Which animal species did regulators accept for approved small molecules?

“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.”

“Pivotal repeat-dose toxicity studies were conducted in rats (dermal), dogs (subcutaneous), and minipigs (dermal).”

“The dog is the most appropriate animal species for the major metabolites.”

“The parent compound was adequately tested in a standard battery of general toxicology studies in mouse and dog.”

“Mice were selected as pharmacologically responsive species and because of their similar metabolic profile to humans, whereas dogs were chosen due to the established experience with glucocorticoid effects in this species.”

“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.”

“Metabolism was comparable between animal species and humans.”

“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)”

“Comparison of human, mouse and rat T cells demonstrated a comparable inhibitory effect across all species, supporting the in vivo species selection.”

“Repeat dose oral toxicity 26-week rat and 39-week dog study reviews included below are from PharmTox review by Dr. Miyun Tsai-Turton, dated December 16, 2021, conducted under the IND.”

“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.”

“There were no histopathology findings consistent with kidney injury in chronic toxicology studies in two non-human species (Study 20141689, 26-week toxicity study in rats and Study 21141692, 39-week toxicity study in dogs)”

“Overall, there was no significant difference observed in PK profiles between animals and humans that would limit the interpretation of animal toxicology studies and the nonclinical species used were considered appropriate for the safety of acoramidis and its metabolites in human.”

“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.”

“Rats (Sprague-Dawley) and monkeys (cynomolgus) are considered relevant toxicological species based on 100% sequence homology for the target binding sites and similar metabolism.”

“The nonclinical development program for avutometinib and defactinib consisted of studies in mice, rats, dogs, and monkeys to evaluate the primary and safety pharmacology, pharmacokinetics, general toxicology, and genotoxicity.”

“The Applicant evaluated the toxicity of avapritinib in GLP-compliant repeated-dose toxicity studies in rats and dogs.”

“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.”

“In order to use the species with the highest SDX exposure compared to humans in the pivotal embryo-fetal development study and the 6-month juvenile animal study, a cross-species analysis was conducted, and the rabbit was determined to be the most appropriate species.”

“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.”

“amisulpride was administered IV to Charles River Wistar (Crl:WI(Han)) rats at doses of 0, 2, 5 and 10 mg/kg/day.”

“Based on extensive clinical experience with amisulpride, outside of the Unites States, at higher doses, the Division agreed that a 28-day repeat dose toxicity in a single species would be adequate for the proposed indication in which only a single dose will be administered.”

“A comprehensive toxicology program was conducted in both rats and cynomolgus monkeys.”

“The cynomolgus monkey renin-angiotensin system closely resembles the human system, making it a relevant species for assessing pharmacodynamic efficacy and toxicity.”

“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.”

“Mice and dogs were pharmacologically relevant species for toxicity evaluation, based on their high BCL2 sequence homology with humans, comparable metabolism profiles with humans in in vitro studies, and adequate bioavailability.”

“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.”

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

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

“repeat-dose toxicology studies conducted in the rat and dog for durations up to 26 weeks and 39 weeks, respectively”

“brensocatib is an effective reversible inhibitor of recombinant dipeptidyl peptidase 1 (DPP1) in humans, mice, rats, and dogs, and confirmed the subsequent inhibition of NSP activities (NE, PR3, CatG) in human samples obtained from subjects treated with clinically relevant doses. The in-vitro data also support the selected test species for safety studies with regard to pharmacologically relevance”

“Zanubrutinib was administered once daily to rats and dogs in studies up to 6 months in rats and 9 months in dogs.”

“Rats and dogs were chosen for the in vivo toxicity evaluation, as they are pharmacologically relevant species based on BTK sequence homology and functional assay.”

“In general, findings in the pivotal repeat-dose toxicity studies with the API in monkey and minipig were limited to expected pharmacology and local toxicity.”

“These two pivotal studies were selected for detailed review because the study investigated infusion dosing with the clinical formulation.”

“The nonclinical safety profile of odevixibat has been extensively explored in (1) single and repeated dose toxicity studies in rats (up to 6 months) and dogs (up to 9 months)”

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

“The test species were justified as the rodent and non-rodent species with the highest systemic exposure. All selected species are considered relevant from a metabolite perspective.”

“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.”

“Mavacamten is slightly more potent in the species used for general toxicological assessment, and comparable potencies were exhibited by the recombinant wild type human beta cardiac myosin and five HCM mutants.”

“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 Applicant was unable to identify an alternative nonclinical species with a similar metabolic profile to humans and, therefore, the rat and dog were used.”

“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.”

“Rats (rodent) and monkeys (nonrodent) were selected as appropriate animal species for toxicity testing because etripamil is rapidly metabolized to a primary inactive metabolite (MSP-2030) similarly in rats, monkeys, and humans.”

