [AST]), skin”

“The safety margins in toxicity studies were 0.8 (15mg/kg/day) and 1.0 (20 mg/kg/day) at the NOAEL in rat and monkeys.”

“Leniolisib-related toxicities included immune suppression (rats & monkeys), skin lesions (rats & monkeys), germ cell depletion (rats), GI tract inflammation (monkeys), and QTc prolongation (monkeys).”

“26-week rat study Oral 37.5 1640 0.8 52-week dog study Oral 3 2850 1.4”

“26-week rat study Oral 37.5 1640 0.8 52-week dog study Oral 3 2850 1.4”

“In the 9-month monkey study, the NOAEL was 0.12 mg/kg/day with a mean AUC(0-24h) of 77.6 ng•h/mL 0.95-fold of the steady-state AUC(0-24h) of 81.36 ng•h/mL at 1 mg QD.”

“In the 9-month monkey study, the NOAEL was 0.12 mg/kg/day with a mean AUC(0-24h) of 77.6 ng•h/mL 0.95-fold of the steady-state AUC(0-24h) of 81.36 ng•h/mL at 1 mg QD.”

“These AUC values are approximately equivalent to or 32-times the AUC at the maximum recommended human dose (MRHD) in males and females, respectively (Table 66).”

“The no observed adverse effect level (NOAEL) was determined to be 50 mg/kg/day in male rats based on significant body weight reductions (>10%), and 600 mg/kg/day in female rats”

“Etripamil was well tolerated in nonclinical studies following intranasal administration at exposures approximately 1- to 4- fold Cmax and 1- to 2- fold AUC at the MRHD.”

“In the 6-month monkey and 14-day rat studies, there were no significant systemic toxicities observed up to the highest doses tested. However, local nasal toxicity at the site of administration was noted at all doses in both species.”

“Thus, clinical exposure multiples at the no-observed-adverse-effect levels (NOAELs) in the pivotal nonclinical studies were limited to one- to fourfold the maximum recommended human dose (MRHD).”

“The target organs for crinecerfont were liver (mouse, rat, and dog), thyroid gland (rat and dog), gastrointestinal (GI) tract (mouse and rat), and coagulation-associated effects.”

“At least 1 x exposure margin was achieved in either the 14-day or 28- day repeat-dose studies in dogs or rats.”

“Target organs of toxicity identified after cipepofol administration were the central nervous system and cardiovascular system.”

“The No-Observed-Adverse-Effect-Level (NOAEL) of pralsetinib in the 13- week studies was 10 mg/kg/day in both species, corresponding to exposure (AUC) margins of 1 times relative to the human exposures.”

“Target organs in both species included the bone marrow, with findings of decreased cellularity histopathologically consistent with decreases in red blood cells (RBCs) and mild decreases in white blood cells (WBCs), kidney (decreased weight and tubular basophilia/mineralization), and lung (macrophage aggregation).”

“In the 26-week repeat-dose toxicity study in rats, the NOAEL of 2 mg/kg/day resulted in steady state Cmax and AUC0-24 levels that were 1-fold (equivalent) to human levels at the MRHD.”

“In repeat-dose general toxicity studies, vasculopathy (inflammation, haemorrhage, and necrosis of in and around blood vessels) was the primary nerandomilast-related adverse finding observed in rats and minipigs.”

“The safety margins reported for the 13-week repeat-dose toxicology studies in mouse and monkey are approximately 1 based on AUC at the recommended dose.”

“The Severely Toxic Dose in 10% of animals (STD10) in the 4-week study in mice was 50/30 mg/kg/day, and the No Observed Adverse Effect Level (NOAEL) in the 13-week study in mice was 25 mg/kg/day. After 4-weeks of dosing in cynomolgus monkeys, the Highest Non-Severely Toxic Dose (HNSTD) was 3 mg/kg/day.”

“Comparisons between the AUC values observed in the toxicology studies and those in the pivotal clinical study show that the safety margins range between 1- and 12-fold for unbound olutasidenib.”

“Overall, adverse findings included altered glucose and lipid metabolism, inflammation, electrolyte imbalance, and toxicities in the GI tract, liver, cardiovascular system, kidneys, and hematopoietic system.”

“The seminiferous tubule degeneration was observed at ≥6 mg/kg/day (0.13-fold human AUC) in SD rats but not in dogs with 10 times higher exposure (30 mg/kg/day, 1-fold human AUC).”

“Belzutifan caused reversible decreases in red blood cell parameters at ≥ 2 mg/kg/day in rats and ≥ 1 mg/kg/day in dogs (approximately ≥ 0.05 times the human exposure at the recommended human dose of 120 mg daily).”

“No treatment related effects on embryofetal toxicity or malformations were noted at 40 mg/kg/day (~1 times the MRHD based on Cmax comparisons).”

“In both the rodent and nonrodent models target organs of toxicity after repeat dosing were consistently limited to smooth muscle, kidney and red blood cells.”

“NOAEL =250 Male 607 1.3 Female 484 1.1”

“Minimal necrosis and/or regeneration in kidney proximal tubule cells was observed in mid- and high-dose males and female dogs receiving 500 and 1000 mg/kg/day WCK 5107 (zidebactam).”

“26-Week Oral Rat, Daily 300 983,000 28.8 26-Week Oral Monkey, Biweekly 300 42,400 1.20x”

“Therefore, all findings in the 26-week study were considered non-adverse. Thus, the NOAEL was 300 mg/kg/day, the highest dose tested”

“NOAEL is 25 mg/kg/BID (1.2× MRHD, based on AUC) and 50 mg/kg/BID (2.2× MRHD, based on AUC) in males and females, respectively, based on the occurrence of subcapsular inflammation/necrosis at higher doses.”

“NOAEL is 25 mg/kg/BID (1.2× MRHD, based on AUC) and 50 mg/kg/BID (2.2× MRHD, based on AUC) in males and females, respectively, based on the occurrence of subcapsular inflammation/necrosis at higher doses.”

