How long were the pivotal tox studies for approved small molecules?

“Study title: An 18-Month Chronic Oral Toxicity in Rats”

“drug-induced hepatocellular hypertrophy and/or vacuolation were observed at comparable doses in previous 13-week and 18-month repeat-dose studies in rats of both sexes.”

“Table 92. Study: 1-Year Toxicology Study in the Monkey (GLP)”

“The nonclinical studies for the NDA included toxicity studies conducted with xanomeline alone via dietary administration in the rat and mouse, nasogastric intubation in the monkey, and subcutaneous injection in the rat and monkey. In addition, the Applicant conducted toxicity studies with the xanomeline/trospium combination via oral gavage, including repeat-dose toxicity studies in the rat for up to 90 days”

“TK results from pivotal 6-month rat and 12-month dog studies are presented in Table 97 and Table 98 below.”

“The assessment of the pivotal chronic 6-month rat and 12-month dog studies are summarized in Sections 19.1.7.1.1 and 19.1.7.1.3, respectively.”

“A chronic (12 month) oral [capsule] toxicity study of MJ 13805-1 in Beagle dogs.”

“Below I have presented the results from the 3-month study in rats and the 1-year study in dogs. Only exposure verification, not kinetic analysis, was performed on longer studies in rats (see summary of 6-mo study results, below, and reviews of 12-mo general toxicity study and 2-yr carcinogenicity study, in their respective sections below).”

“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and monkey studies of up to 12 months)”

“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and monkey studies of up to 12 months)”

“Pivotal studies included a 13-week study in rats and dog studies of 8, 16, 30, and 52 weeks.”

“None of the repeated-dose toxicology studies were GLP-compliant. Pivotal studies included a 13-week study in rats and dog studies of 8, 16, 30, and 52 weeks.”

“Study title / number: 52-Week oral gavage toxicity and toxicokinetic study of CTP-543 in Beagle dogs with an 8-week recovery”

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

“Repeat-dose po administration of seladelpar was evaluated at up to 13 weeks in CD-1 mice, up to 26 weeks in Sprague-Dawley rats, up to 4 weeks in dogs, and up to 52 weeks in cynomolgus monkeys.”

“Repeat-dose po administration of seladelpar was evaluated at up to 13 weeks in CD-1 mice, up to 26 weeks in Sprague-Dawley rats, up to 4 weeks in dogs, and up to 52 weeks in cynomolgus monkeys.”

“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day”

“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”

“Pivotal repeat-dose toxicology evaluations for maribavir included good laboratory practice studies of up to 52 weeks duration in monkeys, 26 weeks duration in rats and 13 weeks duration in mice”

“Pivotal repeat-dose toxicology evaluations for maribavir included good laboratory practice studies of up to 52 weeks duration in monkeys, 26 weeks duration in rats and 13 weeks duration in mice”

“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”

“Pivotal oral (gavage) toxicity studies were conducted in Wistar rat (up to 26 weeks) and cynomolgus monkey (up to 52 weeks).”

“Dose and frequency of dosing: 0, 25, 50 and 160 mg/kg/day (80 mg/kg in 2 divided doses) daily for 52 weeks”

“Histological examinations did not detect any lesions or toxic effect of chronic administration of the test article for 6 months in the rat or 12 months in the dog.”

“0 (vehicle), 6, 20 and 60 mg/kg/day, once daily for 52 weeks”

“In conclusion, safety margins established from the 26-week rat and 52-week monkey studies support the proposed 180 mg/day dose of bempedoic acid”

“Dog: Re-analysis of brain sections from the 26- and 52-week studies in dog (26-week: 0, 0 (vehicle), 16, 80, or 400 mg/kg/day; 52-week: 0, 10, 30, or 100 mg/kg/day) did not reveal evidence of brain mineralization”

“in the 26-week toxicity study in Sprague-Dawley rat (0, 3, 6, 30, or 160 mg/kg/day) at the highest dose tested, based on a re-examination of brain sections from these studies.) Brain mineralization was not detected in beagle dog in the 26- or 52-week toxicity studies”

“Study title: 52-week oral (gavage) toxicity study in the Cynomolgus monkey with an 8-week recovery period.”

“In the subchronic and chronic toxicity studies in rat (up to 6 months) and monkey (up to 52 weeks) and in the carcinogenicity studies in mouse and rat, opicapone was tested at doses up to 1000 mg/kg/day, which was identified as the NOAEL in all three species.”

“Study title: ACT-128800: 52-Week Follow-up Oral (Gavage) Toxicity Study in the Beagle Dog”

“After chronic treatment for 26 weeks, NOAELs for systemic toxicity were established at 30 mg/kg/day in rats and at 2 mg/kg/day in dogs. In the 52-week toxicity study in dogs, the applicant derived a NOAEL at 3 mg/kg/day.”

“Pivotal repeat-dose toxicity studies have been performed in mice (up to 3 months), rats (up to 6 months with a 3-month recovery period) and dogs (up to 12 months with a 13 weeks recovery period).”

“Pivotal repeat-dose toxicity studies have been performed in mice (up to 3 months), rats (up to 6 months with a 3-month recovery period) and dogs (up to 12 months with a 13 weeks recovery period).”

“The 52-week chronic toxicity study in the monkey initially included oral doses up to 27 mg/kg/day,”

“The toxicology package included repeat-dose toxicity (up to 13 weeks in mice, 26 weeks in rats, and 52 weeks in monkeys, in vitro and in vivo genotoxicity,”

“The nonclinical safety profile of lonafarnib was evaluated in cardiovascular safety pharmacology studies in monkeys, repeated dose oral toxicology studies in rats for up to 6 months and in monkeys for up to 1 year”

“Overall, the toxicity profile of lonafarnib has been characterized via single-dose toxicity studies in mice and rats, repeat-dose toxicity studies (up to 6 months in Sprague Dawley rats and 12 months in cynomolgus monkeys)”

“In the 12-month dog study (1245-011; oral doses of 0, 3, 10, or 15 mg/kg/day, preformulated suspension), dose-dependent clinical findings related to the sedative effect (decreased activity, tremors, ataxia, prostration, and unresponsiveness) were seen at all doses.”

“The primary drug-related toxicity observed in the general toxicology studies of duration up to 6 and 12 months in Sprague Dawley (SD) rat and beagle dog, respectively, was sedation, which in some cases was associated with death or premature sacrifice.”

“The Sponsor conducted oral toxicology studies up to 26 weeks in rats, 13 weeks in hamsters, and 44 weeks in monkeys.”

“The Sponsor conducted oral toxicology studies up to 26 weeks in rats, 13 weeks in hamsters, and 44 weeks in monkeys.”

“Dog, juvenile 43-week (GLP)”

“In repeat-dose toxicology studies of up to 26-weeks in rats and 43-weeks in dogs, clinical signs related to CNS stimulation, reductions in food consumption, and lower body weight and/or body weight gain were observed dose-dependently across studies in both species.”

“The Division noted that in the 40-week dog study (Study #PL15XK), a no observed adverse effect level (NOAEL) was not established with respect to coronary artery vasculopathy.”

“As listed in Table 39, general toxicity studies with ensifentrine were conducted in rats and dogs with dosing durations up to 6 months and 9 months, respectively.”

“repeat-dose subcutaneous (SC) toxicity studies with treatment durations up to 39 weeks in dogs, dermal toxicity studies with treatment durations up to 26 weeks in rats and 39 weeks in minipigs”

“repeat-dose subcutaneous (SC) toxicity studies with treatment durations up to 39 weeks in dogs, dermal toxicity studies with treatment durations up to 26 weeks in rats and 39 weeks in minipigs”

“Oral administration of vamorolone (0, 2, 10, or 50 mg/kg/day) for 39 weeks to dogs resulted in spermatocyte and spermatid degeneration in the testes and oligospermia and germ cell debris in the epididymis in males at the high dose and absence of corpora lutea in the ovaries in females at all doses.”

“Vamorolone was evaluated in oral repeated-dose toxicity studies for up to 6 months in mice and 9 months in dogs”

“In a GLP study, Beagle dogs (4 animals/sex/group) were administered VNZ by oral gavage once daily at 0 (vehicle), 1.5, 4, or 10 mg/kg for 39 weeks”

“The GLP-compliant definitive repeat dose VNZ single agent studies were carried out for durations up to 28-days in mouse, 6 months in rat and 9 months in dog.”

