Which risks did regulators probe for approved small molecules?

“OPA-15406 ointments did not show skin sensitization potential in guinea pigs under the study conditions.”

“Tissue concentrations of radioactivity in the fetus and in fetal blood, liver, kidney, and lung were higher than maternal blood, indicating 14C-OPA-15406-dependent radioactivity crosses the placental barrier.”

“As expected from the immunosuppressive activity of vamorolone and other glucocorticoids, 100 mg/kg/day vamorolone and prednisolone doses ≥10 mg/kg/day comparably inhibited the TDAR in female mice, while TDAR was completely abolished in male animals.”

“A subsequent Quantitative Whole Body Autoradiography (QWBA) study revealed wide tissue distribution of 14C-labelled vamorolone in pigmented rats with highest radioactivity levels in the gastrointestinal tract and liver. A slight distribution to melanin-containing pigmented layer of the retina was also detected.”

“decreases in lymphocytes in the spleen, thymus, and lymph nodes for males ≥25 mg/kg/day and females ≥12.5 mg/kg/day.”

“Distribution was highest in the GI-tract, liver and kidneys for all three compounds in rats. No substantial binding to melanin-containing tissues was observed.”

“Delgocitinib was immunotoxic in a 4-week oral dose study in rats; however, this is an expected effect because of the pharmacological/immunosuppressive nature of delgocitinib.”

“Distribution study in dogs with 14C-delgocitinib indicated binding of radioactivity to melanin-containing tissues including skin and eyeballs.”

“In addition to reductions in red blood cells and hemoglobin, animals also had increased leukocytes and fibrinogen, indicating an inflammatory response.”

“Highest tissue concentrations were observed 0.5 hr after dosing, in the small intestine, spleen and bone marrow. CNS concentrations were low but persisted until the end of the study, similar to other tissues.”

“In rats, non-adverse decreased lymphocytes in circulation and in multiple lymphoid organs were observed at ≥15 mg/kg (M) and at ≥5 mg/kg (F).”

“The distribution of repotrectinib was widespread by 1 hour post-dose with the highest exposures in pigmented skin, uveal tract, liver, renal cortex, and kidneys with low distribution into non-circumventricular CNS tissue (protected by blood-brain barrier).”

“Histopathology findings of hyperplasia of the lymph follicle, increased plasma cells of the medulla, and inflammatory cell infiltrates in the sinus of the lymph nodes were noted in both species.”

“radioactivity was reported in the pigmented tissues (pigmented skin, eye [uveal tract, lens]), indicating a possible affinity of defactinib to melanin.”

“All effects were reversible or reversing with three notable exceptions: effects in the lymphoid system (spleen and thymus), brain and the gonads.”

“The concentration of [14C]-avapritinib-derived radioactivity in the uveal tract and skin of pigmented Long Evans rats was eliminated more slowly and was approximately 2 to 330-fold higher than in these tissues in nonpigmented rats.”

“Erdafitinib was considered to cause skin sensitization in the murine local lymph node assay”

“By 24/72 hours post dose, radioactivity was either close to or below the limit of quantification in the majority of the tissues, except the eye (T1/2 182.5 hours) and lacrimal gland (T1/2 135.7 hours).”

“HD males: 24% decrease in lymphocytes and 19% decrease in total white blood cells”

“The levels of radioactivity detected in the meninges up to 336 hours and uveal tract up to 840 hours post-dose suggest an affinity of amisulpride for the melanin pigmented tissues.”

“Baxdrostat was well tolerated despite dehydration (increased incidence of thinness and skin tenting), reduced body weight gain, and histological changes in adrenals, kidneys, spleen, thymus, and mesenteric lymph nodes (decreased lymphocytes).”

“Tissue distribution studies revealed widespread tissue distribution with highest exposures in adrenal gland, liver, cecum, and kidney (tissue-to-plasma ratios up to 17.3 for adrenal gland). Brain and spinal cord showed substantially lower concentrations, while pigmented tissues demonstrated selective melanin binding in Long Evans rats.”

“Mortality was only noted in 1 male at 100 mg/kg/day and was most likely caused by an opportunistic infection secondary to lymphoid depletion.”

“Sonrotoclax distribution in the mouse included the small intestine, large intestine, kidney, spleen, liver, muscle, bone marrow, and uterus.”

“Minimal to mild lymphoid depletion of the thymus in high dose rats appears likely to be stress-related (5/10 males, 2/10 females).”

“At 7 days only the ocular uveal tract was above 10 μg equiv/g (at 125.551 μg equiv/g), and at 35 days the meninges (3.318 μg equiv/g) and ocular uveal tract (84.123 μg equiv/g) were the only tissues above the LoQ.”

“Thymus: Very slight lymphoid necrosis in the thymus was observed in 3/10 HD males and moderate lymphoid necrosis was observed in 1/10 HD females.”

“Extensive distribution to tissues was observed with the highest concentrations in large intestine, pituitary gland, bone marrow, and liver followed by lung and kidney, minimal concentrations in male reproductive organs, and no detectable radioactivity in brain and CNS tissues.”

“No dedicated immunotoxicity investigations were conducted and there was no evidence of a concerning immunotoxicological risk based on a comprehensive weight-of-evidence evaluation in”

“Highest radioactivity tissue concentrations were in the liver and preputial gland in albino rats and in the uveal tract in the pigmented rats, suggesting melanin binding of brensocatib or its metabolites. There is low CNS penetration.”

“Other findings in the dog included lymphoid depletion and reduced red blood cells (RBCs) and lineages, which may be at least partially related to bleeding noted on histopathology.”

“BGB-3111 showed preference for stomach, small intestine and liver. Very low concentration was found in brain and testes, however elimination from testes appeared to be slower than for other tissues.”

“There were no findings indicating an influence of remimazolam on the immune system.”

“Placenta penetration of remimazolam and/or its derivatives was very limited and did not lead to a sustained exposure of the fetus. Remimazolam and/or its derivatives easily accessed breast milk; the concentrations determined in milk were linked to maternal plasma concentrations.”

“The risk of immunotoxicity has been evaluated based on results from the standard toxicity studies. No obvious signs in related organs have been detected in response to odevixibat treatment (e.g. changes in thymus, spleen, lymph nodes, bone marrow).”

“Most of the radioactivity was found in the content of the gastrointestinal tract, whereas none was detected in the central nervous system (CNS).”

“CAB was negative for immunosuppression in a T-cell–dependent antibody response (TDAR) study in rats, and was not associated with skin sensitization, skin irritation, ocular irritation, or phototoxicity.”

“Very small amounts were also detected in the brain, indicating that low levels of CAB cross the blood–brain barrier. CAB was also detected in fetal tissue in an investigative toxicokinetic (TK) study in pregnant rats.”

“Other target organs of toxicity in both rats and dogs were liver (centrilobular necrosis, congestion and vacuolation), lungs (increased alveolar macrophages and inflammation) and thymus (decrease in size as a result of decreased cellularity).”

“Low radioactivity concentrations were documented in central nervous system tissues (cerebellum, cerebrum, medulla, and spinal cord). Low levels of [14C]MYK-461-derived radioactivity were selectively associated with melanin-containing tissues of the eye”

“A KLH study was performed in monkeys from the 9-month study. Abrocitinib exposure gave reduced IgG and IgM values (with dose relation) from 15mg/kg/day with partial recovery.”

“The brain:plasma AUClast ratio was <0.1, indicating that the passage over blood-brain barrier was low.”

“Xanomeline is a moderate skin sensitizer with an EC3 (3-fold stimulation index) potency of 125 µg/cm2”

“Subcutaneous administration of xanomeline to pregnant rats resulted in low levels of exposure to xanomeline and its metabolites in fetal tissues, suggesting potential transplacental transfer of xanomeline and/or its metabolites. In pre- and postnatal developmental studies in the rat, after maternal oral administration, xanomeline and trospium were detected in neonatal pup blood on postnatal Day 4, suggesting potential lactational transfer of both drugs.”

“The bacterial infections likely originated from indwelling catheters but the failure to clear the infections suggest a compromised immune response, consistent with trilaciclib-mediated leukocyte and thrombocyte suppression during treatment.”

“Highest radioactivity, representing drug or metabolite tissue distribution, was seen in thyroid, kidney, harderian gland, adrenal gland, lacrimal glands, spleen, and liver in non-pigmented rats with additional distribution in eye/eye uveal tract and meninges in pigmented rats.”

“The changes in leukocytic parameters and lymphocyte subpopulation and T-cell-dependent antibody responses were small in magnitude and occurred in one sex (males) and showed no remarkable evidence of immunotoxicity in rats.”

“Crinecerfont crossed the placenta and distributed to the fetal liver (at low levels) in pregnant rats and rabbits. Low crinecerfont exposure was observed in brain, skin, and testis.”