“91-day rat female 10 15.1 2.04 1.3 3.3 13-week monkey 150 24.1 2.75 2.1 4.4”

“In the 91-day rat study, oral administration of SUZ to female rats for 91 days resulted in ovarian cyst formation, decreased number of corpora lutea, pituitary gland hyperplasia, and mammary hyperplasia/dilatation.”

“26-week rat study 9 196 20.6 26-week dog study 2 13.3 1.4 39-week dog study 8 51.4 5.4”

“drug-related adverse findings were evident in the 8 and 50 mg/kg dosing groups in epididymis and testis (male), lungs, lymphoid tissues, spleen, kidney, and teeth.”

“30 mg/kg/day. At this NOAEL, the AUC0-24 was 3950 ng.h/mL, which represents a narrow safety margins of 1.5, over the exposure in humans receiving daily 150 mg doses of BCX7353.”

“The target organs of toxicity of berotralstat in monkeys were the kidney, liver, intestine, lung, spleen, lymph nodes, and bone marrow.”

“which provided a safety margin of ~1.5 -fold relative to the proposed MRHD of 50 mg, based on both Cmax and AUC.”

“Based on the cataplexy-like clinical signs and increased liver enzyme levels, the NOAEL is considered to be 10 mg/kg/day in both males and females in the 39-week dog study.”

“Based on the adverse kidney findings noted at 100 and 200 mg/kg/day in both sexes, the no observed adverse effect level (NOAEL) was determined to be 30 mg/kg/day (1.5-fold the human exposure at the maximum recommended human dose)”

“Based on the adverse kidney findings noted at 100 and 200 mg/kg/day in both sexes, the no observed adverse effect level (NOAEL) was determined to be 30 mg/kg/day (1.5-fold the human exposure at the maximum recommended human dose)”

“In monkeys, GI findings included emesis, watery/soft feces, diarrhea, large intestine inflammation, and altered microflora (28-day good laboratory practice [GLP] study; no observed adverse effect level [NOAEL] 300 mg/kg/day; 1.5 times maximum recommended human dose [MRHD] based on exposure), and minimal cecal erosion in the 13-week monkey study (NOAEL 300 mg/kg/day; 0.9 times the MRHD based on exposure)”

“Because of the low incidence, low severity and the absence of dose-dependency of findings in the stomach and heart, the NOAELs of the GLP 28-day study and non-GLP 14- and 28-day studies in rats are considered to be the high dose of 1000 mg/kg/day and the NOAEL of the non-GLP 90-day study in rats is considered to be 300 mg/kg/day”

“The NOAEL doses in male and female rats are 1.8 times and 5.9 times the recommended daily clinical dose of 100 mg (1,7 mg/kg/day).”

“These adverse gastrointestinal effects in rats are expected pharmacological effects of tenapanor. The NOAEL was determined to be 3 mg/kg/day for males and 10 mg/kg/day for females.”

“Safety margins achieved at the no-observed-adverse-effect levels were 2- to 3-fold in rats and 6- to 9-fold in dogs compared to the steady-state AUCs in humans at the maximum recommended human dose (MRHD).”

“Safety margins achieved at the no-observed-adverse-effect levels were 2- to 3-fold in rats and 6- to 9-fold in dogs compared to the steady-state AUCs in humans at the maximum recommended human dose (MRHD).”

“Safety Margin Multiples Based on Exposure1 4-week rat 150 12.7 0.3 28-day dog 125 143.5 3 13-week rat 750 197 4 13-week dog 60 82.3 2”

“In a 4-week repeat dose study of gepotidacin in rats, tubular basophilia and dilation of proximal and distal tubules in the kidney were observed at doses at and above 450 mg/kg/day (about equal to the clinical exposure based on AUC)”

“The plasma AUC values associated with the No-Observed-Adverse-Effect Level (NOAEL) and Lowest-Observed-Adverse-Effect Level (LOAEL) doses in rabbits are approximately 2- and 5-times respectively the plasma AUC exposures expected for fed patients.”

“Several ibrexafungerp-related toxicities with potential clinical relevance occurred in a dose-dependent manner in the 1-month toxicology study in rats including degeneration of skeletal muscle cells and stomach glandular mucosa and single-cell necrosis of hepatocytes.”

“The dose of lumateperone that corresponds to the NOAEL was 2 times the MRHD of 42 mg on a mg/m2 basis.”

“Adverse effects in the central nervous system of dogs occurred at doses of lumateperone that are 4 times the MRHD of 42 mg on a mg/m2 basis. The dose of lumateperone that corresponds to the NOAEL was 2 times the MRHD of 42 mg on a mg/m2 basis.”

“The AUC margins at NOAEL in the repeat-dose studies were around 5/13 (M/F) in the 26-week rat study and 2/11 (M/F) in the 52-week monkey study.”

“The main target organs of toxicity were liver, skeletal and cardiac muscle, stomach, and kidney.”

“The arimoclomol NOAEL of 200 mg/kg/day in the rat will provide a two-fold safety margin for the 600 mg/day clinical dose, whereas the NOAEL of 160 mg/kg/day in the dog provides a 10-fold safety margin for the clinical dose.”

“In the pivotal toxicology studies, the NOAEL for arimoclomol is 200 mg/kg/day in rats, and 160 mg/kg/day in dogs.”

“In the rat studies, the 450 mg/kg/day relebactam dose associated with neurological clinical signs produced plasma relebactam exposures approximately 7 times higher than the expected clinical exposures, but NOAEL doses in the rat studies were about 2-fold higher than the expected clinical exposures.”

“In the rat studies, the 450 mg/kg/day relebactam dose associated with neurological clinical signs produced plasma relebactam exposures approximately 7 times higher than the expected clinical exposures, but NOAEL doses in the rat studies were about 2-fold higher than the expected clinical exposures.”

“No adverse findings were noted in a chronic rat study at a dose level resulting in exposures 13 times higher than the proposed clinical dose. In a chronic dog study, no adverse findings were noted at a dose level resulting in exposures 2 times higher than the proposed clinical dose.”