“repeat-dose toxicity studies in mice (dermal; 3 months), rats (oral; up to 6 months), dogs (oral; up to 9 months), and minipigs (dermal; up to 9 months)”

“repeat-dose toxicity studies in mice (dermal; 3 months), rats (oral; up to 6 months), dogs (oral; up to 9 months), and minipigs (dermal; up to 9 months)”

“Levacetylleucine (0, 100, 200, and 600 mg/kg/day) administered by oral gavage in dogs in a 39-week toxicity study followed by a 4-week treatment-free period was without adverse effects with NOAEL of 600 mg/kg/day.”

“There were no toxicologically significant findings in the 26-week rat and 39-week dog oral gavage toxicology studies conducted with levacetylleucine.”

“Repeated dose toxicity studies comprised studies in rats and dogs with once daily administration of acoramidis by oral gavage during up to 26 and 39 weeks, respectively.”

“The pivotal repeated dose toxicity studies comprised studies of 4, 13 and 26 weeks in rats, and of 4, 13 and 39 weeks in dogs.”

“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.”

“Local tolerance was assessed by reviewing the digestive track changes in the GLP-compliant 28-day and 3-month toxicology studies in rats and dogs.”

“In a 39-week oral gavage toxicity study in cynomolgus monkeys with a 4-week recovery phase, baxdrostat was administered at doses of 0, 1, 3, or 6 mg/kg/day.”

“Baxdrostat was evaluated in repeat-dose oral toxicology studies of up to 6 months in rats and 9 months in monkeys.”

“Monkeys were administered bexagliflozin orally at doses of 2, 6, 20, or 60 mg/kg/day for 39 weeks.”

“general toxicology studies (up to 6 months in rats and 9 months in monkeys)”

“In the 39-week GLP study in dogs, animals were administered 0 (vehicle), 1, 2, 4 or 8 mg/kg/day brensocatib orally for 39 weeks with a 26-week recovery period.”

“Table 47. Summary of Brensocatib Exposures in Repeat-Dose Toxicity Studies Study NOAEL (mg/kg/day) AUC (µmol.h/L) Systemic Exposure Margina 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”

“In the 39-week study in dogs, zanubrutinib was administered orally at doses of 10, 30, or 100 mg/kg/day with a 4-week recovery period.”

“Zanubrutinib was administered once daily to rats and dogs in studies up to 6 months in rats and 9 months in dogs. The studies were conducted using the oral route of administration, which is consistent with the intended clinical route of administration.”

“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).”

“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).”

“Pivotal repeat-dose toxicology evaluations for CAB included GLP studies of up to 26 weeks duration in rats and 39 weeks duration in monkeys.”

“Pivotal repeat-dose toxicology evaluations for CAB included GLP studies of up to 26 weeks duration in rats and 39 weeks duration in monkeys.”

“A consistent finding in all repeat-dose toxicity studies (up to 26 weeks in rats and up to 39 weeks in dogs) was dose-dependent reduction in cardiac contractility.”

“A consistent finding in all repeat-dose toxicity studies (up to 26 weeks in rats and up to 39 weeks in dogs) was dose-dependent reduction in cardiac contractility.”

“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”

“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”

“In a pivotal 39-week oral repeat dose toxicity study in monkeys, abrocitinib (doses: 0, 15, 35, and 75 mg/kg/day) decreased lymphocytes at all dose levels consistent with its intended pharmacological effect, but had no adverse effects.”

“Oral repeat dose toxicity studies in rats (up to 6 months in duration); oral repeat dose toxicity studies in monkeys (up to 9 months in duration)”

“The toxicity of trofinetide was tested in Sprague Dawley rat (4- and 26-week) and beagle dog (39-week); trofinetide was administered by oral gavage.”

“The 26- and 39-week studies were conducted in juvenile animals; dosing was initiated at 2 weeks (postnatal days 13-14) and 5- 6 months of age, respectively.”

“The general toxicity of orally administered lemborexant at doses up to 1000 mg/kg/day was evaluated in rats and monkeys up to 6 months and 9 months in duration, respectively.”

“The conducting laboratories were different for the 13/26- week rat study and 39-week monkey study.”

“The no observed adverse effect level (NOAEL) for daily administration of triheptanoin for 9 months in minipigs was 50% DCI.”

“In the dietary administration of UX007 to male and female juvenile minipigs at doses of 0%, 10%, 30%, or 50% DCI for 9 months with a 4-week recovery and a 3-month interim sacrifice”

“At the same high dose in a 39-week monkey study, findings consisted of transient gait abnormalities and decreased grip strength, increases in ALT and bilirubin, bile duct hyperplasia, and reduced bone marrow cellularity; reduced thymus weight was seen at all doses (0, 5, 12, and 30 mg/kg).”

“The toxicity of orally administered givinostat was investigated in single and repeat-dose studies for up to 13 weeks in mice, 26 weeks in rats 4 weeks in dogs and 39 weeks in monkeys.”

“Repeated dose toxicity studies included studies in Wistar Hannover rats (adults) and cynomolgus monkeys (sexually immature), with administration of risdiplam, by daily oral gavage, during up to 26 and 39 weeks, respectively.”

“dose range-finding and 4- and 26-week definitive toxicity studies in adult Wistar rats, a 26-week non-GLP toxicity study in Brown Norway rats, dose range-finding and 2- and 39-week definitive toxicity studies in young cynomolgus monkeys”

“Reversible thyroid follicular cell hypertrophy and thyroid organ weight increases were observed at clinically relevant exposures in toxicology studies at doses ≥50 mg/kg/day in the 26-week study in rats and at ≥5 mg/kg/day in the 39-week study in dogs.”

“Reversible thyroid follicular cell hypertrophy and thyroid organ weight increases were observed at clinically relevant exposures in toxicology studies at doses ≥50 mg/kg/day in the 26-week study in rats and at ≥5 mg/kg/day in the 39-week study in dogs.”

“General toxicity studies were conducted for durations up to 13 weeks in mice, 26 weeks in rats, and 39 weeks in monkeys.”

“General toxicity studies were conducted for durations up to 13 weeks in mice, 26 weeks in rats, and 39 weeks in monkeys.”

“In a 39-week oral toxicity study in monkeys, the highest dose tested 0.1 mg/kg/day (HED=1.95 g/day; 1. 5-fold of the recommended human dose) was well tolerated.”

“Single-oral and intravenous (IV) dose toxicity studies in CD-1 mice and Sprague-Dawley (SD) rats were conducted followed by oral repeat-dose studies in SD rats (up to 26 weeks) and cynomolgus monkeys (up to 39 weeks).”

“The Good Laboratory Practice repeat-dose studies in rats were 1 month, 3 months and 6 months in duration, and the repeat-dose studies in monkeys were 1 month, 3 months, and 9 months in duration.”

“The Good Laboratory Practice repeat-dose studies in rats were 1 month, 3 months and 6 months in duration, and the repeat-dose studies in monkeys were 1 month, 3 months, and 9 months in duration.”

“Vibegron was tested up to 9 months in monkeys and 6 months in rats.”

“General toxicity of chronic oral administration of vibegron was adequately evaluated in rats (3 & 6 months) and monkeys (3 & 9 months).”

“In a 9-month toxicology study in dogs, tenapanor was administered orally to beagle dogs at doses of 50, 300 and 1000 mg/kg/day.”

“In support of the safety of tenapanor, the Applicant submitted the following nonclinical studies: pharmacology, PK, single dose and repeat dose oral toxicity studies in rats (up to 6 months) and dogs (up to 9 months)”

“repeat-dose toxicology studies in mice, rats, and monkeys for durations up to 3, 6, and 9 months, respectively”

“repeat-dose toxicology studies in mice, rats, and monkeys for durations up to 3, 6, and 9 months, respectively”

“This includes a single-dose rat study, a battery of definitive repeat-dose general toxicity studies in rats (up to 26 weeks) and dogs (up to 39 weeks), a full battery of genetic toxicity studies, mouse and rat carcinogenicity studies”

“13-week repeat dose studies (with 4 weeks recovery) in the rat and the dog, 26-week repeat dose study (with 4 weeks recovery) in the rat, and 39-week repeat dose study (with 4 weeks recovery) in the dog.”