“There were no significant drug-related findings in any immune function assessments: Immunophenotyping, natural killer cell activity, peripheral blood granulocytes functions, cytokine release.”

“Lemborexant is rapidly and extensively distributed to tissues in rats and monkeys with the highest levels found in liver and no accumulation in melanin-containing tissues in rats. Lemborexant and its metabolites readily cross the blood brain barrier and drug concentrations in cerebral spinal fluid are higher than that of plasma.”

“Guinea pig studies with Defencath showed that the product was not irritating when injected intradermally and it was nonsensitizing in these animals.”

“ADME/PK studies were not conducted with Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”

“Triheptanoin was not a dermal sensitizing agent in male albino guinea pigs.”

“The dose-related increase in the primary metabolites (heptanoic acid and C5 ketone bodies) showed systemic exposure to UX007, but no accumulation after 9 months of treatment.”

“This lymphoid depletion led to atrophies of thymus, lymph nodes, bone marrow and spleen. This interference of givinostat with the white blood cell lineage likely reflects its anti-inflammatory activity and was partially reversible in rats and monkeys.”

“In rats, givinostat primarily distributed into gastrointestinal tract tissue (intestine > duodenum > stomach) and in organs involved in elimination (liver > kidney > bladder), but not significantly into the brain.”

“No difference between the test and the control group was seen after epidermal challenge application, which suggests that the drug may not produce contact dermatitis.”

“Drug distribution was extensive in rats with only a slight accumulation in most organs and tissues investigated after 10 daily oral doses of 1 mg/kg. The accumulation of radioactivity was between 2-fold (thyroid and skin) and 6-fold (brain)”

“Microscopic findings in adrenals, kidneys and thymus were also apparent at sebetralstat 500/300 or 300 mg/kg/day.”

“The extent of placental transfer of total radioactivity was investigated in rats (study 187593) by QWBA where limited placental transfer was observed. Moreover, data suggest a moderate binding affinity of sebetralstat for melanin.”

“Additional findings in the 4-week dog study included increased creatine kinase, histologic lymphoid depletion in the spleen, and up to marked hypocellularity of the bone marrow.”

“While ensartinib was eliminated from most tissues after 24 hours, 87% of the Cmax was still detected in the testes. Ensartinib was detected in the skin (melanin-containing tissue), but distribution to the eye was not evaluated in this study.”

“Decreases in the B lymphocyte relative percentages and absolute counts were observed in HD males and females at all doses.”

“Substantial distribution into melanin-containing parts of the eye (choroid + retinal pigment epithelium [RPE], iris, sclera) was demonstrated in rats and monkeys, and ocular RIS concentrations remained high for considerable periods after the end of dosing.”

“At 24 and 48 hours after the challenge patch removal, the guinea pigs induced and challenged with AAI101 did not exhibit any skin responses and received the same Magnusson and Kligman grades (0% positive reaction) as the vehicle control group.”

“There was no preferential distribution to or retention in the skin, the eye or the uveal tract, i.e., no specific binding of [14C]-enmetazobactam and drug related radioactivity to melanin was indicated.”

“Additional target organs in both species included the reproductive system (atrophy and single cell necrosis), lymph nodes (increased lymphoid cellularity), digestive tract (decreased epithelial thickness), eyes (atrophy of the corneal epithelium), and larynx (decreased epithelial thickness).”

“Following single oral administration, [14C]mobocertinib-derived radioactivity distributed widely to rat tissues including the liver, adrenal gland, kidney, alimentary canal, uveal tract, and thyroid but brain penetration was low.”

“At the end of the dosing period (Day 42) a greater number of plasmablasts were observed in the mesenteric lymph nodes of dose group animals relative to controls with the highest numbers observed in the 70 mg/kg group. Following the recovery period (Day 56) there was no difference in lymph node plasmablasts between controls and dose group animals.”

“The amount of radiolabel (gepirone-equivalents per gm) was essentially identical in maternal plasma and total fetus, at all time-points, and very similar for maternal and fetal hearts, whereas maternal liver levels were much (5-24-fold) greater than those in fetal liver. Geprione and/or metabolites crossed the placental barrier from mother to fetus.”

“T-Dependent Antibody Response (TDAR) assay conducted with blood from dogs in 39-week toxicology study presented minimal effects on the humoral responses with reduced IgM and/or IgG titers following primary response to KLH challenge in both genders.”

“In pigmented animals, iptacopan was detected in melanin containing eye tissues (choroid and ciliary body) up to 168 hrs which suggests affinity to ocular melanin.”

“In the 1-month and 3-month repeat-dose toxicity studies in rats, development of germinal centers in the spleen, which suggested an enhanced antibody production, was observed. This change is considered to be an immune response possibly associated with the weak antigenic stimulation by cefiderocol, however, there was no evidence of anaphylaxis in either study.”

“CNS exposure was low and brief. Most tissue levels were lower than plasma levels. Binding to RBC was negligible. Preferential binding to melanin not observed.”

“In dogs, alkaline phosphatase and cholesterol increased and thymus weights decreased at all doses.”

“Fexinidazole penetrated the blood brain barrier with a brain Tmax of between 2 and 8 hours after dosing in rats. The level of fexinidazole in brain was approximately 0.6 times the levels in plasma.”

“gastric system (stomach, duodenum and pancreas), reproductive system (ovary and corpora lutea) and lymphoid organs (lymphoid depletion of thymus, lymph nodes and spleen).”

“In pigmented rats, melanin binding to the choroid layer of the eye was apparent and levels decreased steadily over 120 hours post-dose.”

“The non-GLP dog studies identified liver, kidney, GI-tract, adrenal gland, and immune system (thymus and spleen, and lymph nodes in the 39-week study) as target organs.”

“Following a single oral dose of radiolabeled fruquintinib, wide distribution of fruquintinib was observed with the highest radioactivity observed in the esophagus, large intestine, small intestine, stomach, bladder, uveal tract, and pigmented skin.”

“Although no dedicated immunotoxicity studies were conducted with pralsetinib, some of the toxicological findings reported in repeat-dose toxicity studies were related to its actions on immune system (i.e., decreased cellularity of multiple haematopoietic and lymphoid organs in rats, and bone marrow cellularity and decreased cellularity of lymphoid organs in monkeys).”

“Following single oral administration, 14C-pralsetinib-derived radioactivity distributed widely to rat tissues especially the small intestine wall, liver, adrenal gland, uveal tract, and pigmented skin. Pralsetinib crossed the blood-brain barrier in rats”

“findings correlated with histologic signs in the lymph nodes in the 3-month studies in rats and dogs, including minimal to moderate lymphoid hyperplasia, lymphoid depletion, and increases in plasma cells, as well as hypocellularity in rats.”

“For all tissues, the highest measured concentrations were observed within 4 hours and 0.5 hours post dose for the oral and IV routes, no specific retention was observed in melanin-containing tissues.”

“Treosulfan showed in vivo myeloablative and immunosuppressive activity in a murine allogeneic bone marrow transplant model.”

“Highest concentrations of treosulfan were observed in kidneys, and lowest quantifiable levels of treosulfan and EBDM were observed in the brain tissue.”

“Immunotoxicology: slight to moderate fluctuations in blood, spleen, and thymocyte populations”

“Brain-to-plasma ratios were ≤0.01, suggesting zongertinib showed minimal crossing of the blood-brain barrier in rats. Zongertinib was detected for up to ~200 hours in the total eyeball, and up to ~470 hours in the melanin-containing region of the ocular bulb of the eye”

“Additional target organs in the monkey included the thymus (up to severe atrophy, severe decreased adipose tissue), and mesenteric lymph node (marked decreased adipose tissue, slight increased cellularity).”

“There was notable distribution of sevabertinib to the melanin-containing tissues of the eye and skin with long-term retention in the eye tissue”

“Histological examinations of these animals showed hemorrhage and acute inflammation of the cecum; luminal dilatation of the duodenum, jejunum, ileum, and colon; and lymphoid depletion in the spleen and thymus.”

“Excluding the uveal tract in the Long Evans rat, radioactivity concentrations in tissues of both rat strains were measurable only in the liver and GI tract at 24 hours postdose.”

“Additional findings were noted in the thymus (atrophy), lymph nodes (erythrophagocytosis, foamy macrophages), and kidneys (basophilic casts, dilation, hyperplasia, vacuolation).”

“Taletrectinib was distributed throughout rat tissues. There was notable distribution of taletrectinib to melanin-containing tissues of the eyeball and skin. Taletrectinib also accumulated in the choroid plexus region of the brain indicating the drug can cross the blood brain barrier.”

“The most clinically relevant finding was dose- and duration-dependent decreases in lymphocytes, which was consistently observed in two mouse strains.”

“ISL also demonstrated strong affinity for melanin-containing tissues (e.g., uveal tract) in pigmented rats and readily crossed the placental barrier in pregnant rats, resulting in significant fetal exposure.”