“A No Observed Adverse Effect Level (NOAEL) of 20 mg/kg/day was established for this study based upon observed histopathological findings in the kidneys at 50 mg/kg/day.”

“A NOAEL was set at 2 mg/kg/day in the 13-week study. The safety margins obtained were around 2.”

“A NOAEL was set at 2 mg/kg/day in the 13-week study. The safety margins obtained were around 2.”

“The safety margin at the NOAEL in males (10 mg/kg) and females (1.5 mg/kg) based on deaths and sedation was 3 and 2 times, respectively, relative to the exposure at the maximum recommended human dose (MRHD) of 50 mg.”

“The safety margin at the NOAEL in males (10 mg/kg) and females (1.5 mg/kg) based on deaths and sedation was 3 and 2 times, respectively, relative to the exposure at the maximum recommended human dose (MRHD) of 50 mg.”

“In rats, the NOAEL was determined to be 30 mg/kg/day (~ 21.3-fold AUC at the clinical dose of 75 mg) and in monkeys, a NOEL (due to ECG findings) was determined to be 25 mg/kg/day (6.4-fold Cmax at the clinical dose of 75 mg, 2.1-fold AUC).”

“In rats, the NOAEL was determined to be 30 mg/kg/day (~ 21.3-fold AUC at the clinical dose of 75 mg) and in monkeys, a NOEL (due to ECG findings) was determined to be 25 mg/kg/day (6.4-fold Cmax at the clinical dose of 75 mg, 2.1-fold AUC).”

“The safety margins for E4 at the NOAEL in the chronic rat and monkey studies were 3.3x and 2.1x the MRHD, respectively, on an AUC basis.”

“E4 demonstrated an ability to stimulate mammary and uterine epithelium proliferation, inhibit estrous cyclicity, depress erythropoiesis, and cause cholestasis in both rats and monkeys.”

“The margins of exposure at the NOAEL of 30 mg/kg/day for embryo-fetal lethality and at the NOAEL of 10 mg/kg/day for skeletal effects to the clinical exposure at 200 mg in terms of total AUC are presented in SmPC section 5.3 as 10 and 2.3-fold, respectively.”

“Abrocitinib produced reversible, dose-related urinary crystals at doses ≥45 mg/kg/day. The NOAEL was 30 mg/kg/day, which corresponds to Day 182 AUC24 and Cmax of 58500 ng·hr/mL and 9110 ng/mL, respectively.”

“9-month dog 5 Combined 16000 2.4X NOAEL = no observed adverse effect level”

“Consistent target organs of toxicity were the liver, kidney, and adrenals.”

“The steady-state exposure level at the NOAEL of 120 mg/kg/day was 79.7 µg·h/mL for AUC0-24 and 15.8 µg/mL for Cmax, 2.8 and 2.4 times the mean AUC of the clinical IV or oral dose, respectively.”

“With IV administration, tolerability was limited by local reactions at the administration site in both rats and monkeys. No systemic target organ was identified in studies up to 13 weeks of administration.”

“Increased bilirubin and multifocal canalicular pigment deposits in 9-month dog study (not fully reversible, for females at ≥10 mg/kg and males at 30 mg/kg) with the NOAEL at 10 mg/kg/day (Day 1 AUC =51 µg.h/ml, SF =2.6).”

“In repeated-dose toxicity studies, the target organs of toxicity were testes, kidneys, and adrenal gland in rats and liver in dogs.”

“Ocular safety margins to the clinical dose are 2.66X in both rabbit and dog, based on direct dose comparison”

“Test-article related microscopic findings were noted in body weight, skin/mucosa, ovary, lung, adrenal, pituitary (males only) and thymus in rats. Mortality due to early sacrifice of moribund animals occurred at 60 mg/kg/day in female rats and at ≥40 mg/kg/day in male rats.”

“The exposure margin for the highest enmetazobactam dose not associated with increased liver enzymes and liver histopathology in the 28-day dog study was 2.8-times the maximum recommended human dose of enmetazobactam.”

“In the 28-day study in dogs, the increased liver enzymes correlated with microscopic evidence of single-hepatocyte necrosis, and in the combination toxicology study, liver enzyme increases correlated with granular hepatocellular inclusions.”

“The systemic exposure (AUC) at the redefined NOAEL of 100 mg/kg/day in rats and 10 mg/kg/day in dogs was approximately 13 and 3-fold human systemic exposure.”

“Drug-related findings included increased white blood cells (WBCs) and differentials, multi-organ inflammation, GI tract necrosis, multi-organ hemorrhage, and lymphoid depletion. The findings were more prominent in the rat, particularly those in the pancreas (e.g. fibrin deposit and hemorrhage).”

“The NOAEL for maternal and embryofetal toxicity was 75 mg/50 mg/kg/day for the combination, which is approximately three and eight times the xanomeline and trospium dose, respectively, at the MRHD of 125 mg/30 mg xanomeline/trospium, BID, based on BSA.”

“The target organs include the hepatobiliary, cardiovascular, CNS, and gastrointestinal (GI) systems.”

“No adverse effects were observed at doses less than or equal to 7 mg/kg/day (3 times the MRHD based on body surface area).”

“The NOAEL is determined at 3 mg/kg/day based on the microscopic findings in choroid plexus, kidney, and stomach at ≥10 mg/kg/day.”

“Males Females 0.5 5 2110 59500 116 3267 3X (2X) 86X (57X)”

“Target organs of exaggerated pharmacology after chronic treatment were the adrenals in both the rat and dog and also the prostate in the dog (decrease in prostate size and weight not accompanied by histopathological changes).”

“4-week oral rat 200 1075 [3]”

“The NOAEL in this study was the low dose of 100 mg/kg/day, based on the reduced RBC parameters, increased bilirubin, and testicular degeneration seen in the mid dose group (200 mg/kg/day).”

“The NOAEL was determined to be 10 mg/kg/day, which was three-fold the clinical dose of 60 mg/day, based on an AUC0-τ of 2890 ng·h/mL.”