“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”

“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”

“39-Week Oral Gavage Chronic Toxicity and Toxicokinetic Study with LCI699 in Dogs with a 4-Week Recovery Period”

“The NOAELs observed in the 26- and 39-week repeated-dose toxicity studies in the rat and the dog were 2.0 and 10 mg/kg/day, respectively, based on the frequency and severity of findings in the liver and female reproductive”

“Repeat-dose toxicity studies with nerandomilast were performed by the oral route of administration in rats, minipigs, and cynomolgus monkeys in studies of up to 26, 39, and 39 weeks, respectively.”

“As listed in Table 46, the Applicant characterized the toxicity profile of nerandomilast with general toxicity studies in rats (13 weeks and 26 weeks), minipigs (13 weeks and 39 weeks), and monkeys (39 weeks).”

“Title/ Study No.: GSK1278863A: A 39-week Oral (Gavage) Toxicity Study in the Cynomolgus Monkey with a 6-week Recovery Period /2011N126131”

“Title/ Study No.: GSK1278863A: A 39-week Oral (Gavage) Toxicity Study in the Cynomolgus Monkey with a 6-week Recovery Period /2011N126131”

“general toxicity studies with leniolisib were conducted in rats and monkeys with dosing durations up to 6 months in rodents and 9 months in non-rodents.”

“general toxicity studies with leniolisib were conducted in rats and monkeys with dosing durations up to 6 months in rodents and 9 months in non-rodents.”

“Even so, general toxicity studies using oral gavage exposure are available for mouse, rat and dog, where rat and dog are considered main general toxicology species and have been used for studies of up to 26- and 39-weeks duration respectively.”

“Even so, general toxicity studies using oral gavage exposure are available for mouse, rat and dog, where rat and dog are considered main general toxicology species and have been used for studies of up to 26- and 39-weeks duration respectively.”

“A series of general toxicology studies were completed with relacorilant, including a 28-day study in mice (Table 51), 2-week (Table 52) and 13-week GLP studies in rats (Table 6) and monkeys (Table 7, Table 53), a 26-week GLP study in rats (Table 8), and a 39-week GLP study in monkeys (Table 9).”

“A series of general toxicology studies were completed with relacorilant, including a 28-day study in mice (Table 51), 2-week (Table 52) and 13-week GLP studies in rats (Table 6) and monkeys (Table 7, Table 53), a 26-week GLP study in rats (Table 8), and a 39-week GLP study in monkeys (Table 9).”

“In the pivotal 26- and 39-week oral repeat dose toxicity (RDT) studies in rats and dogs, respectively, ritlecitinib displayed reversible effects consistent with its intended pharmacology”

“In the pivotal 26- and 39-week oral repeat dose toxicity (RDT) studies in rats and dogs, respectively, ritlecitinib displayed reversible effects consistent with its intended pharmacology”

“This was demonstrated in some of the studies that used cyclosporine A as a comparator including the pivotal 26-week study in rats and 39- week study in monkeys.”

“This was demonstrated in some of the studies that used cyclosporine A as a comparator including the pivotal 26-week study in rats and 39- week study in monkeys.”

“Toxicity of SAM was evaluated in Sprague-Dawley rats and Beagle dogs up to 6 months and 9 months in duration, respectively.”

“Toxicity of orally administered SAM was evaluated in rats and dogs up to 6-months and 9-months in duration, respectively.”

“In dogs, 500 mg/kg/day (maximum tested dose) was tolerated for 39 weeks, although minimal body weight loss was observed during the first two weeks of the 39-week dog study.”

“GI effects in the 26-week rat and 39-week dog oral toxicity studies were limited to mild, reversible, fecal alterations in both species and mucosal basophilia/hypertrophy (minimal to slight) in the large intestine in rats.”

“Pivotal GLP-compliant repeated dose studies were conducted in Sprague Dawley (SD) rats and Cynomolgus monkeys and comprised studies of 4, 13 (two studies), and 26 weeks duration in rats and 4, 13 (two studies) and 39 weeks duration in monkeys.”

“In the pivotal chronic toxicity studies conducted by the Applicant, including a 26-week study in SD rats (Study R-13894) and a 39-week study in monkeys (Study R-13895), elinzanetant increased levels of the liver-associated enzymes ALT, AST, and ALP.”

“Repeat oral dose toxicology studies up to 26 weeks in rats and 39 weeks in dogs were conducted to support the chronic oral administration of aficamten intended for clinical use.”

“Repeat oral dose toxicology studies up to 26 weeks in rats and 39 weeks in dogs were conducted to support the chronic oral administration of aficamten intended for clinical use.”

“The toxicity profile of estetrol has been characterised in the toxicology programme performed in mice, rats and monkey in doses up to 39 weeks duration.”

“Repeated-dose toxicity has been evaluated in Sprague-Dawley (SD) rat and Cynomolgus monkey in studies of up to 6 and 9 months respectively.”

“The Applicant conducted general toxicology studies to evaluate the effects of daily oral administration of darolutamide in rats for up to 26 weeks and in dogs for up to 39 weeks.”

“Study title/ Study number : ODM-201-39-week oral (gavage) toxicity study in the Beagle dog followed by an 8-week treatment-free period/Study number AB19526.”

“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”

“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”

“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”

“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”

“The toxicity of momelotinib was assessed in rats for up to 26 weeks and in dogs for up to 39 weeks.”

“The toxicological assessment of orally administered momelotinib was carried out in good laboratory practice (GLP)-compliant nonclinical toxicity studies in rats up to 26 weeks and dogs up to 39 weeks.”

“The GLP monkey 39-week topical ocular toxicity study with omidenepag isopropyl did not identify a NOAEL.”

“The general toxicology study package spans two species: two topical ocular monkey studies, and a series of subcutaneous-route studies in the Sprague Dawley rat.”

“The repeat-dose toxicity studies for relugolix were conducted in mice (up to 13 weeks), rats (up to 26-weeks) and monkeys (up to 39 weeks) using the intended oral route of administration.”

“The repeat-dose toxicity studies for relugolix were conducted in mice (up to 13 weeks), rats (up to 26-weeks) and monkeys (up to 39 weeks) using the intended oral route of administration.”

“General toxicity studies included chronic oral toxicity studies in rats and monkeys (treatment durations of up to 26 and 39 weeks, respectively).”

“General toxicity studies included chronic oral toxicity studies in rats and monkeys (treatment durations of up to 26 and 39 weeks, respectively).”

“Repeat dose toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”

“Repeat dose toxicology studies were conducted with elacestrant in rats and monkeys for up to 26 and 39 weeks, respectively, administered via daily oral gavage”

“Single-dose toxicity studies and repeat-dose toxicity studies were performed in Sprague-Dawley rats (2-, 4-, 13- and 26-weeks duration) and in Cynomolgus monkeys (2-, 4-, 13- and 39-weeks duration).”

“Single-dose toxicity studies and repeat-dose toxicity studies were performed in Sprague-Dawley rats (2-, 4-, 13- and 26-weeks duration) and in Cynomolgus monkeys (2-, 4-, 13- and 39-weeks duration).”

“The prolonged QT and QTc intervals could have been related to the poor condition of the animals, as they were not seen in the 39-week study at comparable (slightly lower) exposure levels.”

“0, 15, 50 and 250 mg/kg/day, oral gavage 26 weeks with 4 weeks recovery”

“These studies included repeat-dose toxicology studies in rats (up to 26 weeks) and dogs (up to 39 weeks), and reproductive and developmental toxicology studies in rats and rabbits.”

“The pivotal toxicity studies were performed up to 26 weeks in rats and up to 39 weeks in dogs with appropriate recovery periods.”

“repeat dose toxicity studies (in mice, rats, and monkeys, for up to 39 weeks)”

“GLP-compliant repeat-dose toxicity studies of 14 days, 3 months, and 6 months duration were conducted in rats and studies of 2 weeks, 3 months, and 9 months duration were conducted in cynomolgus monkeys. In all studies, doses were administered daily by oral or nasogastric gavage corresponding to the proposed clinical oral dosing regimen.”