“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)”

“rats and monkeys were used for the general toxicology programme, as these species have previously been used in development programmes for other similar JAK inhibitors and they are sensitive to the pharmacological action of JAK inhibition.”

“The binding affinity and functional activity of xanomeline at the mAChR receptors were generally similar between human and animal species (rat and monkey), therefore, supporting the use of the rat and monkey as the nonclinical species for pharmacology and toxicology evaluation.”

“The binding affinity and functional activity of xanomeline at the mAChR receptors were generally similar between human and animal species (rat and monkey), therefore, supporting the use of the rat and monkey as the nonclinical species for pharmacology and toxicology evaluation.”

“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.”

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

“The metabolism of crinecerfont was similar among species, with no unique or disproportionate human metabolites (Figure 29).”

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

“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 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.”

“A single dose intraperitoneal study conducted with Defencath in mice and a 14-day repeat-dose intravenous study conducted in rats (discussed in additional detail below) did not reveal signs of toxicity.”

“However, the medical reviewers found that previous clinical experience with taurolidine (particularly as a component of CLS) was adequate to support the clinical development of Defencath and the toxicology reviewer deferred to their judgement.”

“A 9-month repeat dose oral toxicity study in juvenile minipigs was submitted in support of the safety of long-term administration of triheptanoin in adult and pediatric patients. In addition, a published 9-month dietary toxicity study of triheptanoin in rats was submitted in support of the safety in rodents.”

“The toxicity of givinostat was investigated after single and repeated i.v. and oral administration for up to 13 weeks in mice, 26 weeks in rats 4 weeks in dogs and 39 weeks in monkeys.”

“Mice and rats were chosen as pharmacologically responsive rodent species, whereas monkeys were selected due to the limited gastrointestinal tolerability of givinostat in the 4 weeks repeat-dose toxicity study in dogs.”

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

“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).”

“Pharmacology studies sufficiently justified the choice of species for toxicology investigations. The monkey, mouse and rat turned out to be the most relevant species (IC50 of 5.07 nM, 13.9 nM and 69.8 nM respectively).”

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

“Because dog microsomes shared greater metabolic similarities with human microsomes (major metabolites, rate of metabolism, and relative abundance), they were selected by the Applicant as the non-rodent toxicologic species.”

“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.”

“The choice of the animal species was justified based on secondary mRNA splice targets and on metabolism. The SMN2 gene is human-specific.”

“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 metabolic profiles of enmetazobactam in rats, dogs, rabbits and humans were similar which supports the selection of these animal species as the primary toxicology species.”

“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.”

“Repeated-dose toxicology studies of adequate duration and at MTDs were performed in rats and dogs.”

“In humans, 2 major metabolites of gepirone have been identified: 1-PP (which is also a metabolite of buspirone, currently approved and marketed as an anxiolytic) and 3’-OH-gepirone. Both of these metabolites have been identified and found to be present in substantial amounts (many times the levels of gepirone) in plasma of the 2 major species used in the preclinical studies, namely rats and dogs, following gepirone administration.”

“The safety of iptacopan was evaluated in a comprehensive nonclinical program consisting of good laboratory practice compliant toxicology studies in rats and dogs (most sensitive species), a short study in monkeys, reproductive toxicology studies in rats and rabbits, and carcinogenicity assessments in rats and transgenic mice.”

“The safety of iptacopan was evaluated in a comprehensive nonclinical program consisting of good laboratory practice compliant toxicology studies in rats and dogs (most sensitive species), a short study in monkeys, reproductive toxicology studies in rats and rabbits, and carcinogenicity assessments in rats and transgenic mice.”

“The clinical formulation of cefiderocol, was tested in the repeat-dose toxicology studies described below. Rats and monkeys were the primary rodent and nonrodent species used in toxicology testing of this drug product.”

“In the response, the Applicant explained that in exploratory single-dose studies in dog, vomiting was observed several times from during dosing to 1 hour after the end of dosing at 1000 mg/kg, reason for which the Applicant considered that dogs would not tolerate repeat-dosing at the 1000 mg/kg dose level.”

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

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

“As sequence similarity of monkey ETAR and AT1R to human ETAR and AT1R is relatively high, anticipated pharmacology is observed in the monkey safety pharmacology and repeat dose toxicity studies, and considering that pharmacological activity, metabolic profile, and toxicological findings in monkeys are consistent with observations in the rat”

“The selection of animal models to be used in toxicology and safety pharmacology studies (rats and monkeys) was based on PK and/or metabolic profiles of tivozanib.”

“Comparison of the metabolic profile of tivozanib in liver microsomes showed that monkey most closely resembled the human, followed by the rat. These data provided support for species selection.”

“Toxicology studies of orforglipron were conducted in Wistar rats and cynomolgus monkeys.”