“The no-observed-adverse-effect level (NOAEL) (10 mg/kg/day) for nervous system effects in dogs was three-fold the clinical exposures at the MRHD based on area under the concentration-time curve (AUC) and the tremors were observed only at 75 mg/kg/day at approximately 23-fold the MRHD based on AUC.”

“There were about 3-fold ocular safety margins with the RHOD compared to the rabbit and the dog ocular NOAELs and 29- and 9-fold systemic safety margins with the RHOD, in mg/m2 equivalent, compared to the rabbit and the dog systemic NOAELs, respectively.”

“Test-article-related, reversible, nonadverse conjunctival redness and swelling (rabbit) and/or ocular discharge (dog) were observed.”

“The NOAEL for male fertility was 1000 mg/kg/day (1220 μg*h/mL), about 3 times the clinical exposure based on the area under the concentration-time curve (AUC)”

“A no observed adverse effect level (NOAEL) could not be determined because of prostate findings at the lowest dose, but changes reversed by the end of dosing except for prostate and testes weights.”

“The no observable adverse effect level (NOAEL) was established at 10 mg/kg/day in both monkey studies and the safety margin was 3X and 4X, respectively.”

“The NOAEL was 10 mg/kg/day based on adverse findings at 30 mg/kg, including decreased food consumption and body weight loss in females, changes in clinical pathology parameters, along with extensive histopathological changes in several organs.”

“13-week Dog Repeat-dose study (HNSTD) 64,600d ≈ 3.1”

“Toxicity target organs common to rats and dogs were the liver, bone marrow, lymphoid tissues, and reproductive system, with the majority of the findings partially or fully recovered following the 4- or 13-week recovery period, except for some effects in the male and female reproductive system.”

“At the proposed clinical dosing regimen, the ocular exposure margin is 3.6X for the MRHD (60 mg/eye/day), and the systemic exposure margin is 39X for the MRHD (120 mg/day).”

“The systemic no-observed-adverse-effect level (NOAEL) was 427.8 mg/animal/day whereas the ocular NOAEL was 213.92 mg/eye/day. At the proposed clinical dosing regimen, the ocular exposure margin is 3.6X for the MRHD (60 mg/eye/day), and the systemic exposure margin is 39X for the MRHD (120 mg/day).”

“The exposure multiples at the NOAELs in the 2-week, 4-week, and 39-week monkey studies are 1.6, 6.2, and 3.7, respectively.”

“In monkeys, no adverse findings were observed up to the highest doses tested (500 mg/kg/dose) in the 4- and 39-week studies.”

“The safety margin for clinical dose is approximately 4X, and is based on the area under the concentration time curve (AUC) of heptanoate at the NOAEL in the minipig study and the mean AUC in the clinical study (UX007-CL101) at a dose of 1.25 g/kg/day or 30% DCI.”

“The NOAEL for systemic toxicity was the highest administered dose of 50% DCI in minipigs.”

“Plasma exposure (AUC) at the no-effect dose for adverse effects on embryofetal development in rats (200 mg/kg/day) is approximately 4 times that in humans at the maximum recommended human dose (MRHD) of 40 mg.”

“The target organs for istradefylline in rats and dogs are consistent and are the adrenal gland (hypertrophy/hyperplasia) and lung (pneumonitis with septal thickening).”

“According to the provided calculations of exposure multiples, in the longest-term repeated dose toxicity studies (26-week), systemic exposure at the determined NOAEL in monkeys (30 mg/kg) was nearly 6-fold that expected in patients, based on AUC0-168hr; at the NOAEL in rats (45 mg/kg) was nearly 4-fold that expected in patients.”

“In a 26-week study of weekly rezafungin in rats, nerve fiber/axonal degeneration increased in incidence and severity at 25 and 45 mg/kg and persisted at the end of the 26-week recovery period.”

“Exposures of avacopan reached in the pivotal toxicology studies exceeded the expected exposures reached with 30 mg b.i.d. in humans. The AUC exposure margins relative to the human AUC exposure are approximately 4, 15 and 4 in hamsters, rats and monkeys, respectively.”

“No dose-limiting toxicity or target organs of toxicity were identified. The NOAEL was considered as the high dose.”

“There was no adverse changes identified at 15 mg/kg/day; this dose level was considered as the NOAEL corresponding to AUC values 4 (males) or 12 (females) times the recommended human dose.”

“Multiple deaths/euthanasia were noted in those animals with the findings of decreased food intake leading to lower body weight and declining clinical condition with erosion of the glandular mucosa of the stomach. There was no adverse changes identified at 15 mg/kg/day; this dose level was considered as the NOAEL corresponding to AUC values 4 (males) or 12 (females) times the recommended human dose.”

“The safety margin provided in this file, were 1.8 and 4.6 compared to systemic exposure at NOAEL for 13-week toxicity SC study and for 26-week SC toxicity study in rats, respectively. Regarding the 26-week dermal toxicity study in minipigs, the safety margin was 4.9. The safety margins were 8 for the dermal 13-week toxicity study in rats and 7 for dermal 39-week toxicity study in minipigs.”

“The NOAEL in both sexes was 5% cream, which corresponds to day 272 AUC0-24 and Cmax of 269 ng·hr/mL and 16.8 ng/mL, respectively, in females, and 401 ng·hr/mL and 30.1 ng/mL, respectively, in males.”

“At the NOAEL, the sex-averaged exposure (50 μg.hr/mL, AUC0-24, Day 273) represents a 5x exposure multiple of the exposure at the MRHD (200 mg (TID), 10.5 μg.hr/mL AUC0-24hr).”

“In the 39-week toxicity study, danicopan at the dose of 150 mg/kg/day was not tolerated due to cholestatic liver injury. Hypertrophy/hyperplasia of the bile duct was observed in males at greater than or equal to 75 mg/kg/day.”

“NOAEL is 60 mg/kg/day based on the absence of adverse effects at this dose, which is 5- times the human exposure (AUC24h = 1800 ng.h/mL; Css = 74.3 ng/mL) at the MRHD of 90 μg/kg/h.”