“6-month and 9-month repeat-dose toxicity studies in rats and monkeys, respectively”

“6-month and 9-month repeat-dose toxicity studies in rats and monkeys, respectively”

“In the pivotal 9-month oral toxicology study in monkey (4/sex/group, 0, 15, 40, or 300 mg/kg) there were no drug-related findings.”

“The toxicologic and toxicokinetic profile of orally administered atogepant was assessed in a series of single and repeat dose studies in rats and monkeys up to 6- and 9-months’ duration, respectively.”

“repeat dose general toxicology studies in the mouse for up to 28 days, rat for up to 26 weeks, and dog for up to 39 weeks”

“Toxicity Study by the Oral (Gavage) Route in the Beagle Dog Followed by an 8-Week Treatment-Free Period (Study T-16.017)”

“Pivotal toxicity studies consisted of daily oral dosing in SD rat (840 mg/kg AMX0035) and Gottingen minipig (845 mg/kg AMX0035) for 26 or 39 weeks, respectively.”

“Pivotal toxicity studies consisted of daily oral dosing in SD rat (840 mg/kg AMX0035) and Gottingen minipig (845 mg/kg AMX0035) for 26 or 39 weeks, respectively.”

“In the 39-week study, the high dose was reduced to 40 mg/kg/day because of intolerability.”

“General Toxicology: the oral toxicity of lasmiditan was tested in Sprague-Dawley rat (4-week + 2-week recovery, 13-week + 4-week recovery, and 26-week + 8-week recovery) and Beagle dog (2-week, 4-week + 2-week recovery, 13-week + 4-week recovery, and 39-week + 8-week recovery).”

“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and dog studies of up to 9 months)”

“repeat-dose oral toxicology studies (mouse studies of up to 3 months, rat studies of up to 6 months, and dog studies of up to 9 months)”

“Consistent with the intended clinical route of administration and intended dosing schedule, daily oral administration of belumosudil was assessed in repeat-dose general toxicology studies for up to 26 weeks in rats and up to 39 weeks in dogs.”

“Consistent with the intended clinical route of administration and intended dosing schedule, daily oral administration of belumosudil was assessed in repeat-dose general toxicology studies for up to 26 weeks in rats and up to 39 weeks in dogs.”

“In a 39-week GLP oral repeat-dose toxicity study in beagle dogs, animals (4/sex/group) were administered doses of 0 (vehicle), 10, 50, and 300 mg/kg/day remibrutinib.”

“GLP repeat-dose toxicity studies were conducted in rats (up to 26-week daily dosing; dose levels in 26-week rat study were 30, 300, and 1000 mg/kg/day) and dogs (up to 39-week daily dosing; dose levels in 39-week dog study were 10, 50, and 300 mg/kg/day).”

“The GLP-compliant studies included 4-week studies in rats and dogs (each with a 4-week recovery period) followed by chronic toxicity studies in rats (26-weeks duration) and dogs (39-weeks duration).”

“The GLP-compliant studies included 4-week studies in rats and dogs (each with a 4-week recovery period) followed by chronic toxicity studies in rats (26-weeks duration) and dogs (39-weeks duration).”

“GLP repeat-dose toxicity studies were conducted with vimseltinib in rats and dogs up to 26 and 39 weeks of duration, respectively.”

“Repeat-dose toxicology studies were conducted in rats (4-weeks, 13-weeks, and 26-weeks) and dogs (4-weeks, 13-weeks, and 39-weeks).”

“FTR was well tolerated by dogs for 39 weeks at oral doses of ≤60 mg/kg/day.”

“The nonclinical safety profile of FTR supporting this NDA has been extensively explored from (1) single and repeated dose toxicity studies in rats (up to 6-month) and dogs (up to 9-month)”

“The safety of asciminib was assessed in general toxicology (dogs, rats and monkeys up to 4, 26 and 39 weeks, respectively)”

“The safety of asciminib was assessed in general toxicology (dogs, rats and monkeys up to 4, 26 and 39 weeks, respectively)”

“A 39-week study was performed in marmoset monkeys with a 4-week recovery period.”

“The GLP-compliant studies in rats comprised studies with 2- 13- and 26-weeks of treatment followed by, respectively, 2- , 4- and 4- weeks recovery periods. The studies in marmoset monkeys had treatment durations of 2- 13- and 39-weeks”

“Oral toxicology studies of up to 26 and 39 weeks’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”

“Oral toxicology studies of up to 26 and 39 weeks’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”

“Sofpironium bromide (code name; BBI-4000) has been evaluated in repeat-dose subcutaneous toxicity studies in rats for up to 26 weeks, and in repeat-dose dermal toxicity studies in Göttingen minipigs for up to 39 weeks.”

“Sofpironium bromide (code name; BBI-4000) has been evaluated in repeat-dose subcutaneous toxicity studies in rats for up to 26 weeks, and in repeat-dose dermal toxicity studies in Göttingen minipigs for up to 39 weeks.”

“A series of pharmacology, pharmacokinetics (PK)/absorption, distribution, metabolism, excretion (ADME), repeat dose general toxicology studies of up to 26- and 39-week duration in rats and dogs, respectively, as well as reproductive toxicology (male and female fertility and early embryonic development (FEED), single species (rat) embryofetal development EFD) and juvenile animal toxicity studies were conducted.”

“A series of pharmacology, pharmacokinetics (PK)/absorption, distribution, metabolism, excretion (ADME), repeat dose general toxicology studies of up to 26- and 39-week duration in rats and dogs, respectively, as well as reproductive toxicology (male and female fertility and early embryonic development (FEED), single species (rat) embryofetal development EFD) and juvenile animal toxicity studies were conducted.”

“In the 9-month monkey toxicity study, deucravacitinib was orally administered at the doses of 0, 1, 3, and 10→5 mg/kg, once daily.”

“Pivotal repeat-dose GLP studies were conducted in CByB6F1 mice (≤28 days), Sprague-Dawley rats (≤6 months) and cynomolgus monkeys (≤9 months).”

“Pivotal repeat-dose toxicology evaluation for lenacapavir included GLP studies of up to 6-month duration in rats and 9-month duration in dogs via oral or subcutaneous administrations.”

“Pivotal repeat-dose toxicology evaluation for lenacapavir included GLP studies of up to 6-month duration in rats and 9-month duration in dogs via oral or subcutaneous administrations.”

“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”

“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”

“When VX-445 was administered alone chronically (up to 39-week) in dogs (VX-445-TX-006), test item-related microscopic changes were noted at 14 mg/kg/day including hepatocellular hypertrophy, epithelium vacuolation in gallbladder, and testicular seminiferous tubule atrophy/degeneration.”

“As listed in the following table, general toxicity studies with either VX-445 alone or in combination with tezacaftor (VX-661) and ivacaftor (VX-770) were conducted in rats, mice, and dogs with dosing durations up to 6 months in rodents and 9 months in non-rodents.”

“Capivasertib was assessed in GLP-compliant repeat-dose toxicity studies with oral administration in rats for up to 6 months and in dogs for up to 9 months, consistent with the clinical route of administration.”

“Capivasertib was assessed in GLP-compliant repeat-dose toxicity studies with oral administration in rats for up to 6 months and in dogs for up to 9 months, consistent with the clinical route of administration.”

“Study title / number: BGJ398: A 39‐Week Oral Gavage Toxicity Study in Dogs with a 13‐Week Recovery Period / 2821‐002”

“After 26 or 39 weeks of infigratinib administration in rats and dogs, respectively, the main target organ was bone.”

“Repeat dose toxicology studies were conducted in rats (up to 26 weeks) and dogs (up to 39 weeks). These animal species were considered relevant for human risk assessment because pharmacodynamic (PD) and PK/ADME profiles are similar to those in humans.”

“General toxicity studies were conducted for durations up to 26 weeks in rats and 39 weeks in dogs.”

“To assess its safety, the Applicant conducted GLP-compliant toxicology studies of daily oral pexidartinib of up to six months in Sprague Dawley rats and up to nine months in Beagle dogs.”

“To assess its safety, the Applicant conducted GLP-compliant toxicology studies of daily oral pexidartinib of up to six months in Sprague Dawley rats and up to nine months in Beagle dogs.”

“Pivotal 6- and 9-months PO studies in rat and monkey, respectively.”

“Pivotal 6- and 9-months PO studies in rat and monkey, respectively.”