“Wistar rats were selected as the most suitable rodent species; however, rats represent an off-target model of toxicology. Cynomolgus monkeys were selected as the nonrodent species because they are a pharmacologically relevant species.”

“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 species comparison suggests that metabolites in dog represent mostly the metabolites in human but that the rat also has same metabolites present, although in a different ratio.”

“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 dog was also investigated as a non-rodent species, but due to species specific toxicities, related to p38 MAPK inhibition, and exacerbated toxicities following this inhibition, the dog was not suitable for further toxicity studies beyond single dose or 7 days repeat-dose studies.”

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

“The choice of toxicology species rats and monkeys was based on that the metabolic profile of these species is similar to that of human.”

“Exploratory studies were conducted in mice, rats, dogs, and monkeys, while definitive toxicity studies were conducted in rats and dogs.”

“The rat and dog were selected as the general toxicology species based on mirdametinib’s PK and metabolism properties compared across species.”

“Following repeated administration of treosulfan to rats, dogs or monkeys, the targets of toxicity were the haematopoietic and the lymphatic systems.”

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

“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.”

“Rats and cynomolgus monkeys were used in the toxicology program; both species are considered to be pharmacologically active and have a metabolism of sevabertinib comparable to that of humans. Dogs could not be used because of insufficient exposure due to enzyme induction after repeated dosing.”

“Repeated dose toxicology studies of up to 6 months and 9 months were conducted in rats and dogs, respectively.”

“SLC9A3 (NHE3) expression was observed along the entire intestinal tract in the rat, dog, and human. NHE3 expression levels were similar across all three species throughout the intestine with a few segment specific differences noted.”

“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.”

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

“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.”

“Overall, it can be concluded that rats and monkeys are suitable non-clinical species for the safety assessment of imlunestrant. The pharmaco-and toxicokinetics are similar enough to human pharmacokinetics to be representative.”

“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”

“Repeat-dose toxicity studies were performed in rats and dogs. Carcinogenicity evaluation was performed in mice and rats. Embryofetal development studies were performed in rats and rabbits. All species are pharmacologically relevant.”

“In the general toxicology studies, cedazuridine (mice and cynomolgus monkeys) and decitabine (rats) were administered orally once daily for 5 to 7 days in 28-day cycles, similar to the clinical regimen.”

“A literature assessment submitted by the Applicant concluded that humans, mice, and cynomolgus monkeys have similar CDA tissue distribution and activity profiles, and CDA activity was notably absent in rats.”

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

“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)”

“The reports indeed state that dogs are more sensitive to PPAR toxic effects than other species, and that it is recommended to conduct the general toxicity testing for this type of substances in rats and monkeys.”

“In repeated-dose toxicity studies osilodrostat was tested in mice for up to 13 weeks at 10 to 200 mg/kg/day, in rats for up to 26 weeks at 0.2 to 50 mg/kg/day and in dogs for up to 39 weeks at 0.1 to 10 mg/kg/day.”

“Pharmacokinetic and metabolic profiles were qualitatively similar between humans and nonclinical species used for evaluating the potential toxicity or osilodrostat thereby supporting the translatability of the findings from these studies.”

“Inavolisib was evaluated in GLP-compliant, repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs following once daily oral administration, consistent with the clinical route of administration and intended dosing schedule, for up to 3 months in duration.”

“The rat and dog were selected as the toxicology species based on high protein homology of the target, the demonstration of in vivo pharmacodynamics, adequate in vivo exposure, and comparable in vivo metabolic profile to humans.”

“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).”

“The nonclinical species used in toxicology assessment of nerandomilast are considered pharmacologically relevant for various reasons including data demonstrating similar IC50 values for human and minipig for nerandomilast.”

“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.”

“General toxicology studies of 4- and 13-weeks duration were conducted in Sprague Dawley rats and Beagle Dogs with rats receiving daily oral doses by gavage and dogs by capsule. A 13-week toxicity study was also conducted in the cynomolgus monkey with daily dosing by oral gavage.”

“The 3 major circulating human metabolites (M2, M3, and M13) were present in rabbit and monkey plasma with an animal:human AUC ratio of at least 1X in monkeys (comparing the 50 mg/kg MTD dose in the 39-week toxicity study and human exposure at the 48 mg three times a week (TIW) human dose).”

“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 Wistar-Han rat and beagle dog were selected as appropriate species for toxicity based on having metabolite profiles similar to human (inclusive of the main des-ethyl metabolite in patients designated M9) and ability to achieve adequate systemic exposure.”

“The Applicant has conducted subchronic and chronic toxicology studies with leniolisib in both rats and cynomolgus monkeys.”