“NOAEL is 60 mg/kg/day based on the absence of adverse effects at this dose, which is 5- times the human exposure”

“Oral administration of maltol to pregnant rats during organogenesis at doses 6 times the recommended human dose resulted in no adverse developmental outcomes.”

“Test article-related toxicities included reduced food intake, increased platelet counts, alkaline phosphatase activity, and bilirubin concentrations. Liver, kidney, adrenals, and thyroid weights increased. Liver and kidney cells stained for the presence of iron.”

“Based on systemic exposure, at the no observed adverse effect level (NOAEL), lenacapavir was 32-fold the human exposure at the recommended human dose (RHD) in the 2-month rat study and 6- to 8-fold in the 6-month rat study.”

“However, repeat-dose studies up to 9 months in dogs identified the liver, gall bladder, kidneys, and stomach as targeted organs of toxicity.”

“No adverse effects (AEs) were observed in rats or dogs at doses up to 17.8× and 6.2×, respectively, the maximum recommended human dose, when compared to the human equivalent dose (mg/kg/day), based on body surface area.”

“These findings were without histopathological correlates and were considered non-adverse. NOAELs for fosdenopterin were 5 mg/kg/day (rats) and 10 mg/kg/day (dogs), the highest dose levels evaluated.”

“Oliceridine had no effect on embryo-fetal development in rats and rabbits when administered intravenously during organogenesis at doses producing plasma exposures 7 and 8 times the estimated plasma exposure at the maximum recommended human dose (MRHD) on an AUC basis, respectively (see Data)”

“dose-dependent increases in inflammation were observed at infusion sites in the 28-day rat general toxicity study with a no observed adverse effect level (NOAEL) of 0.5 mg/kg/h at a concentration of 0.5 mg/mL”

“The NOAEL was 30 mg/kg/day, which was associated with plasma lasmiditan exposure (AUC of 15368 ng*hr/mL) ∼7 times that in humans at the MRHD.”

“In the 39-week toxicology study in dog, there were lasmiditan-related tremors and hypoactivity. The safety margin was 8-fold compared to the maximum human dose based on AUC at the NOAEL of 30 mg/kg.”

“At the NOAEL of 45 mg/kg/day the AUC-based safety margin to human exposure at the MRHD is approximately 7-fold (mean male and female dog day 272 exposure levels of 54.450 ng*h/ml and human exposure level at 100 mg of 7.740 ng*h/ml).”

“Resmetirom at ≥ 30 mg/kg/day produced an increased incidence of mononuclear cell infiltrates in liver, nonspecific hepatocellular cytoplasmic alteration, and subcapsular/interlobular fibrosis (200 mg/kg/day only; 57 times the maximum recommended dose based on AUC).”

“According to the applicant, the margins between the clinical exposure and the exposures in the lowest dose group at which ritlecitinib-related axonal dystrophies were observed (rostral cerebellar vermis at 10 mg/kg/day, study 20099163) are only 6.0-fold in terms of Cmax and 7.4-fold in terms of AUC24.”

“The NOAEL was 5 mg/kg/day based on microscopic findings in the brainstem at doses ≥20 mg/kg/day and adverse immunosuppressive effects and effects on hearing at the HD.”

“Study Type Species Sex NOEL/NOAEL (mg/kg/day) AUC0-24h (ng*hr/mL) MOEa 26-Week Repeat-dose Rat M 30 15 077 8x”

“the low-observed-adverse level (LOAEL) for male rats and No-observed adverse level (NOAEL) for female rats in 26-week oral sotagliflozin were 30 and 30 mg/kg/day, respectively; the NOAEL in 39-week oral sotagliflozin for male and female beagle dogs was 20 mg/kg/day”

“The NOAELs were the highest doses administered 1000 mg/kg in rat and 600 mg/kg (300 BID) in monkeys and represented 11x/8.0x and 21x/14x for rats and monkeys (Cmax/AUC24), respectively, over the predicted human total PF-07321332 Cmax and AUC24 at a dose of 300/100 mg PF-07321332/ritonavir BID.”

“Pivotal repeat-dose toxicology studies were conducted in rats (2-week and 1-month durations) up to 1000 mg/kg/day and in monkeys (15-day and 1-month durations) up to 600 mg/kg/day. All the findings discussed below are considered drug-related but non-adverse.”

“At the highest dose tested in the 39-week study, safety margins for local and systemic toxicity were approximately 12- and 8-fold, respectively.”

“The primary toxicity following IN administration in rat consisted of olfactory and respiratory epithelium degeneration and regeneration in the 13-week repeat dosing study which resolved over a 4-week recovery period. The NOAEL for IN administration in rat was 12.5 mg/day.”

“11-fold (males) and 8.5-fold (females) compared to the 2 mg human dose.”

“Frequently observed findings were primarily related to the primary pharmacology of baxdrostat, including dehydration (rats and monkeys) and microscopic findings in adrenal glands (zona glomerulosa hypertrophy) and kidneys (juxtaglomerular cell hyperplasia) in monkeys.”

“The developmental NOAEL was 9 and 12 times the MRHD on a mg/m 2 basis in rats and rabbits, respectively.”

“Toxicities were limited to slightly increased incidence of histiocytosis in lungs at the high dose, distended bladders seen at necropsy in high dose males, and some changes in organ weights (increased weights of prostate and ovaries, decreased weights of uteruses) that might indicate “endocrine effects,” a not unexpected effect of serotonergic compounds in rats.”

“5-Day Topical Minipig RDT NOAEL (2 mL/kg/day of 1.0% tirbanibulin ointment) Males Females 100 46 20 9”

“included findings in the thymus (lymphocyte deletion), testes (germ cell degeneration and depletion, sperm granuloma), epididymis (cellular debris, oligospermia), and bone marrow (hypocellularity). These effects tended to reverse during the recovery period.”