“Imlunestrant affected T-cell dependent antibody responses across studies but because animals mounted anti-KLH IgM and IgG responses it was concluded that effects on seroconversion did not functionally suppress the immune response and were considered non-adverse.”

“Concentrations in uveal tract were high through to the end of the study at 672 hours and concentrations seem to be declining only very slowly.”

“and thymic lymphoid depletion (cedazuridine, reversible) and testicular effects (partially reversible) due to decitabine.”

“Overall, cedazuridine did not show a strong tendency to distribute into tissues. The metabolic/excretory tissues (kidney, urinary bladder) as well as the tissues of the GI tract contained the highest distribution of [14C]-cedazuridine derived radioactivity.”

“In conclusion, fedratinib-related effects on the bone marrow (hypoplasia) and lymphoid tissues (lymphocyte depletion in the spleen, thymus and lymph nodes) in all three species are likely symptoms of exaggerated pharmacology and indicate clear immunosuppressive properties of fedratinib”

“Radiolabeled [14C]‐fedratinib was distributed throughout the whole body of the rat, including to the skin and eyes (i.e. melanin‐containing tissues). Elimination from the eyes was approximately 40 days.”

“Thymic atrophy was observed in female dogs starting from 30 mg/kg/day and in male dogs from 100 mg/kg/day.”

“No accumulation of radioactivity was observed in tissues or organs. The highest concentrations were measured in the digestive tract and liver, and no radioactivity was detected in any organ at 168 hours after administration.”

“LCI699 was determined to be a strong sensitizing agent (Category 1A) indicating there is the potential for an allergic response following skin contact.”

“Osilodrostat is distributed into most tissues with the highest levels in the adrenal gland, brain, kidney, liver, pancreas, and spleen. LCI699 was found to bind melanin,”

“Decreases in lymphocytes in lymphoid tissues were observed in dogs administered inavolisib for 4 weeks.”

“In pigmented rats, distribution of inavolisib-derived radioactivity was comparable to that in albino rats, with the exception of melanin containing tissues, such as uveal tract and skin that presented higher levels of radioactivity.”

“An increased IL-6 expression (mRNA and protein) as a consequence of usage of high doses of pan-PDE4 inhibitors has been linked to the development of mesenteric vasculitis in rat [Dietsch 2006].”

“Tissue distribution of radioactivity from whole blood into peripheral tissues appeared to be fast and extensive. In pigmented rats, there was moderate affinity of radioactivity to melanin-containing tissues of the eye, but no discernible affinity to melanin in the skin.”

“Effects on immune system function consisted of a shift in the balance of T, B, and NK lymphocytes, largely due to a decrease in B lymphocytes, and decreased TDAR response to KLH, a foreign antigen. With the exception of the anti-KLH TDAR in male rats, these effects were not considered adverse due to the lack of effect on the overall well-being of the animals.”

“The radioactivity declined over time to below the lower limit of quantitation (< 178 ng-eq) by 168 hours post dose for all tissues but the uveal tract and liver (294 and 262 ng-eq, respectively at 168 hours), with a calculated t1/2 of 66.4 and 56.1 hours, respectively.”

“In monkeys, there were fewer organs of toxicity (only bone marrow [erythroid hypercellulartity], lung [alveolar hemorrhage], thymus [lymphoid atrophy], and stomach”

“Radioactivity concentrations in the uveal tract, pigmented skin, and meninges peak at 1h or 4h declining steadily afterwards until undetectable by Day 7. This finding suggests no irreversible binding to melanin-containing tissues.”

“Dogs had dose-dependent decreased cellularity of lymphoid tissues, including gut-associated lymphoid tissue (GALT), lymph nodes, spleen, and thymus, which did not completely resolve in the 4 mg/kg/day group.”

“Following a single oral dose to rats, 14C-zidesamtinib distributed to nearly all tissues within 15 minutes. Radioactivity was detected in male reproductive tissues (seminal vesicle, prostate gland, epididymis, and testes) and melanin-pigmented tissues (uveal tract and skin).”

“Treatment-related atrophy of the mesenteric lymph node, thymus, and GALT/Peyer’s patches were observed in male and female rats at all doses and attributed to immune suppression based on the pharmacology of leniolisib.”

“In radioactive studies, leniolisib was moderately distributed into tissues (Vss of 1.06 L/kg in rats and 0.657 L/kg in monkeys) with a high skin affinity. After a single oral dose of 10 mg/kg to male rats, the highest exposures were found in the bile, hair follicle, liver, intestinal wall, kidney as well as in melanin-containing structures.”

“SUZ was not a skin sensitizer in a local lymph node assay in the mouse.”

“Radioactivity concentrations in melanin-containing tissues in rats (i.e., the uveal tract, pigmented skin, and meninges) peaked between 1 and 4 hours postdose then declined to undetectable levels by 72 hours postdose.”

“Tirbanibulin ointment exhibited some evidence of potential to induce sensitization when topically applied to the skin of guinea pigs in a Buehler assay.”

“Activity achieved highest levels in plasma, liver, stomach, intestines, adrenals, kidneys, and thyroid.”

“Other target organs included the liver and the thymus, where white blood cell infiltration, vacuolation, and lymphoid depletion was noted microscopically. The microscopic findings persisted at the end of the recovery period.”

“Distribution trends were similar across pigmented and nonpigmented strains, except that radioactivity was distributed in the uveal tract, indicating binding to melanin-containing tissues with evidence of elimination of radioactivity from melanin containing tissues over time.”

“Inflammatory and ulcerative GI tract findings associated with secondary changes in the liver and lymphoreticular system at free exposures approximately 19.5 times the clinical free AUC at the MRHD were observed in mice.”

“Relatively higher concentrations of radioactivity were found in the lung, liver, kidney and adrenal gland at each timepoint. There was no evidence of high affinity melanin-specific binding of radioactivity in the pigmented tissues (pigmented skin and uveal tract).”

“It is further clarified that adagrasib-induced microscopic changes in lymphoid tissues, do not appear to translate into an immunotoxicity risk is supported. Omission of specific immunotoxicity studies is therefore accepted.”

“Following single oral administration to rats, 14C-adagrasib-derived radioactivity distributed to nearly all tissues by 8 hours post-dose. Adagrasib demonstrated affinity for melanin-pigmented tissues.”

“In 26-week juvenile rat and 13-week dog studies, no evidence of tumorigenicity, hyperplasia, preneoplastic lesions, neoplasia, or hormonal/immune modulation was observed.”

“No pharmacokinetic studies on organ distribution were performed with exogenous doxecitine and doxribtimine, since sufficient data was available from literature. Exogenous deoxycytidine and deoxythymidine are distributed extensively in the body, with the highest levels in spleen, liver, kidney, and intestine.”

“Thymus: Mean absolute and relative thymus weights in HD male and female rats were decreased. The thymus weight changes were not accompanied by correlating histopathology.”

“In a mass-balance study, [35S]nifurtimox was shown to extensively distribute to tissues, with the highest concentrations of radioactivity in the kidneys and liver followed by lung, adrenal and thyroid glands, testes, brain, and spinal cord.”

“Lazertinib was classified as a skin sensitizer in a local lymph node assay in mice, but did not meet the requirement for inducing serious eye damage in a bovine corneal opacity and permeability (BCOP) test.”

“Distribution of 14C-lazertinib-derived radioactivity in the uveal tract and pigmented skin indicated melanin binding.”

“The target organs were identified as lymphoid organs in both species, with major study findings including reduced circulating white blood cells and lymphocytes and decreased lymphocytes/cellularity in various lymphoid tissues (including spleen, thymus, lymph nodes, and gut-associated lymphoid tissue).”

“Milk/plasma concentration ratios were approximately 7, 13, 19, and 20 at 1 hr, 2 hr, 4 hr, and 8 hr postdose, respectively.”

“In the 2-week studies, mortality was noted following repeated doses ≥ 200 mg/kg/day in rats and doses ≥ 200/80 mg/kg/day in monkeys. In rats, the deaths were attributed to inappetence and generalized lymphoid depletion.”

“Relacorilant crossed the blood-brain barrier in both mice and rats (Studies S-COR-101 and S-COR-065).”

“In the first 39-week oral RDT study in dogs with 3-month recovery (doses: 0, 5, 20, and 40 mg/kg/day), no ritlecitinib-related effects were noted on mortality, ECG, or ophthalmology. At the HD, ritlecitinib-related immunosuppression was adverse because of skin mites and lung inflammation.”

“However, the low brain: plasma AUC ratio at ~0.04 demonstrates that penetration of the blood-brain barrier is inefficient in the rat. The high AUC and long excretion T1/2 in the uveal tract suggest melanin-related accumulation.”

“Seladelpar did not show potential for immunotoxicity in the repeat-dose toxicity studies and no sensitisation potential was recorded in the local lymph node assay in mouse.”