“The tolerability, potential toxicities, target organs, and toxicokinetics of umbralisib were evaluated in repeat-dose toxicity studies up to 26 weeks in mice and 39 weeks in dogs.”

“The tolerability, potential toxicities, target organs, and toxicokinetics of umbralisib were evaluated in repeat-dose toxicity studies up to 26 weeks in mice and 39 weeks in dogs.”

“The toxicology profile of vadadustat has been evaluated in single- and repeat-dose studies following oral administration across multiple species (mice, rats, and dogs) for up to 6 and 9 months in rats and dogs, respectively, and in reproductive and developmental toxicity studies in rats and rabbits.”

“General toxicology studies were conducted in mice (3-month), rats (4-week, 3-month, 6-month), and dogs (4-week, 3-month, 9-month) using the oral route of administration”

“General toxicity studies were conducted for durations of up to 26 weeks in rats and 39 weeks in dogs.”

“General toxicity studies were conducted for durations of up to 26 weeks in rats and 39 weeks in dogs.”

“Study TX14008: 9-month toxicology study in dogs”

“Repeat-dose toxicity studies of up to six months duration in rats and nine months duration in dogs were conducted to support the chronic use of etrasimod in humans.”

“Repeated dose toxicity studies were conducted in rats up to 26 weeks and in monkeys up to 39 weeks.”

“Pivotal GLP-compliant repeated dose studies were conducted in rats and monkeys and comprised the studies of 4, 13 and 26 weeks duration in rats and 5, 13 and 39 weeks duration in monkeys.”

“daily oral administration of vepdegestrant was assessed in repeat-dose toxicity studies for up to 6 months in rats and up to 9 months in dogs, using the clinical route of administration and intended dosing schedule.”

“daily oral administration of vepdegestrant was assessed in repeat-dose toxicity studies for up to 6 months in rats and up to 9 months in dogs, using the clinical route of administration and intended dosing schedule.”

“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”

“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”

“Study # 2130-001. A 39-Week Oral Toxicity Study of VT-1161 in Dogs With a 33-Week Recovery”

“In contrast, there was no drug-related increase in hemorrhage in the 39-week dog study and the 26-week rat study.”

“Toxicological characterization of pacritinib was assessed in mice (1, 4, and 26 weeks), rats (1, 4, and 13 weeks), dogs (1, 4, and 39 weeks)”

“Toxicological characterization of pacritinib was assessed in mice (1, 4, and 26 weeks), rats (1, 4, and 13 weeks), dogs (1, 4, and 39 weeks)”

“Dose and frequency of dosing: 0, 0.3, 0.6 and 2 mg/kg/day (5 mL/kg), once daily for 39 weeks.”

“Dose and frequency of dosing: 0, 0.3, 0.6 and 2 mg/kg/day (5 mL/kg), once daily for 39 weeks. Route of administration: Oral gavage Formulation/vehicle: 0.5% methylcellulose solution. Species/strain: Beagle dogs”

“No danicopan-related effects were observed on heart rate, RR, PR, QT, QTc (using Van de Water’s formula) intervals, and QRS complex duration at the approximate time to maximum concentration (Tmax) in a repeat-dose oral toxicity study in beagle dogs dosed up to 150 mg/kg/day (75 mg/kg, BID) for 39 weeks (ACH-15-057, GLP-compliant).”

“Toxicological characterization of danicopan was evaluated in beagle dogs (5 days, 2-weeks, 13- weeks, 13-weeks, and 9 months), wistar han (WH) rats (14 days, 28-days, 13-weeks, and 6- months)”

“Twice daily dermal administration of tapinarof cream at doses of 0 (vehicle), 0.5, 1.0 and 3.0% (Formulation F; 0, 10, 20, and 60 mg/kg/day) were applied onto 10% of total BSA of minipigs (3/sex/group) with no occlusion for 39 weeks.”

“Tapinarof (GSK2894512; WBI-1001) has been evaluated in single- and repeat-dose dermal toxicity studies of up to 13 weeks in mice and rats, 28 days in rabbits, and up to 39 weeks in minipigs. Tapinarof was also evaluated in repeat-dose subcutaneous toxicity studies of up to 26 weeks in rats.”

“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”

“The pivotal repeat-dose toxicity studies with tafamidis were conducted in rats for up to 26 weeks of oral dosing and in dogs for up to 39 weeks of oral dosing.”

“Study title: 9 Month Oral (Gavage) Repeat Dose Toxicity Study in the Cynomolgus Monkey with a 4 Week Recovery Period”

“Chronic administration (6 months in rats, 9 months in monkeys) evidenced no significant change on the following parameters: haematology, immune system organ weights and histology, frequency of infections and tumours including in the two carcinogenicity studies.”

“Study 1281-16100: Nine-Month Oral GLP Toxicity Study of Rilzabrutinib in Beagle Dogs”

“repeat-dose toxicity studies in rats (13-day; 2-week; 1-, 3-, and 6-month), and dogs (4-day; 2- and 12-week, 1-, 3-, and 9-month)”

“In a pivotal 39-week dermal repeat dose toxicity study in minipigs, clascoterone cream (concentrations: 0% [untreated], 0% [vehicle], 1%, 2.5%, and 5% applied to ~10% body surface area (BSA);”

“Subcutaneous repeat dose toxicity studies in rats (up to 26 weeks in duration); dermal repeat dose toxicity studies in minipigs (up to 39 weeks in duration)”

“1020-7122: Lotilaner: A 9-Month Repeat-Dose Topical Ocular Toxicity Study Followed by a 4-Week Recovery Period in the Beagle Dog”

“In two ocular GLP toxicity studies with Lotilaner Ophthalmic Solution, 0.25%, in the Dutch Belted rabbit and in the Beagle dog for 6 and 9 months, respectively”

“The safety of mavorixafor (free base form) was evaluated in good laboratory practice-compliant, repeated dose toxicology studies in rats (28 days) and dogs (up to 39 weeks).”

“The safety of mavorixafor (free base form) was evaluated in good laboratory practice-compliant, repeated dose toxicology studies in rats (28 days) and dogs (up to 39 weeks).”

“Intranasal toxicity studies of zavegepant were conducted in Sprague Dawley rat (4-, 13-, and 26-week) and cynomolgus monkey (4-, 13-, and 39-week).”

“Intranasal toxicity studies of zavegepant were conducted in Sprague Dawley rat (4-, 13-, and 26-week) and cynomolgus monkey (4-, 13-, and 39-week).”

“Study Title: A 9-Month Nasogastric Gavage Toxicity Study in Cynomolgus Monkeys”

“Study Title: A 9-Month Nasogastric Gavage Toxicity Study in Cynomolgus Monkeys”

“The main repeated dose toxicity studies have been conducted in Sprague Dawley rats and Cynomolgus monkeys with daily oral administration of ozanimod for up to 26 and 39 weeks, respectively.”

“The main repeated dose toxicity studies have been conducted in Sprague Dawley rats and Cynomolgus monkeys with daily oral administration of ozanimod for up to 26 and 39 weeks, respectively.”

“In the pivotal 9-month study in dogs (0, 0.6, 1.2 and 2.5 mg/kg), sedation, sedation-related clinical signs (impaired equilibrium, hypoactivity, ataxia, tremors, and being prostrate) and increased heart rate and mortality were observed.”

“Dose selection for the 6- and 9-month toxicology studies in rat and dog was based on the results of shorter-duration studies that identified clear dose-limiting toxicity, including premature death and adverse clinical signs (e.g., sedation, convulsions).”

“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”

“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”

“Daily administration of oral ibrexafungerp for 26 weeks in rats, at the highest dose of 80 mg/kg/day (approximately 10 times the RHD based on AUC comparison), was associated with marked, but reversible, phospholipidosis and foamy histiocytes in alveolar tissue in the lung and labored breathing, marked irritation and metaplasia in gastric mucosa, and peripheral nerve degeneration accompanied by hind-limb paralysis.”

“Oral-dose toxicology studies with ibrexafungerp included 1-month and 13-week studies in rats and dogs.”

“General toxicity studies were conducted with intranasal administration of etripamil for durations of up to 14 days in rats (once daily [QD]) and 6 months (once weekly) in monkeys.”