“The changes in the above clinical chemistry parameters at the no-observed-adverse-effect level (NOAEL) of 5 mg/kg/day (9× RHD AUC) are not considered to be clinically meaningful”

“The NOAEL for the 6-month oral toxicity study in rats was 5 mg/kg/day due to the sustained body weight reduction at 15 and 50 mg/kg/day.”

“In the dog, at dose levels up to 15 mg/kg in males and 5 mg/kg in females for 39 weeks, the exposure ratios of at least 11-fold in males and 9-fold in females based on the human AUC at steady state were achieved at the no-observable-effect level.”

“In the pivotal 26-week oral toxicity study in rat (with a 13-week interim sacrifice), the NOAEL was determined at high dose of 30 mg/kg/day”

“The NOAEL for organ toxicity was 15 mg/kg in both sexes based on liver toxicity, which is 9.3-fold higher than the human intended dose.”

“Relugolix caused liver toxicity (increased liver enzymes with or without histopathology correlates of up to severe yellow/brown pigment deposition and up to moderate bile plug) in monkeys at ≥ 50 mg/kg/day (approximately 53x the clinical exposure based on AUC). This effect exhibited some reversibility.”

“At the HD (300 mg/kg) in the 9-month study, the safety margin was 10-fold compared to that at the MRHD based on plasma AUC at the NOAEL.”

“The applicant considers that the NOAEL for atogepant in rats was 100 mg/kg/day in the 6-month study with an AUC0-24hr of 192.5 µM•hr, which represents an approximately 33-fold margin over the clinical exposure of about 5.75 µM•hr following 60 mg QD dosing.”

“In dermal studies, in which no toxicity was observed up to 20 mg/kg/day of delgocitinib in minipigs [20 (M) and 11 (F)-fold higher exposure than human exposure], NOAEL was not identified.”

“The no-observed-adverse-effect level (NOAEL) was 5% (20 mg/kg/day) delgocitinib ointment, the maximum feasible dose. Skin lesions were observed in a 9-month oral toxicity study in dogs at 3.0 mg/kg/day and the dose was lowered to 1.5 mg/kg/day from Week 24. The NOAEL was 0.6 mg/kg/day.”

“Sonrotoclax exposures at the high dose in dogs (AUC = 38800 hr*ng/mL) were approximately 11 times the human exposure (AUC = 3395.1 hr*ng/mL) at the recommended dose of 320 mg once daily.”

“Pathology observations identified the liver, gallbladder, male reproductive tract, skin, and lymphatic system as targets of sonrotoclax.”

“The NOAEL was thus established at 50 mg/kg/day in rats and 5 mg/kg/day in dogs, which represent approximately 14- and 11-fold, respectively, the exposure at the MRHD based on AUC.”

“The NOAEL was thus established at 50 mg/kg/day in rats and 5 mg/kg/day in dogs, which represent approximately 14- and 11-fold, respectively, the exposure at the MRHD based on AUC.”

“The NOAEL for monkeys is 10 mg/kg/day, which is 12-times the MRHD based on AUC.”

“The NOAEL in male and female rats is 100 and 30 mg/kg/day which are 41 times and 12 times the MRHD based on AUC, respectively.”

“safety margins established from the 26-week rat and 52-week monkey studies support the proposed 180 mg/day dose of bempedoic acid and correspond to at least <1 and 13 times the clinical exposure at the human dose of 180 mg, respectively, based on AUC exposures at the nonclinical no observed adverse effect levels (NOAELs).”

“safety margins established from the 26-week rat and 52-week monkey studies support the proposed 180 mg/day dose of bempedoic acid and correspond to at least <1 and 13 times the clinical exposure at the human dose of 180 mg, respectively, based on AUC exposures at the nonclinical no observed adverse effect levels (NOAELs).”

“The margins to clinical exposure are approximately 4 and 14-16 based on Cmax and AUC0-24, respectively.”

“The primary target organs were the adrenal gland, liver, and female reproductive tissues. Adverse effects increased in severity with dosage and study duration, with most demonstrating recovery upon treatment cessation.”

“In 3-month study, NOAEL could be established only in males at 2.5 mg/kg/day, the calculated safety margin was 15 times the clinical total AUC.”

“In addition to the GI tract, the other major target organs in the rodent toxicology studies were the skin and lower urinary tract.”

“No remibrutinib-related adverse effects were observed in the 39-week dog toxicity study (doses up to 300 mg/kg/day), and adverse effects on the endocrine pancreas observed at all tested dose levels in the 26-week rat toxicity study (doses up to 1,000 mg/kg/day) were considered unlikely to translate to human. Exposure multiples ranged from 15- to 146-fold in terms of steady-state AUC0-24h.”

“Target organs of toxicity were identified as the lymph nodes (underdeveloped germinal centers, sinusoidal red blood cells), thyroid gland (follicular hypertrophy), liver (hepatocellular hypertrophy, multinucleated hepatocytes, pigment), pancreas (islet fibrosis, pigment), and blood (prolongation of bleeding, inhibition of platelet aggregation).”

“Safety margins to exposures (based on AUC) at the the clinical dose were obtained at ≥ 16 x for males and ≥ 24 x for females.”

“based on liver vacuolation at all doses (0, 5, 20, or 45 mg/kg) in the 6-month study, a NOAEL was not established in rats. The primary toxicity in monkeys consisted of decreases in weight gain; based on this finding, the NOAEL for daily administration of BHV-3000 for 9 months was 15 mg/kg.”

“The NOAELs for VNZ 6-month rat study were 12 mg/kg/day in males and 12.5 mg/kg/day in females. At the NOAELs EMs were 21× in males and 59× in females.”

“In the general toxicology program for VNZ in rats, the major target organs of toxicity were the stomach (erosion/ulcers) and liver (hepatocellular vacuolar degeneration, multifocal hepatocellular necrosis) at exposures greater than 20 times (males) and 60 times (females) the exposure at the maximum recommended human dose (MRHD) of 20 mg VNZ.”

“Exposure (AUC) at the NOAEL in 28-day studies and the MTD in rabbit exceeded exposures at the MRHD by not less than 7-fold and in the 6-month rat study by not less than 21-fold.”