“Seladelpar was widely distributed in rats, as demonstrated by quantitative whole-body autoradiography (QWBA) data in both non-pigmented and pigmented rats with the highest radioactivity detected in the liver, kidney, and bladder.”

“Maribavir was not immunotoxic in rats at up to 100 mg/kg/day.”

“In pigmented rats, concentrations of radioactivity in the uveal tract were approximately 6-fold higher than those observed for albino rats, and were measurable through the last timepoint, indicating retention of DRM beyond 504 hours postdose.”

“pituitary gland (increased weight and hypertrophy of pituitary basophils of the pars distalis), thymus (decreased weight and decreased lymphoid cellularity), and gallbladder (bile sludge).”

“Following single oral administration, 14C-sotorasib-derived radioactivity distributed widely to rat tissues especially the liver, kidney, thyroid, pancreas, exorbital lacrimal gland, intra-orbital lacrimal gland, and adrenal gland, but brain penetration appeared low.”

“In general, the adverse findings with the different proportions of cis:trans isomers of voclosporin were due to drug-related immunosuppression (e.g., thymic medullary atrophy, absence of germinal centers, lymphomas, decreased lymphocyte counts)”

“Drug-derived radioactivity distributed to the eye (target tissue) following oral administration of 14C-voclosporin, although at low levels. The distribution profile of drug-derived radioactivity was similar in pigmented and non-pigmented rats, suggesting negligible binding of the drug and/or its metabolites to melanin.”

“Non-adverse, partially reversible decreases in thymus weights with corresponding microscopic findings of lymphoid depletion were observed in males only after treatment with OLZ, SAM, and the combination.”

“SAM is highly distributed to tissues in rats and was found to bind to melanin-containing tissues including skin and eyes and is mainly excreted in urine in rats and dogs.”

“In addition, thymus atrophy, reduced thymus weight or lymphoid depletion of the thymus were noted. The effects observed in adrenal glands and thymus were discussed to be related to treatment-induced stress and non-adverse.”

“Autoradiographic studies revealed that, following the oral administration of radiolabeled elinzanetant to different species, radioactivity distributed to major organs, including the liver and pigmented tissues (e.g., the uveal tract and the retina). In typical PK studies, elinzanetant was also found to cross the blood brain barrier.”

“Lymphoid tissues (depletion) were target organs in all species and was accompanied by decreased circulating levels of WBC and lymphocytes; this effect of siponimod was attributed to the pharmacological action of the drug.”

“In rats, siponimod was detected in brain and CSF after oral administration. Siponimod exposures in brain and spinal cord were between 0.8- and 4.4-fold that in blood.”

“Dosed at the maximum tolerated dose or higher, arimoclomol affected hematology parameters(e.g. reduced mean corpuscular volume, hemoglobin concentration and erythrocyte count), lymphoid and bone marrow depletion, and atrophy/reduced weight of the spleen and thymus.”

“Low level distribution of arimoclomol to the skin, brain and eyes was observed with elimination occurring within 24 hours.”

“A sensitization Study of CK-3773274 by Dermal Administration in Guinea Pigs – Modified Buehler Design Negative, aficamten did not induce erythema after 48 hours of topical application.”

“Pigmented skin showed higher concentrations of radioactivity than nonpigmented skin, which, together with the prolonged presence of radioactivity in eye uveal tract, indicated (reversible) melanin binding.”

“Lymphoid atrophy was noted in all species evaluated. Thymus weight was reduced in all species, associated with minimal to severe lymphoid atrophy.”

“E4 and its metabolites were widely distributed in rat tissues after a single oral dose of [14C]-E4 and are rapidly eliminated with no evidence of retention in any organ or tissues, including melanin-containing tissues.”

“Neither ASA nor PCA reactions were found and no specific antibodies to KW-6002 were detected. Under the conditions of this study, no antigenicity was determined with KW-6002.”

“In two studies of radiolabeled istradefylline in pregnant or nursing rats, the radioactivity persisted for a longer time and at higher levels in both fetuses and neonates than in dams.”

“The corresponding microscopic findings included reduction of secretion in the prostate gland, vacuolation of the epididymal epithelium and a possible reduction in the normal involution of the thymus.”

“In mice, darolutamide and keto-darolutamide and in rats total radioactivity exhibited low penetration into brain (brain/plasma ratio of AUC(0-24) < 0.05).”

“No studies on antigenicity, immunotoxicity, dependence, or metabolites have been conducted.”

“In both the pigmented and nonpigmented rats, the highest concentrations of fosdenopterin were observed in the kidney, bone epiphyseal line, skin, liver, and esophagus.”

“Further, no hormonal perturbation, histopathological changes in endocrine or reproductive organs or effects on the immune system were observed in pivotal non-clinical studies.”

“A single-dose tissue distribution study in pigmented and albino rats demonstrated that rimegepant is widely distributed extravascularly and likely binds to melanin.”

“One male dog administered 500 mg/kg/day AZ13420914 was euthanized early for low feed consumption and body weight loss. The cause of morbidity in this animal appeared to be due to marked necrosis and inflammation of the ileum and gut-associated lymphoid tissue.”

“In an IV dosed tissue distribution study with radiolabeled zoliflodacin in rats, the highest levels were detected in kidneys and liver, and the zoliflodacin concentration was not higher in pigmented tissues.”

“In the 3‐month rat study, ovarian atrophy, alterations in the estrous cycle and decreased cellularity in gut‐associated lymphoid tissue (GALT) in females, and decreased cellularity of mesenteric lymph nodes in males and females at 5 mg/kg/day was observed.”

“Excluding excreta, the highest Cmax levels of radiolabeled [14C] nirogacestat were uveal tract, liver, adrenal gland, spleen, and pituitary gland. Radiolabeled [14C] nirogacestat exhibited an affinity for pigmented ocular tissues containing melanin.”

“Effects on thyroid gland (follicular call atrophy), thymus and mesenteric lymph node (minimal to mild depletion) did not resolve at the end of the recovery period in the 3-month study.”

“Notably, brain exposure was measurable (brain/plasma AUC ≈ 0.6), supporting blood–brain barrier penetration adequate for the treatment of paediatric low-grade gliomas. Tovorafenib also demonstrates a reversible affinity for melanin-rich tissues, including pigmented skin, the uveal tract or substantia nigra.”

“Consistent with drug pharmacology as a JAK inhibitor, momelotinib targeted hematopoietic tissues, i.e., bone marrow, spleen, lymph node and thymus.”

“Radioactivity was nonquantifiable in bone, brain, spinal cord, and testis at all sampling times suggesting low penetration of 14C-MMB-derived radioactivity across the blood-brain and blood-testis barriers.”

“Stress- or dehydration-related changes in clinical chemistry, hematology (such as reduced white blood cells and lymphocytes), and histopathology (such as increased hypertrophy of adrenal cortex corresponding to increased adrenal weight as well as minimal thymus atrophy) were observed across nonclinical studies”

“Total radioactivity (parent and metabolites) is distributed widely after IV dosing of oliceridine in rats, with 14C-concentrations found in well-perfused (liver, kidney) and poorly-perfused (skin, skeletal muscle) tissues.”

“In all dosed groups there was a slight increase in the Thelper (CD3+/CD4+)lymphocyte populations, with no alteration in function or response to sheep RBC’s.”

“the highest tissue levels were found in the liver, kidney cortex, and renal medulla (7163, 4243, and 3806 ng equiv/g, respectively). Concentrations in brain were found to be below the limit of quantification at all time points.”

“Furthermore, there were no findings suggestive of effects on the immune system in general toxicity studies conducted in mice for up to 13 weeks, rats for up to 26 weeks, or monkeys for up to 39 weeks.”

“Following a single oral dose of radiolabeled relugolix to rats, the highest radioactivity was observed in liver, intestine, thyroid, stomach and pituitary gland. Radioactivity in the eyes, mainly localized to the melanin rich tissues - anterior and posterior parts, was detected at 4 h and sustained for up to 12 weeks post-dose.”

“Phospholipidosis-related findings included vacuoles in the epithelium and mucosa of the intestine, kidney, and choroid plexus (rats); foamy macrophages and histiocytes in the spleen, thymus, and intestine; and foamy Kupffer cells in the liver.”

“BCX7353 was found to bind to melanin-containing tissues. At 1440 hours post-dose, the highest concentration of radioactivity was quantified in the uveal tract of the eye.”

“Monkeys also exhibited positive Coombs test results that tended to increase with sulopenem etzadroxil dose and likely contributed to antibody mediation of minimal erythrocyte loss and compensatory erythropoiesis in monkeys.”

“The tissues with the highest AUC exposures to radioactivity over a period of 168 hours after dosing were in descending order: kidney, liver, lung, skin, pancreas, spleen, and blood.”