“Characterization and structural elucidation of metabolites in plasma, urine or bile from nonclinical species have demonstrated the similarities in the metabolic profiles between these species and humans. It is noted that no major human metabolites were identified in completed clinical studies.”

“The following studies were submitted: primary and secondary pharmacology, safety pharmacology in the monkey in addition to in vitro human ether-à-go-go-related gene (hERG) assays; absorption, distribution, metabolism, excretion (ADME) and pharmacokinetic (PK) studies; repeat-dose toxicology studies in the rat and monkey for durations of 28 days and 13 weeks”

“Based on similarities in potency against NaV1.8 and metabolic profile between monkeys and humans, monkeys were considered an appropriate species for use in the pivotal nonclinical safety studies.”

“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.”

“Both species are considered pharmacologically relevant based on appropriate binding data and formation of metabolites.”

“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.”

“This study involves exposure to the to-be-marketed formulation once daily for five days via the clinical route of exposure, utilizing the best available nonclinical model for topical application to skin.”

“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.”

“In vitro metabolism in liver microsomes from the toxicological test species, mouse and dog, and humans was similar and there were no unique human metabolites.”

“The Applicant evaluated the toxicity profile of selumetinib in rats, mice, and monkeys in GLP-compliant studies with durations of up to 3 months (rats) and 26 weeks (mice and monkeys).”

“The Applicant chose the mouse as the rodent species for the long-term toxicology and developmental studies due to detectable levels of the active N-desmethyl metabolite in this species that allowed for toxicological coverage;”

“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 rat and dog were selected as preclinical species for toxicology studies based on results from in vitro and in vivo metabolism studies, which is supported.”

“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 studies, conducted in alignment with ICH guidelines, utilized mouse, rat, rabbit, and dog models, leveraging shared mitochondrial TK2 nucleoside phosphorylation and cytosolic nucleoside pathways, as well as conserved mitochondrial genomes and incorporation pathways analogous to those in humans.”

“repeated-dose toxicology studies in rats (28-day and 13-week studies) and dogs (28-day and 52-week studies)”

“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.”

“Overall, the PK profile in rats and dogs appears to be well described, and comparisons with human PK data supported the rat and dog as relevant non-clinical species for testing toxicity.”

“Pivotal repeat-dose toxicity studies were conducted in rats and dogs.”

“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”

“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.”

“The selection of multiple species for the non-clinical programme was justified by the sensitivity differences towards PPARs between species.”

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

“Maralixibat has to be characterised as a substance of very low bioavailability, with a local mode of action. Overall, the study programme appears to be appropriate and complete, justifying from pharmacokinetic point of view the species involved in toxicity testing.”

“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”

“Mice, rats and monkeys were chosen for single and repeat-dose toxicity studies because the main human metabolite of maribavir, VP 44469 was present in all of them and these species are common species for toxicity testing.”

“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 human metabolites formed in vitro were also produced in the rat and dog in vitro (liver microsomes/hepatocytes).”

“The rat and monkey were determined to be the most appropriate toxicological species, given the emetic effect observed in dogs.”

“agrees based on the higher systemic exposure (and consequently, higher sensitivity) observed in the rat and the more similar metabolic profile of the monkey compared to humans. The reviewer agrees the emetic effect in the dog would lead to drug exposure inconsistencies and problems with data interpretation.”

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

“The overall pharmacokinetic profile of SAM in dogs is more closely related to humans than rats, including lack of sex difference in metabolism.”

“Linerixibat has been evaluated in oral repeat-dose general toxicity studies of up to 4, 26, and 39 weeks in mice, rats, and dogs, respectively.”

“The consistent absorption, distribution, metabolism, and excretion profile across rats, dogs, and humans supports the use of these nonclinical species for toxicological evaluation and provides confidence in the safety assessment for human use.”

“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.”

“SD rats and Cynomolgus monkeys were selected as species for the investigation of systemic toxicological effects based on pharmacological responsiveness (potency, sequence homology, and pharmacologic effects on the NK receptors) as well as based on the pharmacokinetic and metabolic profile.”

“The Applicant conducted general toxicology studies in rats and dogs.”

“A similar metabolism was seen in rat, dog and human, such as O-demethylation, mono- or di-oxidation, hydration, and Phase II (cysteine or N-acetylcysteine conjugation) conversion.”

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

“These species are pharmacologically relevant for the assessment of the safety of siponimod.”

“based upon the 28-day ocular toxicity study in rabbits (# AB21563), 7-day oral toxicity study in rats (# AB21526)”

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

“in both rodents (Sprague-Dawley rats) and nonrodents (Beagle dogs) (Studies ONC201-TX-100, ONC201-TX-101; m4.2.3.2). This program was consistent with ICH S9, the guideline for nonclinical evaluation for anticancer pharmaceuticals (ICH 2010).”