“In the 6-month study in rat, the MD (500 mg/kg/day) was the NOAEL due to increased bilirubin levels (in the absence of histologic changes) at the HD of 1000 mg/kg/day.”

“The no-observed-adverse-effect level (NOAEL) was the high dose of 3 mg/kg/day for both males and females (36 times the maximum recommended human dose (MRHD) for males and 23 times the MRHD for females, respectively, based on area under the plasma concentration-time curve [AUC] comparison).”

“There were no significant systemic or dermal toxicities noted in these studies, except a decrease in body weight gain observed in a 26-week dermal toxicity study in rats.”

“The exposure margin of these toxicology studies were at least 25-fold higher than human exposure based on baseline-adjusted AUC0-24.”

“In repeat-dose toxicity studies conducted in mice, rats, and dogs, no target organ toxicity or other toxicologically significant findings were identified. The no observed adverse effect level (NOAEL) corresponded to the highest dose level evaluated in each species: 400 mg/kg/day in mice, 2000 mg/kg/day in rats, and 100 mg/kg/day in dogs.”

“No treatment-related fetal malformations or variations were reported at the 100 mg/kg dose (27-fold higher exposure than the expected clinical exposure based on exposure data extrapolated from nonpregnant rats).”

“In repeated dose toxicology studies in rats, the stomach, liver, thyroid, and adrenal glands were identified as target organs of toxicity. In dogs, the stomach was the main target organ of toxicity.”

“NOAEL: 150 mg/kg Safety margin1 31 (males), 41 (females)”

“The NOAEL (no observed adverse effect level) in the 26-week oral toxicity study in rats and the 39-week oral toxicity study in dogs was the high dose (300 mg/kg/day and 150 mg/kg/day, respectively).”

“In the 6-month rat (up to 160 mg/kg) and 9-month monkey (up to 175 mg/kg) studies, there were no adverse findings. The safety margins based on AUC at the highest doses tested were 34- and 78-fold in rat and monkey, respectively, relative to that at the maximum recommended human dose (MRHD) of 200 mg/day.”

“In the 6-month rat (up to 160 mg/kg) and 9-month monkey (up to 175 mg/kg) studies, there were no adverse findings.”

“Reproduction studies of amisulpride were conducted in pregnant rats administered oral doses up to 160 mg/kg/day (43 times the exposure based on area under the curve (AUC) at the highest recommended dose of 10 mg) throughout the period of organogenesis. No adverse embryo-fetal developmental effects were observed at any dose level.”

“Microscopic examinations showed changes in the mammary area (feminization in surviving males and acinar proliferation/secretory activity in surviving females) in all dose groups. These findings were reversed following 14-day treatment free period.”

“In the pivotal 26-week rat and 39-week monkey studies, the mid-dose levels of 200 (rat) and 25 (monkey) mg/kg/day fezolinetant were the NOAELs, with margins of 148X and 43X MRHD based on AUC, respectively.”

“In the 39-week monkey study (Study No 8331280), fezolinetant was administered orally by daily gavage to sexually mature female monkeys at a dose of 0, 10, 25, or 40 mg/kg. High doses of fezolinetant resulted in weight loss and microscopic findings (hyperplasia of lymphocytes in lymph nodes, spleen, and lung, as well as perivascular inflammation in the kidney).”

“The low dose (LD) was identified as an NOAEL. Plasma siponimod exposures (AUC) at that dose were 95400 and 124000 ng*hr/mL in males and females, respectively, which provide substantial safety margins (>50-fold) compared to that at the recommended human daily dose.”

“The NOAEL for lung toxicities were <5 mg/kg in mice, 50 and 10 mg/kg in M and F rats, and 100 mg/kg in monkeys.”

“In embryofetal development studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis produced no maternal toxicity, skeletal anomalies, nor reduction in fetal body weight at 1.5 mg/kg/day (approximately 110-fold and 70-fold the human plasma exposure to the metabolite, 3-quinuclidinol, in rats and rabbits, respectively, at the MRHOD, assuming administration of 2 drops/eye/day).”

“The chronic ocular toxicity of aceclidine hydrochloride was investigated in rabbits, with no adverse ocular or systemic effects at a dose of”

“In both monkeys and rats, the no observed adverse effect level (NOAEL) was the highest dose tested, which corresponded to 78 and 89 times the clinical dose of 20 mg, respectively, based on AUC.”

“In both monkeys and rats, the no observed adverse effect level (NOAEL) was the highest dose tested, which corresponded to 78 and 89 times the clinical dose of 20 mg, respectively, based on AUC.”

“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day with an area under the concentration-time curve from time 0 to 24 h (AUC0-24h) of 57.7 ng•h/mL on Day 358 (96 to 358-fold the human AUC of 0.6 and 0.161 ng•h/mL at 50 and 20 mg/day, respectively).”

“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day with an area under the concentration-time curve from time 0 to 24 h (AUC0-24h) of 57.7 ng•h/mL on Day 358 (96 to 358-fold the human AUC of 0.6 and 0.161 ng•h/mL at 50 and 20 mg/day, respectively).”

“There were no systemic toxicities identified in the repeat-dose toxicity studies that were not already identified in the safety pharmacology study up to 120 mg/kg/day in monkey and minipigs (safety margin >100x based on AUC at MRHD of 30 mg/kg/day).”

“Local toxicities included thickened intima and partially recoverable endothelial fibrosis of blood vessels at 2.5 mg/mL in monkey.”

“The no-observed-adverse-effect levels (NOAELs) are 3 mg/kg/day in rats and 20 mg/kg every three days (Q3D) in monkeys, at exposures (based on AUC0-24h) 119 and 539 times higher than human exposure at the RHD, respectively.”

“The no-observed-adverse-effect levels (NOAELs) are 3 mg/kg/day in rats and 20 mg/kg every three days (Q3D) in monkeys, at exposures (based on AUC0-24h) 119 and 539 times higher than human exposure at the RHD, respectively.”