“Histopathology changes in rats and monkeys, other than those of the male and female reproductive organs (discussed below under fertility studies), were generally observations of increase in macrophage and/or neutrophilic infiltrates in mesenteric lymph node, lung, small and large intestines”

“Following a single oral administration of elacestrant in rats, radiolabeled elacestrant was detected in the majority of tissues, including ocular melanin containing tissues (eye uveal tract of Long Evans rats), but not in the brain, eye lens, spinal cord, and testes”

“2) The immunosuppressive action of voxelotor, manifested as increased mortality due to opportunistic infections in monkeys, significantly reduced IgG (rats, monkeys) and IgM (monkeys) titres, delayed antibody response (monkeys)”

“Radioactivity was found to cross the blood brain barrier, but exposure was at least 30-fold lower than in the blood. As pigmented and non-pigmented skin were similarly labelled, it is concluded that there is no melanin binding.”

“The Applicant has justified that no dedicated immunotoxicity study was performed, since no immune adverse effects are expected from the pharmacological properties. In addition, no immunotoxicity findings were observed in the non-clinical or clinical program.”

“Minimal brain to plasma ratio of paltusotine (<0.05) was observed in rats. QWBA study demonstrated a preferential binding to melanin containing tissues, namely the meninges, uveal tract, and the pigmented skin.”

“Pemigatinib induced multi-organ histologic mononuclear cell infiltration in both species.”

“Following single oral administration, 14C-pemigatinib-derived radioactivity distributed widely to rat tissues especially excretory, endocrine, alimentary canal, and pigmented tissues, but only minimally in CNS tissues.”

“The effects in the hemolymphoid system included inflammation and/or suppressive effects in the bone marrow, spleen, thymus, or lymph nodes.”

“Nonclinical ADME studies indicated distribution of radioactivity to hair and eyes of pigmented rats, thus alpelisib and/or its metabolites can bind melanin.”

“The TDAR results suggest that there is immune suppression during the dosing of ponesimod that recovers when dosing is stopped.”

“In albino rats, radioactivity was widely distributed into most tissues and was maximal at 1-4 hours post-dose. The highest exposures were found in GI tract and liver but was also observed in the brain and spinal cord at higher levels than blood at 1-4 hours post-dose.”

“Signs of immunotoxicity were seen in most of the repeat-dose toxicity studies and in all three species, such as lymphoid depletion in the spleen, thymus, Peyer’s patches and bronchial-associated lymphoid tissue in the lungs, and alterations in lymphoid organ weights.”

“In a study of radiolabeled PA-824 in rats, the highest tissue concentrations were measured in the Harderian gland, liver, renal medulla, adrenal gland, kidney, renal cortex, exorbital lacrimal gland, and spinal cord.”

“thymus with correlative decreased thymus weight in both sexes and arterial inflammation or degeneration in males. These findings were most likely secondary to the stress and poor condition of the animals, rather than a direct drug effect, and were reversible after recovery.”

“These data suggest that viloxazine or its metabolites do not preferentially distribute to or accumulate in the skin; viloxazine and its metabolites reversibly bind to melanin in the uveal tract but are rapidly dissociated or eliminated.”

“The weight of the thymus was reduced which correlated with the decreased number of lymphocytes observed microscopically.”

“Radiolabel associated with [14C]-ripretinib was extensively bound to melanin-containing tissues in pigmented LE rats such as eye ciliary body, eye uveal tract, and eyes, and the radiolabel binding showed a long half-life.”

“The applicant has provided a weight of evidence review in accordance with ICH S8 which did not reveal any concerns.”

“Most tissues had concentrations similar to those in blood, except for central nervous system tissues, eye and bone, which had negligible concentrations.”

“Absolute and relative thymus weight was decreased at the high dose.”

“Radioactivity levels in the brain and fetuses were much lower than that of plasma; drug-related radioactivity was not observed in the brain after repeat dosing.”

“Findings included GI toxicity, myelosuppression, thymic toxicity, electrolyte imbalance, and immune activation (elevated fibrinogen was secondary to immune activation).”

“In a mouse QWBA study, distribution of [14C]-daraxonrasib was widespread with the highest concentrations of radioactivity generally associated with tissues involved in excretion and elimination.”

“Similar findings included: changes in hematopoietic, lymphoid, and GIT systems, liver and altered inorganic phosphorus levels (hyperphosphatemia).”

“Tissues from male rats that received 10 mg/kg [14C]-labeled selpercatinib showed the highest levels in uveal tract (24 hours post-dose), eyes (24 hr), Harderian gland (2 hr), meninges (72 hr), and pigmented (melanin-containing) skin (8 hr).”

“Hematological changes were generally more pronounced in rats than dogs and included decreases in absolute white blood cells, reticulocytes, lymphocytes, monocytes, eosinophils, and basophils with microscopic correlates of decreased hematopoietic cellularity in bone marrow (rat), decreased lymphocytes in thymus (rat and dog), and spleen (dog).”

“Following IV administration of [14C] gedatolisib to pigmented male and female rats, radioactivity was highly concentrated and retained for a prolonged period for up to 672 hours and 96 hours in the uveal tract of the eye and pigmented skin, respectively.”

“Decreased thymus weights correlated with lymphoid atrophy in males and females at all doses.”

“The eye uveal tract had a Cmax of 19,500 ng eq/g at 168 hours post-dose at concentrations that were sustained through 672 hours post-dose.”

“In all HD animals, hepatocellular hypertrophy, foamy alveolar macrophages, epithelial vacuolation in the seminal vesicle, vacuolation and lymphoid depletion of the marginal zone in the spleen, cortical hypertrophy of the adrenals, decreased hematopoietic tissue in the bone marrow, and thymic involution were also observed”

“Distribution studies (with [14C]lasmiditan) in rat show that lasmiditan crosses the blood brain barrier, with brain to plasma ratios of approximately 3 over a 24-hour period after IV dosing. The highest concentrations of [14C]lasmiditan were found in the urinary bladder and uveal tract of the eye.”

“Resmetirom induced an increase in spleen weight of female mice at 3 and 100 mg/kg/day dose, however since correlation with other immune-related finding was not observed, the risk of immunotoxicity was considered low.”

“Liver AUC and renal cortex AUC for total radioactivity after dosing with [14C]MGL-3196 were approximately 10 times and 3 times the plasma AUC value, respectively. [14C]MGL-3196-related radioactivity was not specifically associated with the melanin-containing tissues in the pigmented LE rats.”

“hematopoietic system (reduced RBCs and lineages, increased WBCs and differentials, increased platelets, and lymph node cellular depletion).”

“A QWBA distribution study in rats demonstrated tissues with the highest radioactivity concentrations were small intestines, cecum, and liver. Olutasidenib crossed the blood brain barrier in rats with unbound ratios of cerebrospinal fluid to plasma and brain to plasma of 0.29 and 0.1, respectively.”

“In addition, reduced thymus weights correlated with increased incidence and/or severity of thymic lymphoid depletion in HD males and females. Thymic lymphoid depletion was not observed in recovery males or females.”

“All tissues demonstrated clearance and no appreciable radioactivity was observed in the brain. Melanin-containing tissues (uveal tract and pigmented skin) demonstrated higher tissue retention, indicating some affinity of belumosudil for melanin.”

“Rezafungin induced an acute transient histamine-release response in rats. In monkeys, both the vehicle and rezafungin induced a mild transient histamine-like response in some studies.”

“Tissue distribution was evaluated in rats after IV administration of rezafungin, demonstrating widespread exposure in various organs, with tissue/plasma AUC ratios that were comparable (approximately 4-fold higher in tissue than plasma) for major (kidney, lung, liver, spleen) organs with the exception of the heart and brain.”

“Remibrutinib inhibited primary antibody responses to certain, but not all, tool antigens in rodent pharmacology studies at pharmacologically relevant exposure, considered related to the role of BTK in B cells.”

“A single oral dose of remibrutinib resulted in broad distribution in all tissues except for the brain, lens of the eye, spinal cord, and white fat, with a Tmax of 0.5 to 8 hours.”

“The findings included decreases in circulating lymphocytes and lymphoid depletion in spleen, thymus, and lymph nodes.”

“Radioactivity concentrations were below measurable levels in the CNS tissues and the lens of the eye at all collection times throughout the study. Radioactivity was present in the uveal tract through 192 hours postdose and a slower clearance in pigmented skin indicating an apparent affinity for melanin.”

“In rats, dose-limiting toxicity included bone marrow suppression, lymphoid tissue hypocellularity and/or necrosis at the highest dose tested in the 28-day study leading to termination of all animals for welfare reasons.”

“Radioactivity was cleared from most tissues by 168 hours post dose, but was still quantifiable in the meninges, eye uveal tract, eye(s), and eye vitreous humour at 672 hours, suggesting melanin binding.”

“Lymphoid depletion was observed at ≥25 mg/kg/day in the 4-week study in spleen, and also in lymph nodes and thymus at ≥200 mg/kg/day in the 4-week 2x2 intermittent dosing and 14-day studies.”