“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.”

“Both species are considered pharmacologically relevant given the high conservation of the cardiac myosin motor between species and based on in vitro and single-dose in vivo pharmacology studies.”

“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).”

“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”

“From the pharmacokinetic point of view, the rats and monkeys were the most relevant species for non-clinical efficacy and safety studies.”

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

“In human studies, MI was the primary metabolite and no novel metabolites were identified when compared to the rat and dog data.”

“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.”

“In terms of pharmacokinetics, the qualitative metabolite profiles of darolutamide in rats as well as the overall biotransformation pathways seem to be quite comparable to the profiles obtained in human plasma. However, the metabolite profiles of darolutamide between dogs and human are different.”

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

“The MoCo-synthesis is considered highly conserved between species, and cPMP is considered identical between species. Thus, rat and dog are considered relevant species for toxicity studies.”

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

“Comparing activity across species, rimegepant exhibits similar receptor affinities at both human (Ki of 33 pM) and nonhuman primate (marmoset (92 pM) and cynomolgus monkey (60 pM)) CGRP receptors, with more than 1,300-fold less activity at dog (43 nM), rat (209 nM) and mouse (104 nM) CGRP receptors as compared to human.”

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

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

“The rat and dog were selected as the toxicology species based on nirogacestat PK and metabolism properties compared across species.”

“The Applicant has conducted subchronic and chronic toxicology studies with ensifentrine in both rats and dogs.”

“Sprague Dawley rats and cynomolgus monkeys were used as relevant species based on comparison of metabolite profiles generated by isolated hepatocytes from mice, rats, dogs, rabbits, cynomolgus monkeys, and humans.”

“Sprague Dawley rats and cynomolgus monkeys were used as relevant species based on comparison of metabolite profiles generated by isolated hepatocytes from mice, rats, dogs, rabbits, cynomolgus monkeys, and humans.”

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

“Rats and dogs were considered pharmacologically relevant nonclinical species based on similar sensitivity to momelotinib compared to humans.”

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

“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.”

“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 cynomolgus monkey was selected as the non-rodent species because of the high sequence homology with the human GnRH receptor (97.5% compared to 92.1% in dog) and the similar affinity and potency at the GnRH receptor relative to dogs.”

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

“monkey and rat plasma with mean EC50s of 5.4, 5.2, and 7.2 nM (Study BR-7353-005-REV-01), supporting the suitability of monkey and rat as the non-clinical species used for toxicology 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.”

“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”

“The Applicant provided a justification for the use of non-human primates as non-rodent species, indicating that morphological and hormonal changes in the reproductive system and menstrual cycle phases of monkeys closely resemble those of humans.”

“Single-dose and repeat-dose general toxicity studies were performed in Sprague-Dawley rats (up to 26-weeks duration) and in cynomolgus monkeys (up to 39-weeks duration). In rats, the primary target organs of toxicity included incisors, kidneys, and liver.”

“Major findings associated with repeat-dose administration of voxelotor in mice, rats and Cynomolgus monkeys were changes in hematopoietic parameters and gastrointestinal (GI) intolerance that was attributed to local irritation.”

“The exposure in dogs in the 4-week study at the highest tolerated dose was not sufficiently high to cause decreased tissue O2 extraction and dogs did not have erythroid or bone marrow changes, therefore dogs were not further considered as test species.”

“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 rat and dog were selected as the species for non-clinical toxicity studies based on similarity in the metabolic profiles compared to humans. Both species are also pharmacologically relevant.”

“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.”

“The species used for the GLP compliant pivotal studies included rats and monkeys based on similar PK profile seen in these species compared to human. Furthermore, the pharmacological target of PF-07321332 is an exogenous entity (virus-specific protein) and therefore there are no pharmacologically relevant species.”

“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.”

“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 pharmacodynamic target and the major pathways of alpelisib metabolism in humans were all represented in these species.”

“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 pivotal nonclinical studies were conducted in CD-1 mouse, Wistar rat, beagle dog, and New Zealand White rabbit.”

“In in vitro PD studies ACT-128800 was found to have a 5-fold reduced potency on rat S1P3 receptor as compared to the human counterpart. Nevertheless, the rat is considered a relevant species for the evaluation of the safety of ACT-128800.”

“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.”

“Rats and monkeys were chosen as target species for the toxicology studies. These species showed extensive metabolism and it has been shown that all human circulating extractable metabolites detected following a single oral dose of pretomanid were formed in the relevant toxicological animal species”

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

“The dogs were a hypersensitive species, thus the applicant has preferred the use of rat and monkeys only for the repeat dose toxicity studies.”

“There are substantial species differences in the metabolism of viloxazine between the nonclinical species (rats and dogs) and humans.”