“The NOAEL was 1 mg/kg/min, with the average AUC0-96h of 281.2 µg.h/mL providing ~136-fold margin to the MRHD based on AUC.”

“Steady state was reached within 1 hr and constant changes occurred over time until 4-weeks. The NOAEL was 1 mg/kg/min, with the average AUC0-96h of 281.2 µg.h/mL providing ~136-fold margin to the MRHD based on AUC.”

“The exposure parameters (Cmax and AUC) in participants with moderate HI following a 40- mg dose were significantly lower than the exposures for the no observed adverse effect level dose in GLP toxicology studies (140- to 145-fold lower AUC and 1198- to 1226-fold lower Cmax gender-averaged exposure in GLP toxicology rat and dog studies, respectively).”

“The findings in these studies were not considered adverse and the no observed adverse effect level (NOAEL) in the 26-week rat and 39-week dog studies were the highest doses administered (1000 and 500 mg/kg/day, respectively).”

“Safety margins at the NOAEL compared to the MRHD are approximately 311- and 455-fold for males and females, respectively based on AUC.”

“• NOAEL: 100 mg/kg for both sexes, associated with a mean Cmax of 7860 and 11,800 ng/mL, and a mean AUC24h of 115,000 and 168,000 h*ng/mL in males and females, respectively, in Week 26 of dosing.”

“No adverse effects were observed in rats or dogs at exposures up to 738- and 446-fold, respectively, the exposure at the MRHD (based on AUC comparison).”

“In repeat-dose toxicity studies, mortalities, decreased body weight gain, and histopathological findings in the liver and thymus were observed in rats at exposures > 1000-fold the exposure at the maximum recommended human dose (MRHD) of 2 mg/day (based on AUC comparison).”

“A diluted solution of Defencath did not cause toxicity in rats when administered intravenously daily for 14 days.”

“In rats, which are not a pharmacologically relevant species, no adverse off-target effects were observed up to the maximum feasible dose, at systemic exposures up to 35-fold the MRHD, based on AUC, when administered orally up to 6 months.”

“No target organ toxicity or adverse histopathologic effects were noted in monkeys or rats up to the highest doses tested for each species.”

“In the other repeat-dose studies, adverse effects were observed at the lowest dose tested.”

“Drug-related adverse findings included bone marrow suppression, lymphoid atrophy in spleen, thymic hemorrhage and atrophy, GI tract hyperplasia, muscle necrosis, multi-organ inflammation, and injection site reactions.”

“In summary, the main repeat-dose toxicity findings from studies conducted in mice, rats, and monkeys were characterized by reversible myelosuppression (leukopenia, neutropenia, lymphopenia, and/or decreased platelet counts) due to decitabine, or both (ASTX727), reversible reproductive tract effects due to cedazuridine”

“Therefore, the safety margins are lower than the optimal 10x. However, the toxicological profile of voclosporin was similar to that of cyclosporine”

“The adverse findings observed were either expected due to drug-related immunosuppression (e.g., thymic medullary atrophy, absence of germinal centers, lymphomas, decreased lymphocyte counts) or to the known drug class specific adverse effects (e.g., renal toxicity, neurotoxicity, gingival hyperplasia, liver toxicity).”

“While the no observed adverse effect level in dogs provided adequate nonclinical safety margins, cardiac and vascular disorders were evaluated as safety topics of interest.”

“Target organs of toxicity were identified as mandibular and parotid salivary glands (acinar cell hypertrophy), testis (tubular degeneration/atrophy), and epididymis (intraluminal germ cell debris) in rats, and heart (coronary artery vasculopathy) in dogs.”

“No NOAEL. The low dose, 0.9 µg/eye/day is the LOAEL, based on two findings in the nasal cavity:”

“No NOAEL. The low dose, 0.9 µg/eye/day is the LOAEL, based on two findings in the nasal cavity:”

“For the NOAEL determined in the pivitol toxicology studies with sofpironium bromide, there are adequate safety margins when systemic exposure of sofpironium bromide is compared between animals and humans topically treated with sofpironium bromide gel, 15%. The NOAEL of sofpironium bromide gel in animal dermal toxicology studies are generally 20% which is higher when compared to the 15% concentration in clinical studies.”

“The major treatment-related effects observed in repeat-dose studies were findings at the test article administration sites. Pharmacologic anticholinergic effects were observed in rats with subchronic or chronic subcutaneous administration at doses of ≥1.5 mg/kg/day.”

“It is noted that AUC ratio was within the same range, indicating small safety margins, when compared exposure in humans and NOAEL values established by the company in the nonclinical species (rat and dog).”

“The applicant established the NOAEL values (40 mg/kg/day for males and 20 mg/kg/day for females in the case of rat, and 30 mg/Kg/day for monkey species), based on the findings observed”

“In the chronic toxicology studies of atrasentan in the rat and dog, a no-observed-adverse-effect level (NOAEL) was not established.”

“In the chronic toxicology studies of atrasentan in the rat and dog, a no-observed-adverse-effect level (NOAEL) was not established. In male rats, the lowest dose tested, i.e., 5 mg/kg/day, was considered to be the lowest-observed-adverse-effect level (LOAEL) because of modest testicular degeneration”

“For the no-observed-adverse-effect-level (NOAEL) determined in the general toxicity studies with tapinarof, there are modest (dermal studies) to large (subcutaneous studies) safety margins when systemic tapinarof exposure is compared between animals and humans topically treated with tapinarof cream, 1%.”

“The major test article-related findings observed in repeat-dose dermal and subcutaneous studies were related to the skin, liver, kidney, and thymus with associated secondary clinical pathology findings.”

“dogs' 12-month repeat-dose toxicity study, exposure margins reached 6.01-7.85 fold at the highest tested dose of 15 mg/kg/day.”

“The most common effect observed in the pivotal repeat-dose toxicology studies in adult rats and dogs was dose-related, reversible sedation, an expected pharmacological action of a positive modulator of GABAA receptors. Otherwise, there was little evidence of target organ or systemic toxicity in either species.”