“In addition, after repeated oral doses brain-to-plasma concentration ratios of entrectinib were higher at 24 hours post last dose in mice (~0.4), rats (0.6–1.5), and dogs (1.4-2.2), indicating brain penetration occurred under steady-state conditions.”

“The potential effects of FTR on the T-cell dependent antibody response (TDAR) to KLH were evaluated in accordance with ICH S8 as part of the pivotal 26-week oral rat toxicity study. From this study there is no indication of an immunotoxic potential for FTR.”

“These findings suggest a potential association with melanin containing tissues of the eye uveal tract. Distribution studies performed in pregnant rats revealed significant transfer across the placenta with foetal exposure to all tissues examined including the brain.”

“necrosis of thymus lymphocytes, lymphoid depletion in spleen, lesions in the GI (ulceration and inflammation) in one rat at 200 mg/kg/day.”

“Melanin binding of asciminib was observed. The brain tissue/blood Cmax ratio of 0.0149 indicated little penetration of the blood-brain barrier.”

“No immunotoxicity assessments were performed as no sepiapterin-related effects on the immune system were observed in repeat-dose mammalian toxicology studies.”

“Distribution of radioactivity to certain melanin-containing tissues, such as the meninges and uveal tract was low and there was no extended retention, indicating that [14C]-sepiapterin-derived radioactivity was most likely not associating with melanin in these tissues.”

“Considering the type of molecule (small molecule), investigations of antigenicity and immunotoxicity are not required for omaveloxolone.”

“Following oral administration to monkeys, [14C]RTA 408 was approximately 3.41% bioavailable and was widely distributed to most tissues, including brain, between 8 and 30 h, with the highest concentrations observed in the gastrointestinal tract.”

“Sofpironium bromide is a skin irritant but not a sensitizer.”

“The transfer of 14C-sofpironium and/or its metabolites across the placental barrier is low during both organogenesis (12th day of pregnancy) and late (18th day) pregnancy. Sofpironium or its metabolites were transferred into the milk after a single subcutaneous administration of 0.5 mg/kg to lactating rats on postpartum Day 10.”

“No evidence of hormonal effects or immunosuppression”

“In autoradiography tissue distribution studies, palovarotene exhibited a slow but extensive distribution into the tissues.”

“In rats, dose-dependent minimally to moderately decreased lymphocyte counts (including total T, helper T, cytotoxic T, B, and NK cells) generally correlated with decreased spleen and thymus size and weights, decreased lymphoid cellularity in lymph nodes, thymus and splenic white pulp, and decreased TDAR to KLH-specific IgM and IgG responses.”

“In pigmented rats, there was substantial, but reversible binding of [14C]BMS-986165-derived radioactivity to certain melanin-containing tissues, such as the eye uveal tract, but not in pigmented skin.”

“Using in vitro skin models, lenacapavir was not considered corrosive but was considered positive in two of three skin sensitization assays. However, in the in vivo assessment, lenacapavir was considered negative for sensitization potential.”

“No quantifiable or low levels of radioactivity were detected in brain and testes, respectively, suggesting that distribution of [14C]-lenacapavir-derived radioactivity was restricted by the blood to brain and blood-to-testes barriers.”

“Concerning the immune system, dose-dependent effects of solriamfetol on numbers of immune cells and morphology/weight of immune-system related organs (most prominent in rat studies) were observed.”

“After oral administration, solriamfetol was extensively distributed into pigmented and non-pigmented tissues, including the brain.”

“No specific immunotoxicity studies were conducted with capmatinib”

“In pigmented rats, radioactivity was reversibly distributed into the melanin containing structures such eye choroid. The highest accumulation was observed in eye (lens) and adrenal (medulla).”

“In monkeys, avacopan had no effect on T-cell dependent antibody responses or on relative or absolute values for peripheral blood immunophenotyping (total T lymphocytes, helper T lymphocytes, cytotoxic T lymphocytes, B lymphocytes, or natural killer cells).”

“Distribution trends in the pigmented uveal tract suggested that [14C]-avacopan-related radioactivity associated with the melanin-containing tissues of the eye; this association was slowly reversible.”

“In addition, lymphoid hyperplasia occurred in the mesenteric lymph node of a single male dosed at 600 mg/kg/day.”

“Tissues of the CNS were below quantifiable levels.”

“Data collected from repeat-dose toxicity studies in rats and dogs, including haematology and clinical chemistry investigations, absolute and relative weights and histopathology of lymphoid organs were not indicative for an immunotoxic potential of tepotinib.”

“In the remaining body, highest concentrations of radioactivity were detected in the liver, lungs, and kidneys and, 24 hours after administration, in the lymph nodes. In pigmented animals, medium levels of radioactivity were found in the eyes and skin throughout the investigational period of 96 hours”

“Microscopic correlates consisted of cortical hypertrophy/vacuolation in the adrenal glands, atrophy in the prostate, secretory depletion in the seminal vesicles/coagulating glands, germ cell debris/oligospermia in the epididymides, and lymphoid depletion in the thymus.”

“VX-445-related radioactivity crossed the blood-brain barrier, but measured concentrations in the brain were about 3-fold lower relative to plasma. A tissue distribution study in Long-Evans rats showed no significant distribution to melanin-containing tissues (skin, eyes), indicating that VX-445 did not preferentially associate with melanin.”

“Administration of capivasertib to rats resulted in increases in AST, ALT and GLDH, decreases in white blood cells and lymphocytes, increases in TSH”

“Capivasertib was reversibly bound to melanin with persistence up to 168 h in the skin and 504 h in the eyes.”

“The product was not a sensitizer in the local lymph node assay performed with CBA/Ca mice at up to 50% acoltremon applied on the dorsal surface of both ears once daily (25 µL/dose) for 3 days consecutively.”

“in an ocular distribution study in the rabbit where animals received 3 µg/eye/day (1.67-fold the therapeutic dose) for 28 days, acoltremon was detected in the conjunctiva of 2 out of 8 eyes, while cornea, conjunctiva, aqueous humor, iris/ciliary body, vitreous humor, and retina were below the LLOQ of 5.05 ng/mL in all animals.”

“Additional target organs in rats included the hemolymphoid system (lymphoid depletion), male and female reproductive organs, and skeletal muscle (myofiber degeneration/regeneration and hemorrhage) in male rats in the 28-day study.”

“the highest distribution of tucatinib in rats was in the uveal tract, eyes, pigmented skin, liver, testes, epididymis (male), and thymus (female); tucatinib was not detected in CNS tissues.”

“Pexidartinib-related observations on the lymph/hematopoietic compartments include lymphoid depletion of the thymus with decreased thymus weight and lymphocyte counts and lymphoid hyperplasia with lymph node enlargement and increases in neutrophils and large unstained cells (LUC).”

“Tissues with the highest exposure (Cmax) to pexidartinib were the uveal tract, liver, pancreas, Harderian gland, and the entire eye. At the last sampling time of 336 hours post-dose, pexidartinib was still present in the eye including the uveal tract.”

“Drug-related findings included decreased white blood cells (WBCs) and differentials, increased liver weights and alkaline phosphatase (ALP) levels, and lymphoid depletion.”

“In mice, umbralisib was widely distributed, with the highest concentrations in the gastrointestinal, metabolic/excretory, fatty, secretory, and endocrine tissues and the lowest concentration in brain, demonstrating penetration of umbralisib occurred in richly perfused organs, while passage to the CNS was limited.”

“Orally administered tebipenem pivoxil was negative in a delayed hypersensitivity study using guinea pigs and in antigenicity studies in mice and guinea pigs.”

“Tissue distribution of radiolabeled tebipenem pivoxil was evaluated using quantitative whole-body autoradiography in male rats and showed extensive quantifiable levels of radioactivity measured in most analyzed tissues, with the exception of the brain medulla, spinal cord, abdominal fat, and eye lens.”

“It is considered acceptable that no information has been submitted on immunotoxicity as no relevant findings have been observed in the repeat-dose toxicity studies in rats and dogs to indicate an immunotoxic potential.”

“Administered to pregnant rats and lactating rats, vadadustat related compounds were detected in the fetal tissues and the milk, demonstrating that vadadustat can cross placental tissues and can be delivered to newborns via nursing.”

“Hematologic and lymphoid toxicities were common and attributable to exaggerated pharmacology.”

“Binding to melanin was evident as pigmented skin accumulated about 9-fold more radioactivity than non-pigmented skin.”

“In addition, the repeat-dose toxicology studies in rats for up to 6 months and in dogs for up to 9 months do not suggest an immunosuppressive effect of atrasentan.”

“Low concentrations were observed in testes, eyes, bone marrow, and fat. Radioactivity was not detected in the brain.”

“No dedicated immunotoxicity studies have been performed with remdesivir. This is considered acceptable as no concerns were identified by standard assessments in repeat-dose toxicology studies.”