“General toxicity studies were conducted with intranasal administration of etripamil for durations of up to 14 days in rats (once daily [QD]) and 6 months (once weekly) in monkeys.”

“the Applicant characterized the toxicity profile of sebetralstat with general toxicity studies in dogs (up to 4 weeks), and rats and monkeys (4 weeks, 13 weeks, and long-term dosing at durations up to 6 months).”

“To support the marketing authorisation, the applicant performed GLP-compliant repeat-dose studies in Crl:WI(Han) rats and in Cynomolgus NHP via oral route for up to 26 weeks.”

“Repeat-dose toxicity studies were conducted with imlunestrant in rats (≤ 150 mg/kg/day) up to 6- months duration and monkeys (≤ 600 mg/kg/day) up to 3-months duration.”

“Imlunestrant has been administered by QD oral gavage to rats for up to 6 months and to monkeys for up to 3 months.”

“The nonclinical safety of selumetinib has been evaluated in repeat dose oral toxicity studies of up to 3 months in rats and up to 26 weeks in mice and monkeys;”

“The nonclinical safety of selumetinib has been evaluated in repeat dose oral toxicity studies of up to 3 months in rats and up to 26 weeks in mice and monkeys;”

“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”

“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”

“Ocular instillation of F6H8 at the dose of 427.8 mg/animal/day, four times daily bilaterally (~3 hours apart) for up to 26 weeks in NZW rabbit was well tolerated and did not induce any ocular or systemic signs of toxicity.”

“In a 26-week ocular toxicity study in rabbits, ocular instillation of perfluorohexyloctane ophthalmic solution, 100% (code name: F6H8) at the dose of 427.8 mg/day, four times daily bilaterally for up to 26 weeks was well tolerated and did not induce any ocular or systemic signs of toxicity.”

“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).”

“repeat-dose toxicity studies in mice (13 weeks), Fisher rats (1, 3, and 6 months), Han Wistar rats (3 months), and dogs (1 and 3 months)”

“Pivotal repeated dose toxicity studies include studies in rats and cynomolgus monkeys with treatment durations, in both animal species, of 4, 13 and 26 weeks.”

“Pivotal repeated dose toxicity studies include studies in rats and cynomolgus monkeys with treatment durations, in both animal species, of 4, 13 and 26 weeks.”

“Alcon completed 6-month repeated dose ocular GLP toxicity studies in rabbits (Study AR-15512-AS03) and dogs (Study AR-15512-AS04) and 28-day repeated dose intravenous GLP toxicity studies in rats (Study STF-G10986 AVX-012).”

“Alcon completed 6-month repeated dose ocular GLP toxicity studies in rabbits (Study AR-15512-AS03) and dogs (Study AR-15512-AS04) and 28-day repeated dose intravenous GLP toxicity studies in rats (Study STF-G10986 AVX-012).”

“Table 42. 6-Month Ocular Toxicity Study in Rabbits, Study 21-1257”

“Table 42. 6-Month Ocular Toxicity Study in Rabbits, Study 21-1257 Study Features and Methods Details GLP compliance Yes”

“Toxicology program for lurbinectedin was investigated in rats, dogs and NHPs for up to 24 weeks.”

“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 Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”

“The Applicant evaluated the safety of repotrectinib administered orally once daily in 28-day and 91-day GLP-compliant general toxicology studies using rats and cynomolgus monkeys.”

“The Applicant evaluated the toxicity of avutometinib in GLP-compliant, daily oral repeat-dose general toxicology studies in rats and monkeys for up to 13-weeks duration.”

“The Applicant conducted GLP-compliant, daily oral repeat-dose general toxicology studies of defactinib in rats and dogs for up to 13-weeks duration.”

“Repeat Dose Toxicology Studies: The Applicant conducted oral repeat-dose general toxicology studies (up to 13 weeks) of erdafitinib in rats and dogs.”

“Rats and dogs were selected as relevant species for the pivotal 1- and 3-month repeat-dose toxicology studies since erdafitinib was shown to be pharmacologically active in both animal species.”

“The GLP-compliant repeat-dose toxicology studies of up to 13 weeks of dosing were conducted in mice and dogs with animals dosed daily via oral gavage.”

“The nonclinical toxicity and toxicokinetic profiles of sonrotoclax were characterized in single-dose (GLP), 14-day (non-GLP, dose-range finding), 28-day (GLP), and 13-week (GLP)”

“toxicology studies (repeat-dose studies in rats (up to 13 weeks) and dogs (up to 13 weeks)), genetic toxicology assays (in vitro and in vivo), and reproductive and developmental toxicity in rats and mice.”

“toxicology studies (repeat-dose studies in rats (up to 13 weeks) and dogs (up to 13 weeks)), genetic toxicology assays (in vitro and in vivo), and reproductive and developmental toxicity in rats and mice.”

“TCBZ was administered as a diet admixture to rats and beagle dogs at doses of 10, 100 and 1000 ppm daily, for 13 weeks.”

“TCBZ was administered as a diet admixture to rats and beagle dogs at doses of 10, 100 and 1000 ppm daily, for 13 weeks.”

“To assess the safety of ensartinib, the Applicant conducted repeat-dose toxicology studies up to 13 weeks in duration in rats and dogs.”

“In the 13-week GLP-compliant toxicology studies, ensartinib was administered QD via oral gavage to rats (12.5, 25, or 50 mg/kg) and dogs (5, 10, or 20/15 mg/kg).”

“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”

“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”

“The Applicant evaluated the toxicity profile of mobocertinib in Sprague-Dawley rats and Beagle dogs in GLP-compliant studies with treatment durations up to 3 months.”

“The Applicant evaluated the toxicity profile of mobocertinib in Sprague-Dawley rats and Beagle dogs in GLP-compliant studies with treatment durations up to 3 months.”

“This finding was not associated with renal degeneration in either species, even when the animals were treated for 3 months with up to 1500 mg/kg/day in rats and 1000 mg/kg/day in monkeys.”

“This finding was not associated with renal degeneration in either species, even when the animals were treated for 3 months with up to 1500 mg/kg/day in rats and 1000 mg/kg/day in monkeys.”

“Given the indication was in the scope of ICH S9 guideline, the two 13-week GLP compliant studies could be considered as the only pivotal studies in the submitted non-clinical package.”

“Overall, the toxicity profile determined in rat and dog in the non-GLP studies (4-week studies and 26 or 39-week studies with an intermediate 13-week analysis) appears affected a larger number of target organs than the one observed in GLP pivotal studies (two 13-week studies).”

“The Applicant evaluated the safety of pralsetinib using Sprague-Dawley rats and Cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 13 weeks duration.”

“The rat and cynomolgus monkey were used in GLP-compliant 28-days and 13-week repeat dose”

“Pivotal studies were performed in rats and dogs up to 3 months.”

“Pivotal studies were performed in rats and dogs up to 3 months. No chronic studies were performed.”

“The repeat-dose toxicity of zongertinib was evaluated in rats and dogs for up to 13 weeks daily oral treatment.”

“The Applicant evaluated the safety of zongertinib administered orally once daily in rats and dogs in 28-day and 91-day GLP-compliant general toxicology studies”

“The toxicity, the reversibility of effects, and exposures of sevabertinib were assessed in repeat dose, toxicology studies, up to 13 weeks duration in rats and monkeys.”

“Daily oral administration of sevabertinib to rats and monkeys over 2, 4, or 13 weeks revealed adverse effects characterized by general signs of toxicity, such as reduced food intake, changes in laboratory parameters, diarrhea, and degenerative and inflammatory processes in epithelial and mucosal tissues.”

“A 92 Day Toxicity Study of E7727 Administered via Oral Gavage in Cynomolgus Monkeys Followed by a 21 Day Recovery”

“Cedazuridine monotherapy was assessed in repeat-dose toxicity studies up to 13-weeks/4-cycles in duration in mice (up to 1000 mg/kg/dose) and cynomolgus monkeys (up to 200 mg/kg/dose).”

“Preliminary and definitive GLP repeat-dose toxicity studies were conducted with inavolisib in rats and dogs up to 13 weeks of duration.”

“In the 4-week and 13-week repeat-dose toxicology studies with inavolisib in rats and dogs, histopathology changes observed in reproductive organs suggest that inavolisib has the potential to impair male and female fertility.”