“It should be noted that despite the differences in the metabolic profiles, the exposure level to both the parent drug and its major human metabolite (glucuronidated-5-hydroxy-viloxazine) are adequately represented and characterized in rat”

“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.”

“The justification for the relevance of these test species includes: in vitro studies of metabolic stability and metabolite identification comparing mouse, rat, dog, monkey, and human, where rat and/or dog were demonstrated to form the same metabolites as humans.”

“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.”

“The ADME data submitted for rat and rhesus monkey provide supporting evidence for the use of these species in the atogepant toxicity studies.”

“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”

“Species selection was based on pharmacologically relevant binding to Orexin receptors in humans and in these non-clinical species with high selectivity and potency, metabolically relevant pathways in these species are similar to those in humans, as well as close plasma protein binding properties for some species only.”

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

“Landiolol is metabolized in all species by hydrolysis of the ester moiety that produces M-1, which undergoes β-oxidation to the M-2 metabolite.”

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

“Mice and cynomolgus monkeys were considered the relevant test species for in vivo toxicology studies based on cross-species PK exposures, metabolic profiles, similar (mouse) or identical (monkey) binding affinity to human cyclophilin A (CypA), and identical cross-species KRAS protein sequence in the guanosine 5' triphosphatase (GTPase) domain to which daraxonrasib binds.”

“In 1- and 3-month repeated-dose toxicology studies, relebactam produced only limited toxicity. Two dose-dependent toxicities with clinical relevance were CNS toxicity primarily in rats and minimal kidney toxicity primarily in monkeys.”

“The selection was based on the in vitro and in vivo metabolic profiles and the demonstration of satisfactory pharmacokinetics in these species. The monkey had previously been used as the non-rodent species for the assessment of toxicological profile of imipenem/cilastatin including the evaluation of renal toxicity caused by imipenem.”

“The pivotal (GLP-compliant) oral toxicity studies were conducted in Sprague Dawley rat and minipig (Gottingen, Hanford).”

“An additional study was initiated in beagle dog but was discontinued due to emesis, retching, tremors, loose feces, and increases in respiratory rate at all doses, including the low dose of 62.5 mg/kg PB/20.83 mg/kg TUDCA.”

“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.”

“Rats (Sprague-Dawley) and minipig (Göttingen) were chosen as relevant rodent and non-rodent species for toxicology program based on pharmacokinetic and metabolic considerations.”

“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 use of the rat and dog as the rodent and non-rodent species for the pivotal repeat-dose toxicity studies of revumenib is supported by the in vitro metabolism and nonclinical PK data observed.”

“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).”

“In humans, the major circulating metabolites are M8 and[S,R]-M18, which account for 47.5 and 10.5% of drug-related material in circulation. Both metabolites were produced in mouse, rat, rabbit, and dog.”

“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)”

“since the bioavailability in monkey was determined to be approximately 3%, it was not selected as a suitable”

“Repeat-dose studies in rats and monkeys were conducted to assess the general toxicology of olutasidenib.”

“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.”

“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.”

“Cynomolgus monkeys were chosen as the nonrodent toxicology species due to similar in vitro metabolic stability and protein binding characteristics to humans and because monkeys have been shown to be predictive for echinocandin-induced toxicity in humans.”

“As listed in the table below, general toxicity studies with remibrutinib were conducted in rats for up to 26 weeks and in dogs for up to 39 weeks.”

“The toxicological assessment was performed in pharmacologically relevant species (mouse, rat, rabbit and dog) that were sufficiently exposed to remibrutinib following the intended clinical route of administration (i.e. oral).”

“General toxicology studies were conducted via the oral route of administration in rats and dogs.”

“The selection was based on the systemic exposure in rats and dogs which was much higher than in other investigated species. As discussed in the pharmacokinetics section, these species were shown to have similar elimination pathways and metabolic profiles of upadacitinib as in humans”

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

“Rats, rabbits, dogs, and mice were selected as relevant species in the toxicology studies based on high protein homology (up to 96%) of the pharmacologic target of vimseltinib.”

“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.”

“Sequence comparisons showed 100% or near 100% sequence homologies in the entrectinib binding site, building confidence on the theoretical validity of the selected species used for the safety validation.”

“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)”

“Both the rat and dog formed BMS-646915 and BMS-930644 at adequate exposure levels (greater than human exposure).”

“The safety of asciminib was assessed in general toxicology (dogs, rats and monkeys up to 4, 26 and 39 weeks, respectively), genotoxicity (in vitro and in rats), and reproductive and developmental toxicology (rats and rabbits) studies.”

“Because there is a very high overall protein sequence conservation of ABL1 and ABL2 kinase domains across human and toxicology relevant species (mouse, rat, rabbit, dog, minipig, cynomolgus and rhesus monkeys)”

“repeated dose toxicity studies in rats (up to 6 months) and marmosets (up to 9 months)”

“Rats and marmoset monkeys were selected as the primary species for toxicology studies based on similarities in their PK and metabolic profiles to humans.”