“Low levels of radioactivity were detected in testes, suggesting [14C]remdesivir-derived radioactivity crossed the blood to testes barrier. Radioactivity was eliminated from majority of the tissues by 96 hours postdose in both SD and LE rats. No melanin binding was observed.”

“Dose-dependent decreases in circulating lymphocytes were observed in both rats and dogs and correlated with lymphoid depletion in the lymph nodes and spleen of rats only; these findings were attributed to the pharmacological activity of etrasimod and not considered adverse.”

“[14C]etrasimod distributed to tissues of GI tract, organs of clearance (kidney and liver), myocardium, secretory glands (adrenal and thyroid), and the non-circumventricular central nervous system tissues (spinal cord and brain) in non-pigmented and pigmented rats.”

“No antigenicity and immunotoxicity studies have been conducted with fezolinetant since these studies were not considered necessary.”

“The highest levels of fezolinetant in tissues were associated with the kidney cortex, clitoris, uveal tract/retina, adrenal gland (cortex and medulla) and liver.”

“As there were no indicators of effects on the immune system, no further specific evaluation was conducted.”

“Melanin binding of vericiguat and/or its metabolites was also observed for the substantia nigra. Elimination occurred with longer terminal half-lives in melanin-containing tissues”

“Lymphoid tissue depletion and concomitant changes in white blood cell parameters, consistent with bone marrow suppression, were observed in mice, rats, and dogs”

“Pacritinib exposure levels within these three tissues were highest in the lungs (increased 19-fold versus plasma, area under the concentration-time curve [AUC]) followed by the brain (increased 2-fold versus plasma, AUC) and plasma.”

“Additional organs of toxicity in the rat included middle ear, eye, gastrointestinal tract, kidney, lymph nodes, pancreas, Peyer’s patches, pituitary, skin, spleen, and thymus.”

“There was no significant distribution to melanin-containing tissues. Brain to plasma ratios ranged from 0.604 to 1.24 in rats from the 28-day and 13-week repeat-dose general toxicology studies with ratios decreasing with an increase in dose.”

“results suggests that when anti-Nm antibody titers are low (i.e., prevaccination), CAP-mediated amplification is required to elicit effective SBA, and hence, there is an increased risk of danicopan promoting bacterial infections under these conditions.”

“Distribution studies in either pigmented rats or pigmented rabbits showed that danicopan crosses the blood-retina barrier, enters the neural retina (a tissue that does not contain melanin), and associates with ocular tissues containing melanin (e.g., uvea and choroid-retinal pigment epithelium) and with the skin in pigmented rats.”

“Additionally, lymphoid depletion was seen in males and females at doses of 10 or 40 mg/kg/day and correlated with thymus weight decreases.”

“In male pigmented rats following a single SC administration of [14C]-tapinarof at 2 mg/kg, radioactivity was rapidly and widely distributed throughout the body with all tissues containing quantifiable radioactivity concentrations by 1-hour post-dose.”

“No specific immunotoxicity studies were submitted.”

“Tafamidis was observed to cross the placental barrier and distribute to the foetal tissues to an extent of 3-4% of the administered dose in rats. More than 30% of the dose of tafamidis was transferred to milk when administered to lactating rats.”

“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. Therefore, immunotoxicity aspects were not investigated further.”

“Radioactivity was measurable in the milk of lactating rats at concentrations 1 to 3 times higher than measured in plasma.”

“No dedicated immunotoxicity studies were submitted in Module 4.2.3.7.2 of this dossier.”

“Rilzabrutinib concentrations in the pigmented tissues (eye uveal, skin) were higher than nonpigmented tissues suggesting rilzabrutinib may interact with melanin.”

“belzutifan does not show off-target activity, did not induce proliferative changes or potential endocrine/hormonal perturbations, or immunosuppression in repeat-dose toxicity studies”

“Distribution studies showed distribution of belzutifan to mostly excretory organs and the GI tract in rats. No gender differences were observed and no melanin binding was evident.”

“The changes observed in the white blood cells population, in the adrenals and in the lymphoid organs (spleen, thymus) were probably related to the weak glucocorticoid activity of the clascoterone.”

“After repeated administrations in some toxicity studies in rats and in minipigs, a significant accumulation was observed (e.g. in 9 months dermal in minipigs, the ratio of AUC ranged from 6.38 to 20.3), varying in extent depending on the doses and treatment duration.”

“Lymphoid hyperplasia of bone marrow was seen at the end of the treatment period in the MD and HD groups and was still present after the recovery period at the HD.”

“Tissue distribution of [14C]-CBM in male S-D rats following a single oral dose showed the highest tissue-to-blood ratios in kidney (4.7) and liver (2.7), with most ratios (including brain) around 1.”

“In a Local Lymph Node Assay in the mouse, ACH 2224920 did not have the potential to cause skin sensitization.”

“Overall, the data indicated that inferior and superior eyelid margins were prone to drug accumulation, coupled with the lowest clearance in these tissues and an AUC inf 10-fold higher than in all other ocular tissues.”

“A SI of 3.8 was recorded for the positive control group and verifies the validity of the conclusion that abametapir is considered as negative for skin sensitization potential under the conditions used in the assay.”

“The highest radioactive concentrations and areas under the curve (AUCs) were observed at the dose site, plasma, kidney (cortex and medulla), uveal tract/retina, and skin (both pigmented and non-pigmented).”

“Following IV administration of lefamulin to rats for 4 or 13 weeks, anemia (all doses), increased coagulation times, and lower organ weights and histopathological changes in spleen (decreased peri-arteriolar lymphoid sheath, decreased size of the marginal zone) and thymus (cortical atrophy) were seen in rats”

“A quantitative whole-body autoradiography in rats after IV bolus administration showed a rapid distribution into tissues and organs consistent with the apparent low protein binding affinity observed in vitro.”

“Immunophenotyping revealed 20-40% decreases in various T-cell and B-cell populations (males and females).”

“Ensitrelvir was highly protein-bound (97.4% to >98.9%) across all species, predominantly to albumin, with highest tissue concentrations in the liver and minimal CNS penetration (rat distribution study), with excretion occurring primarily through feces and urine.”

“Twice daily oral administration of mavorixafor for up to 250 mg/kg/day for 28 consecutive days to Sprague-Dawley rats did not result in immunosuppression.”

“In partially pigmented rats, measurable radioactivity was observed in the uveal tract/whole eye from 8 hours until the final sampling time of 840 hours, suggesting irreversible binding to melanin-containing tissues.”

“Selinexor was also identified as non-phototoxic and to induce mild-grade II dermal contact sensitivity response at 24 and 48 hours.”

“The highest concentrations of radioactivity were observed in the kidneys, liver, and small intestine. There was no specific binding to pigmented tissues.”

“There were increases in the weight of adrenal glands, thyroid/parathyroid, and ovaries and decreases in spleen and thymus in BHV-3500 groups; however, the changes were not dose-related, and there were no histopathological correlates.”

“Following intranasal administration of 14C-zavegepant to rats, plasma:olfactory bulb and plasma:trigeminal nerve radioactivity ratios were 500:1 and 180:1, respectively, at 0.5 hours postdose.”

“The main target organs were GI tract, eyes, skin, lungs, and immune organs, etc.”

“Distribution of sunvozertinib-derived radioactivity in the uveal tract, meninges, and pigmented fur indicated melanin binding. Radioactivity in the brain and spinal cord remained below the limit of quantification, indicating that sunvozertinib has a low tendency to cross the blood-brain barrier.”

“Hematology changes (decreased neutrophils and lymphocytes), immune suppression from lymphoid depletion, and GI toxicity observed in the toxicology studies correlated with neutropenia, infections, and GI toxicity observed in patients in the clinical trials.”

“This longer presence in the pigmented tissue suggests a reversible association with melanin. There was minimal distribution of radioactivity into the brain of any animal used in the study”

“Immunotoxicity assessment revealed the expected pharmacological action of decreased T- and B-lymphocyte counts and an inhibitory effect on primary and secondary T-dependent IgM and IgG antibody responses.”

“At the final time point, radioactivity was still detected in the hippocampus and uveal tract; radioactivity was BLQ in all other tissues.”

“dose-dependent decreases in lymphocytes and neutrophils following repeated lurbinectedin administration suggest that there may have been a general decrease in immune responsiveness.”

“The lowest radioactivity concentrations were detected in the brain (<5 and <2.3 ng-eq/g for male and female rats, respectively) and testes (<12 ng-eq/g). The highest values of total activity were in spleen, followed by lymph nodes, liver, thyroid glands, kidney, lung and skin.”

“In rats, toxicity was seen after 3-months administration of lonafarnib and were attributed as lymphoid hypocellularity and with corresponding weight loss and the affected organs/tissues included spleen, thymus and mesenteric lymph node”

“The AUC ratio of brain to plasma was about 6.5% at each dose level, indicating a low to moderate brain penetration of Lonafarnib.”