“Repeat-dose toxicology studies of up to 3 months were conducted in rats and dogs, using an oral route of administration, consistent with the proposed clinical route.”

“See additional information provided below for the 3-month repeat-dose toxicity studies in rats and dogs.”

“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”

“The Applicant evaluated the safety of zidesamtinib administered orally twice daily in GLP-compliant 28-day and 13-week repeat-dose general toxicology studies in Wistar-Han rats and Beagle dogs.”

“repeat-dose toxicology studies in the rat and monkey for durations of 28 days and 13 weeks”

“In addition, the safety of SUZ and impurities/degradants in the drug substance and drug product was evaluated in 91-day repeat-dose toxicity studies in rats and monkeys.”

“The GLP-compliant repeat-dose toxicology studies with up to 13 weeks of dosing were conducted in mice and dogs with animals dosed twice daily via oral gavage.”

“The definitive nonclinical safety program was comprised of 28-day and 13-week toxicity studies in mice and dogs, as well as the standard battery of genetic toxicology studies, in vitro and in vivo phototoxicity studies, and an embryofetal development study in mice.”

“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”

“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”

“The Applicant evaluated the safety of lazertinib using Sprague-Dawley rats and Beagle dogs in GLP-compliant oral repeat-dose toxicology studies of up to 13-weeks duration.”

“The toxicological profile of lazertinib was assessed in pivotal repeat-dose oral 4-week and 13-week toxicity studies in SD rats and Beagle dogs.”

“The Applicant evaluated the safety of sotorasib using Sprague-Dawley rats and Beagle dogs in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”

“The Applicant evaluated the safety of sotorasib using Sprague-Dawley rats and Beagle dogs in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”

“Futibatinib was dosed orally daily or every‐other‐day in 4‐week and 13‐week GLP repeat‐dose studies.”

“Futibatinib was dosed orally daily or every‐other‐day in 4‐week and 13‐week GLP repeat‐dose studies.”

“The Applicant evaluated the safety of dordaviprone administered orally once or twice weekly in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”

“The Applicant evaluated the safety of dordaviprone administered orally once or twice weekly in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”

“The toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”

“The toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”

“Repeat-dose toxicity studies of up to 3 months in rats and monkeys with QD, Q2D, every 3 days (Q3D), and/or once weekly (QW) PO dosing were performed.”

“Repeat-dose toxicity studies of up to 3 months in rats and monkeys with QD, Q2D, every 3 days (Q3D), and/or once weekly (QW) PO dosing were performed. Since dose range-finding pilot studies with daily dosing showed intolerability in both species, the Q2D regimen showed improved tolerability.”

“The Applicant evaluated the safety of pemigatinib in Sprague-Dawley rats and cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”

“The Applicant evaluated the safety of pemigatinib in Sprague-Dawley rats and cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 3 months duration.”

“The toxicity of alpelisib after repeated oral administration was studied in rats and dogs with dosing up to 13 weeks.”

“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule. The pivotal repeat-dose toxicology studies were conducted in compliance with Good Laboratory Practice regulations (21 CFR part 58).”

“The Applicant has conducted a 28- and 91-day oral (gavage) toxicity studies in Tg.rasH2 mice and rats, respectively, with lactitol at 125, 500 and 2000 mg/kg/day.”

“The Applicant has conducted a 28- and 91-day oral (gavage) toxicity studies in Tg.rasH2 mice and rats, respectively, with lactitol at 125, 500 and 2000 mg/kg/day. These studies were conducted to inform the dose selection of the carcinogenicity studies.”

“To assess its safety, the Applicant conducted GLP‐compliant toxicology studies of daily oral administration of ripretinib up to 13 weeks in Sprague Dawley rats and Beagle dogs.”

“Ripretinib was evaluated in repeat dose toxicity studies in rats and dogs (14 days, 4 weeks with 4 weeks recovery, 13 weeks with 4 weeks recovery).”

“Daraxonrasib was administered once daily by oral gavage in repeat-dose studies to mice and monkeys in toxicity studies for up to 13-weeks in duration.”

“Repeat-dose toxicology studies were conducted in mice (4-weeks and 13-weeks) and monkeys (4-weeks and 13-weeks).”

“In 1- and 3-month repeated-dose toxicology studies, relebactam produced only limited toxicity.”

“The program includes repeat-dose studies up to 3 months exposure in rats and monkeys, and a repeat dose combination study with REL and imipenem/relebactam.”

“To assess the safety of selpercatinib, Loxo conducted GLP-compliant toxicology studies of up to 13-weeks in Sprague Dawley rats and Gottingen mini pigs.”

“Due to sex-specific differences in exposure, in the 13-week toxicology study male rats received selpercatinb at doses of 2, 7.5, or 20 mg/kg while females received 7.5, 25, or 75 mg/kg daily via oral gavage, followed by a 4-week recovery.”

“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off; both durations were followed by a 12-week recovery period.”

“Repeat-dose toxicity studies were conducted with gedatolisib in Sprague Dawley rats and Beagle dogs up to approximately 1-month duration using an every 4-day dosing schedule (8 total doses) and up to approximately 3-month duration using the clinical dosing schedule of once weekly for 3 weeks on followed by 1 week off; both durations were followed by a 12-week recovery period.”

“Toxicology studies with up to 13 weeks of dosing were conducted in rats and dogs.”

“The pivotal 28-day and 13-week oral toxicity studies with recovery were performed in accordance with OECD Principles of GLP”

“The drug was administered for 13 weeks in rats and monkeys via oral administration, which is consistent with the intended clinical route of administration.”

“The drug was administered for 13 weeks in rats and monkeys via oral administration, which is consistent with the intended clinical route of administration.”

“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”

“considering that the majority of toxicology studies, including the pivotal 13-week rat and dog studies, tested the Form II (A) also used in clinical trials, results from toxicology studies are considered reliable for extrapolation to humans.”

“The Applicant evaluated the toxicity profile of capmatinib in GLP-compliant studies in Sprague-Dawley rats and Cynomolgus monkeys with durations of treatment of up to 13 weeks.”

“Pivotal repeat dose toxicity studies were conducted in rats and monkeys for a 4- and 13-week dosing period.”

“To assess the safety of tazemetostat, Epizyme conducted GLP-compliant toxicology studies of up to 13-weeks in Sprague Dawley rats and cynomolgus monkeys.”

“Epizyme also conducted a GLP-compliant toxicology study of up to 13-weeks in juvenile Sprague Dawley rats starting from post-natal day (PND) 7 to 98.”

“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule.”

“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule. The pivotal repeat-dose toxicology studies were conducted in compliance with Good Laboratory Practice regulations (21 CFR part 58).”

“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.”

“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 Applicant evaluated the safety of vorasidenib administered orally once daily in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and cynomolgus monkeys.”

“The safety evaluation included 28-day and 13-week repeat-dose toxicity studies in Sprague-Dawley rats and cynomolgus monkeys”

“The safety of belzutifan was evaluated in GLP-compliant repeat-dose toxicology studies up to 3- month duration in rats and dogs using the intended oral route of administration.”

“The safety of belzutifan was evaluated in GLP-compliant repeat-dose toxicology studies up to 3- month duration in rats and dogs using the intended oral route of administration.”

“No systemic target organ was identified in studies up to 13 weeks of administration.”

“In rats, local intolerance was not observed with a formulation containing 1.875 mg/mL lefamulin dissolved in 10 mM citrate-buffered saline when injected every 12 hours for 13 weeks. In a 13-week repeated dose toxicity study in monkeys”

“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”

“Thirteen-week repeat-dose oral toxicity and toxicokinetic studies were conducted in the rat (0, 0.25, 1, or 4 mg/kg selinexor; 5 total doses given every 2-week period) and monkey (0, 0.1, 0.3, 1 mg/kg selinexor; 2 to 3 times/week) to support the NDA.”

“13-Week Repeat Intravenous Dose Toxicity and Toxicokinetic Study of Zidebactam (WCK 5107) with a 4-Week Recovery Period in Beagle Dogs”

“The nonclinical safety profile of intravenous zidebactam was extensively explored in single- and repeated-dose toxicology studies (a 1-month toxicology study in rats, a 1-month combination toxicology study in dogs and a 13-week toxicology study in dogs)”

“The Applicant conducted 13-week repeat-dose toxicology studies in rats and dogs with a recovery period of 4 weeks.”