“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.”

“GLP-compliant general oral (gavage) toxicity studies of omaveloxolone were conducted in Sprague Dawley rat and cynomolgus monkey, with durations up to 26 and 39 weeks, respectively.”

“Monkeys were chosen as the non-rodent non-clinical species in the omaveloxolone testing programme as dogs have previously been shown to develop species-specific gastrointestinal toxicity following repeated dosing with the chemically related substance, bardoxolone methyl.”

“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.”

“The in vivo metabolite profiles were similar in rats and dogs. No metabolites unique to humans were identified.”

“Deucravacitinib was evaluated in two pivotal repeat-dose general toxicity studies, one in rats and the other in monkeys.”

“All metabolites present in humans were present in at least 1 of the nonclinical safety species, with every human metabolite being detected in rats, and there were no unique human metabolites.”

“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 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 in vivo metabolism profiles of solriamfetol are similar between dogs and humans, for which limited hepatic metabolism is observed and the majority of the drug is excreted unchanged in the urine.”

“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.”

“The rat and monkey were selected as the rodent and non-rodent species, respectively, for repeat-dose toxicity testing because both have historically been used in safety evaluations, and both species have a highly conserved MET receptor target protein sequence.”

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

“The hamster and monkey were pharmacologically relevant species and could assess both potential on-target and off-target toxicity. However, the rat was not a pharmacologically relevant and could only assess potential off-target toxicity.”

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

“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.”

“The rat was the pivotal rodent species in repeat dose toxicity studies with elexacaftor alone or in combination with tezacaftor or ivacaftor. The dog was the pivotal non-rodent species.”

“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.”

“Toxicology studies in rat and dogs assessed the toxicity of infigratinib after once daily oral administration up to 26 weeks in rats and 39 weeks in dog (high dose of 3 mg/kg/day in both species).”

“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).”

“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.”

“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.”

“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 pharmacological relevance of the toxicological species was discussed by the applicant and taking sequence homology information as well as a justification based on historical use (rat) and higher oral tolerability (monkey) into account, the chosen species were considered acceptable.”

“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.”

“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.”

“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).”

“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”

“A dose-related erythropoietic response was observed in mice, rats, and dogs, showing that the appropriate pharmacological response occurs in the toxicological species used.”

“Repeat-dose toxicology studies were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys given quizartinib dihydrochloride for up to 13 weeks.”

“Based on pharmacokinetic (PK) and toxicology data, the cynomolgus monkey was selected as a potential alternate nonrodent model for evaluating the toxicity profile of quizartinib to predict human safety risk.”

“Pivotal chronic toxicology studies were conducted in rats for up to 6 months and dogs for up to 9 months.”

“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.”

“Pharmacokinetic studies supported the selection of the rat and monkey for the assessment of RDV toxicology. Both rat and monkey formed the intermediate metabolite GS-704277 and the nucleoside metabolite GS-441524.”

“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.”

“The overview shows that rats were exposed sufficiently to the metabolites M3 and M6 during toxicity testing.”

“Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys.”

“Cynomolgus monkey was selected as the relevant nonrodent species as nonhuman primates are anatomically and functionally similar to humans in the reproductive system, which is known to be affected by LH change. In addition, according to the in vitro radioligand assay, fezolinetant has a similar affinity for the human and cynomolgus monkey NK3 receptor orthologs.”

“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.”

“From the pharmacokinetic point of view, mouse, rat and dog were the most relevant species for non-clinical efficacy and safety studies.”

“In rats and dogs, oteseconazole exposure was less dose proportional and the drug accumulated up to 126-fold in dogs with repeated dosing over 39 weeks.”

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

“Mice and dogs were considered the most relevant nonclinical species for toxicological evaluations based on the similarity of their pacritinib metabolic profile to humans and the sufficient bioavailability observed in these nonclinical species.”

“Mice and dogs were considered the most relevant nonclinical species for toxicological evaluations based on the similarity of their pacritinib metabolic profile to humans and the sufficient bioavailability observed in these nonclinical species.”

“In repeated dose toxicology studies in rats and dogs, the stomach, liver, thyroid, and adrenal glands were identified as target organs of toxicity following oral administration of vonoprazan.”

“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.”

“Rat and cynomolgus monkey were selected as standard species and due to their metabolite profiles to assess the safety profile of vorasidenib.”

“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)”

“The dog was selected as the nonrodent nonclinical safety species (repeat-dose toxicology), and the off-target activity/toxicity of danicopan was assessed in rats.”

“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.”