“No studies for antigenicity, immunogenicity, photosafety have been conducted.”

“As pigmented and non-pigmented skins were comparably labelled, it is concluded that there is no melanin binding. Radioactivity was found to cross the testis, and blood-brain barrier, and exposure was about 2-fold lower than in blood.”

“In addition, brexanolone showed no sign of dermal irritation, skin sensitization, or hemolytic potential.”

“Radioactivity concentrations were observed in CNS tissues at higher than blood concentrations and in testis at low levels.”

“Radiolabeled iron from ferric maltol in the rat intraduodenal administration studies was found bound to transferrin with a time to half maximal concentration (T½) of 133 minutes. Ferric maltol as single 1000 µg or 1 mg IV doses of iron was administered to rats, resulting in highest iron concentrations in the liver and bone marrow, with the iron being bound to proteins.”

“No studies of distribution, of excretion in milk and placental transfer with levacetylleucine have been carried out, as levacetylleucine is metabolized by deacetylation (a robust and ubiquitous mechanism), giving rise to a single metabolite, L-leucine, which is endogenously present in humans.”

“Overall, there was no accumulation or retention of radioactivity in tissues. The data also suggested that [14C]acoramidis derived radioactivity did not selectively associate with melanin containing tissues in the pigmented rat.”

“[14C]SDX-related radioactivity widely distributed in rat tissues with the highest radioactivity concentrations observed in eye uvea, kidney cortex and medulla, liver, gastric mucosa of stomach, and small intestine.”

“In a distribution study in rats, the kidney medulla and cortex, liver, adrenal cortex and medulla, pancreas, harderian gland, and preputial gland showed the highest bexagliflozin concentration between 4 to 12 hours postdose.”

“Notably the uveal tract/retina contained 64% and 42% of peak concentrations of radioactivity 336 hr and 840 hr post-dose, respectively, indicating lumateperone-related material may bind to melanin.”

“Central nervous system tissues (cerebrum, cerebellum, medulla, and spinal cord) had low exposure to radioactivity (<100 ng equiv/g).”

“Following IV administration of cipepofol injectable emulsion, extensive tissue distribution was observed in Sprague-Dawley rats, with the highest exposures found in the adrenal gland, fat, skin, ovary, pancreas, and kidney. Cipepofol was demonstrated to cross the blood-brain barrier.”

“Following administration of a single oral dose of 14C-trofinetide (200 mg/kg) to male Sprague Dawley rats, tissue distribution of radioactivity was widespread, with the highest concentrations in gastrointestinal tissue (small and large intestine wall), kidney, and liver;”

“No affinity for tissues containing melanin was noted and no quantifiable amount was detected in the eye lens. In all tissues, the elimination of radioactivity was complete by 168 hours postdosing.”

“While radioactivity was detected in the amniotic sac and placenta of pregnant rats, it was not detected in fetal blood, fetal tissues, or amniotic fluid, indicating that orforglipron did not cross the placental barrier in rats.”

“suggesting that vibegron is associated with eye melanin but not irreversibly bound.”

“There was no significant accumulation of radioactivity in the central nervous system (CNS), and radioactivity was not selectively associated with the melanin-containing tissues or red blood cells.”

“Similar results were obtained in pigmented Long Evans rats and there was no indication of any specific affinity of substance-associated radioactivity to melanin bearing tissues such as eye wall or skin.”

“Due to maralixibat’s low bioavailability, distribution to other tissues is low, although maralixibat was also found in the liver and pancreas of the rat at levels approximately 10 times higher than plasma.”

“Tissue distribution studies using radiolabeled linerixibat revealed that drug-related material was almost exclusively confined to the gastrointestinal tract following oral administration.”

“At 336 hrs post dose, radioactivity was still high in the uveal tract and retinal epithelial cells and low but measurable in blood, kidney, heart and skin (pigmented).”

“Following the repeated topical ocular dose of 14C-perfluorohexyloctane, rank order of highest mean concentrations (>5000 ng equivalents 14C-F6H8/g) was: tears > meibomian glands > cornea > palpebral conjunctiva > accessory lacrimal gland > main lacrimal gland > bulbar conjunctiva.”

“Dordaviprone distributed to the uveal tract, eye, endocrine system, GI tract, and meninges in rats. Brain exposure was minimal for radiolabeled-dordaviprone in rats.”

“Tradipitant was excreted in milk of lactating rats that received tradipitant at 100, 300, or 1000 mg/kg (2.3, 2.4, and 3.3 times the exposure to tradipitant at the MRHD) during pregnancy from gestation day 6 through lactation day 20.”

“The highest concentrations were found in liver, kidney and lung and contents of the GI tract. The liver is the main target organ of toxicity in rats (see section 4.2). There was no retention in melanin-containing tissue.”

“Radioactivity was not detectable in the brain or spinal cord in the rats.”

“Distribution was: cornea > bulbar conjunctiva > trabecular meshwork > palpebral conjunctiva > sclera > aqueous humor > iris > ciliary body > choroid-retinal pigmented epithelium (RPE) > plasma > blood.”

“liver, with no evidence of binding to melanin-containing tissues. Oveporexton can be transferred into the fetus via the placenta during gestation and is also secreted into milk in lactating rats.”

“The tissues with the highest Cmax values (Tmax = 4 hours for most tissues) excluding the gastrointestinal tract were observed in the liver, kidney, pancreas, and adrenal gland. [14C]nirmatrelvir-derived radioactivity did not cross the blood:brain barrier to a quantifiable extent.”

“Distribution study was not performed. However, GI distribution of lactitol was examined in a pharmacology study in rats after an oral dose of 4 g/kg. Lactitol reached in mg/g levels in all intestinal components including the colon.”

“The distribution of [14C]mitapivat to melanin-containing tissues, such as pigmented skin and the uveal tract of the ocular system, indicates that mitapivat has the potential to bind melanin.”

“There was no significant distribution/accumulation of radioactivity in the uveal tract/retina, pigmented skin, or meninges of the brain, suggesting that daridorexant does not bind to melanin.”

“Brain, seminal vesicles, eye lens and bone were among the tissues with lowest concentrations of radioactivity (<1.5 μg equiv/g at Tmax). The low levels of radioactivity in the brain suggests REL is not prone to pass the blood brain barrier.”

“Based on radioactivity, PB-related material accumulated in kidney while CNS levels were minimal (i.e., 10-fold lower than kidney); radiolabeled TUDCA-related material was below the limits of quantification in CNS tissue.”

“[14C]‐infigratinib was extensively distributed into peripheral tissues in rats after oral and IV doses, including brain, and was specifically taken up into melanin‐containing structures in pigmented rats.”

“The liver, kidney cortex, lung, pituitary, thyroid, and myocardium showed the highest exposures, with peak exposures observed at 8 hours postdose. No relevant retention of radioactivity in the uveal tract/retina, pigmented skin, or meninges of the brain was observed at any time point.”

“Following oral administration to rats and monkeys, [14C]ubrogepant was approximately 23% bioavailable and was widely distributed to most tissues and milk (rat) at similar concentrations to blood.”

“Following oral administration of [14C]- vepdegestrant and whole-body autoradiography, the highest distribution of vepdegestrant in rats was in the liver, ovaries, kidneys, thyroid, spleen, and melanin-containing tissues (uveal tract, whole eye, and pigmented skin).”

“The half-life was 30 days in dogs and 8.5 days in rats. In a tissue distribution study in rats, the highest levels of oteseconazole were observed in the small intestines and in the Harderian gland.”

“3-quinuclidinol distributed to all ocular tissues analyzed within 30 minutes of treatment. The rank order of the exposure was: cornea > iris > choroid > aqueous humor > sclera > retina > lens ≈ vitreous humor.”

“In rats, vonoprazan and its metabolites were widely distributed with higher concentration in the liver, kidney, intestine, lung, and stomach wall than in the plasma, and were low in the brain and the spinal cord.”

“Concentrations in the brain and spinal cord were low throughout with tissue/blood ratios of <0.1, indicating that test material-related radioactivity had not penetrated the blood-brain barrier.”

“Distribution: 100 mg/kg [14C]-WCK 5107, administered intravenously, distributed in the highest concentrations (> 200 to 4420 mcg equivalents/g tissue) to kidney (medulla and inner and outer cortex), plasma, and urinary bladder wall.”

“In a rat exploratory quantitative whole body autoradiography study following a single intravenous administration of 14C radiolabeled ceftobiprole medocaril sodium (20 mg/kg), quantifiable levels of radioactivity (>0.29 mcg-equiv/g) were detected in all tissues with a low overall distribution into most organs and tissues.”

“The brain to plasma ratio of zuranolone was 2.23 after IP injection (1 mg/kg) (SSN-868) in male mice and 3.22 (Study No. SSN-01237) after oral administration in male rats.”