“A series of general toxicology studies in compliance with GLP have been completed, including single-dose oral toxicity studies in Wistar Han rats and Beagle dogs, 4-week and 13-week repeated dose toxicity and toxicokinetics studies in Wistar Han rats and Beagle dogs with 4-week recovery.”

“In 2- 4- and 13-week studies in rats, marmosets, and dogs, injection site findings included thrombus formation, accumulation of inflammatory cells, thickening of the vascular wall in the periphery of the dosing catheter, granulomas, edema/hemorrhage and/or necrosis of tissues around the catheter.”

“In 2- 4- and 13-week studies in rats, marmosets, and dogs, injection site findings included thrombus formation, accumulation of inflammatory cells, thickening of the vascular wall in the periphery of the dosing catheter, granulomas, edema/hemorrhage and/or necrosis of tissues around the catheter.”

“Juvenile rats with normal baseline copper levels were administered CuHis in a 13-week subcutaneous toxicity and toxicokinetic study.”

“Repeat-dose chronic toxicity studies in rodents and nonrodents have not been conducted with CuHis.”

“GLP-compliant 28-day and pivotal 85-day toxicity and TK studies in rats and monkeys confirmed that taletrectinib produced target organ toxicity that would be anticipated for a typical TKI.”

“The Applicant evaluated the safety of taletrectinib administered orally once daily in 28-day and 12-week good laboratory practices (GLP)-compliant general toxicology studies using rats and cynomolgus monkeys.”

“Twenty-eight-day repeat dose oral administration toxicity studies were conducted in dogs with initial ferric maltol doses of 0, 250, 500, and 1000 mg/kg.”

“Study title/ number: Iron Maltol: 28 Day Oral (Gavage/Capsule) Sub-Chronic Toxicity Study in the Beagle/6148-148/40”

“No such observations were evident in the 28-day pivotal repeat dose studies in rat and dog up to doses of 30 mg/kg and 40 mg/kg, respectively.”

“No such observations were evident in the 28-day pivotal repeat dose studies in rat and dog up to doses of 30 mg/kg and 40 mg/kg, respectively.”

“In support of the safety of amisulpride, the applicant submitted the following nonclinical studies: pharmacodynamic studies, a 4-week repeat-dose IV toxicity study in rats, and a battery of genotoxicity and reproductive and developmental toxicity studies.”

“Study title/number: Amisulpride: Intravenous (Slow Bolus) 28-Day Toxicity Study in the Rat with a 14 Day Treatment Free Period (Study # BGX0002).”

“Pivotal 4-week repeat-dose toxicity studies with 2-week recovery groups in minipig and monkey are reviewed in detail in sections 6.2.1 and 6.2.2.”

“Pivotal 4-week repeat-dose toxicity studies with 2-week recovery groups in minipig and monkey are reviewed in detail in sections 6.2.1 and 6.2.2.”

“No drug accumulation was observed in rats and beagle dogs after 7 or 14 injections given every other day over 2 or 4 consecutive weeks, respectively.”

“The Applicant conducted 14- and 28-day repeat-dose toxicology studies in rats and dogs with administration of the test article every other day.”

“Repeat-dose toxicology studies were conducted in rats and dogs for up to 28 days.”

“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.”

“To assess the safety of treosulfan, the Applicant conducted a GLP-compliant toxicology study up to 4 weeks in adult Sprague-Dawley rats.”

“Study title/ number: 4-Week Subchronic Toxicity Study of Treosulfan by Repeated Intravenous Bolus Injection to CD® Rats/ Study # 37259”

“Tirbanibulin was evaluated in repeat-dose general toxicity studies involving topical administration to the skin of rats and minipigs for up to 4 weeks, as well as in studies that involved oral dosing of rats and dogs for up to 4 weeks.”

“Tirbanibulin was evaluated in repeat-dose general toxicity studies involving topical administration to the skin of rats and minipigs for up to 4 weeks, as well as in studies that involved oral dosing of rats and dogs for up to 4 weeks.”

“toxicology studies (repeat-dose studies in rats [up to 4 weeks] and dogs [up to 4 weeks])”

“toxicology studies (repeat-dose studies in rats [up to 4 weeks] and dogs [up to 4 weeks])”

“The nonclinical program supporting clinical development of Oliceridine included a pharmacology, ADME, general toxicology studies (28 days duration in rats and 14 days duration in monkeys), genetic toxicology, and reproductive toxicity studies.”

“The nonclinical program supporting clinical development of Oliceridine included a pharmacology, ADME, general toxicology studies (28 days duration in rats and 14 days duration in monkeys), genetic toxicology, and reproductive toxicity studies.”

“Pivotal toxicology studies that were conducted in support of the NDA in adult animals included 1-month toxicology studies in rats and monkeys with sulopenem etzadroxil and a 14-day combination toxicology study with sulopenem etzadroxil and probenecid in rats.”

“Pivotal toxicology studies that were conducted in support of the NDA in adult animals included 1-month toxicology studies in rats and monkeys with sulopenem etzadroxil and a 14-day combination toxicology study with sulopenem etzadroxil and probenecid in rats.”

“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.”

“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.”

“Reports of intravenous bolus and continuous infusion studies in rats and dogs up to 4-week duration were available.”

“In addition to a single dose 24-hr infusion study conducted by AOP Health, a 4-week i.v. bolus study in rats and dogs and a continuous infusion study of the same duration in dogs with ONO-1101 were cited.”

“oral administration of the proposed clinical formulation, tebipenem pivoxil hydrobromide has been studied in rats and monkeys in repeat dose 28-day GLP toxicology studies, while tebipenem pivoxil has been studied in rats and monkeys in non-GLP studies (i.e. 14-day, 28-day, and 90-day studies).”

“oral administration of the proposed clinical formulation, tebipenem pivoxil hydrobromide has been studied in rats and monkeys in repeat dose 28-day GLP toxicology studies, while tebipenem pivoxil has been studied in rats and monkeys in non-GLP studies (i.e. 14-day, 28-day, and 90-day studies).”

“Repeat-dose toxicity in rats and cynomolgus monkeys have been conducted, 2-week studies with a 4-week recovery period, and 4-week studies in both species.”

“Repeat-dose toxicity in rats and cynomolgus monkeys have been conducted, 2-week studies with a 4-week recovery period, and 4-week studies in both species. The 2-week GLP repeat dose studies incorporated a saline and vehicle control group.”

“A 28-Day Study of ETX2514 by Intravenous Infusion in Beagle Dogs With a 28-Day Recovery Period.”

“Repeated intravenous dosing of sulbactam-durlobactam in rats for 28 days resulted in reversible perivascular inflammation and thrombus at the injection site”

“Study title: A 28-day toxicity study of Abametapir Lotion by dermal administration to minipigs with a 16-day recovery”

“Also the duration of treatment is much greater in the oral rat and dermal minipig studies (i.e., 14 to 28 days) compared to clinical conditions of use (single 10 minute application that is washed off).”

“In a 4-week oral repeat-dose toxicology study in cynomolgus monkeys, ensitrelvir was administered at 0, 3, 10 or 30 mg/kg/day.”

“Evaluation of the safety of S-217622 (ensitrelvir) fumaric acid, included safety pharmacology in rats and dogs, repeat-dose oral toxicity studies in rats and monkeys (2- and 4-week), genotoxicity studies, reproductive and developmental toxicity studies in rats and rabbits, and other mechanistic studies.”

“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”

“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”

“Although neither of these studies were considered adequate for a pivotal nonclinical toxicology study to support human drug development (exposure to taurolidine was not sufficient to explore possible toxicity and identify potential target organs)”

“Thus, additional acute or repeat-dose general toxicology testing in animals was not required for the components of Defencath.”

“day iv toxicity studies were considered the pivotal toxicity studies which cover the clinical dosing route and duration.”

“Additional oral toxicity studies in rats (up to 28-days) and dogs (up to 14-days) assessed longer term trilaciclib exposures and confirmed similar total drug exposure from repeated oral and iv dosing. Dose-limiting toxicity in the 14-day and 28-day studies was consistent with exaggerated pharmacology and generally similar to the 7-day iv toxicity study results.”