“These findings add relevance to the rat, rabbit and dog toxicology studies as they can be expected to exhibit a similar pharmacologic response to tafamidis as in humans.”

“Single and Repeat dose toxicity studies were conducted in mice, rats, and monkeys up to 1-month, 6-month and 9-month in duration, respectively.”

“From the comparison of metabolites formed in vivo in Cynomolgus monkeys and in humans, the applicant did conclude that Cynomolgus monkeys could be used as the non-rodent species for toxicity studies.”

“the rat and dog were considered appropriate primary models for nonclinical safety studies, based on the similarity of oral bioavailability and metabolite profiles in these species to”

“This is because mouse, rat, dog, and rabbit BTK are nearly identical to the human version of the protein (approximately 99% homologous amino acid sequence), with no differences in the sites where rilzabrutinib binds.”

“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.”

“It can be concluded that especially dogs and to a lesser extent rats exhibit a similar pharmacokinetic profile of belzutifan compared to humans and are therefore appropriate for toxicological assessment of belzutifan.”

“Regarding clascoterone, the GLP pivotal repeat-doses toxicity studies were performed in two species, in rats and minipigs.”

“Pivotal nonclinical studies were conducted in rats, mice and dogs.”

“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,”

“Monkey had a similar metabolic profile as the human profile.”

“The nonclinical safety of Lotilaner and Lotilaner Ophthalmic Solution, 0.25% were evaluated in the rabbit, rat and dog which were considered appropriate.”

“The sponsor has conducted single-dose toxicity studies in rats and repeat-dose toxicity studies in rats and minipigs.”

“These data support the use of the minipig and rat as suitable nonclinical animal models in which to assess the potential toxicity of abametapir.”

“Lefamulin was evaluated in 4-week oral toxicology studies in rats and cynomolgus monkeys.”

“The major human lefamulin metabolite, BC-8041 (2R-hydroxy-lefamulin), is present in rat and monkey, the species used in the pivotal toxicology studies.”

“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.”

“Both rats and dogs were considered pharmacologically relevant species for conducting toxicology assessments of mavorixafor based on the observation of the desired pharmacology and similar metabolite profiles compared to humans.”

“Both rats and dogs were considered pharmacologically relevant species for conducting toxicology assessments of mavorixafor based on the observation of the desired pharmacology and similar metabolite profiles compared to humans.”

“Rats were chosen as the rodent species and cynomolgus monkeys as the non-rodent species.”

“Based on available data, both species were determined to be pharmacologically relevant for toxicology studies.”

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

“similar binding affinity was observed to the CGRP receptors in cynomolgus (IC50 = 0.06 nM) and marmoset (IC50 = 0.13 nM) monkeys. In vitro binding affinity was substantially lower to the CGRP receptors in the other animal species tested (IC50 values of 500, 600, 8,700, 25,000, and 140,000 nM for beagle dog, guinea pig, rabbit, rat, and mouse, respectively).”

“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.”

“In addition, in the 28-day, 3- and 6- or 9-month repeat dose toxicity studies, there were no iberdomide-related electrocardiographic findings or CNS-related clinical observations in monkeys up to 1 mg/kg or CNS-related clinical observations in rats up to 50 mg/kg.”

“All metabolites formed in human hepatocytes were also formed in rat or monkey, the 2 animal species used for nonclinical safety testing.”

“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.”

“Ozanimod was pharmacologically active in the nonclinical species (rat, monkey, rabbit, mouse) used to conduct the pivotal toxicology studies.”

“The Sprague Dawley rat, Beagle dog and Cynomolgus monkey were the main species used for toxicological assessment of lurbinectedin.”

“Despite using dogs in the initial 4-week toxicology studies, the Applicant utilized the monkey in the 13-week non-rodent toxicology study due to metabolic data suggesting that monkey metabolism was more similar to human than other tested non-rodent species.”

“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.”

“The Sprague Dawley rat and cynomolgus monkey were selected as the main rodent and non-rodent species in the general toxicity studies.”

“The lack of in vitro potency comparison between species was justified by referring to data showing that the amino acid sequence was highly conserved between humans and the relevant nonclinical species rat, mouse, rabbit and monkey.”

“general toxicology (up to 6 and 12 months in rat and dog), reproductive and developmental toxicology”

“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.”

“The toxicologic and toxicokinetic (TK) profile of orally administered zuranolone was assessed in a series of single and repeat dose studies in rats and dogs for up to 6 and 9 months, respectively.”

“All human metabolites detected at greater than 1% of drug, were also detected in rat or dog plasma.”

“A 13-week juvenile animal study in rats was conducted to evaluate the safety of CuHis and support administration of the product in a pediatric population.”

“A 13-week juvenile animal study in rats was conducted to evaluate the safety of CuHis and support administration of the product in a pediatric population.”