Lynavoy
linerixibat
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“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.”
Why that species
ADME profile in rats and dogs consistent with humans
“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.”
Surrogate molecule
No surrogate; the clinical compound was tested
“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.”
Species: general tox
Rat (26-week) and dog (39-week); mouse up to 4 weeks
“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.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies using oral administration of linerixibat included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“Linerixibat was not tumorigenic in a 2-year oral carcinogenicity study in rats with oral administration of up to 1,000 mg/kg/day (approximately 3,900 times the recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice, no drug-related tumors were observed following administration of linerixibat up to 160 mg/kg/day.”
Surrogate used in
No surrogate used; linerixibat itself tested in mice, rats and dogs
“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.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“In dogs, 500 mg/kg/day (maximum tested dose) was tolerated for 39 weeks, although minimal body weight loss was observed during the first two weeks of the 39-week dog study.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“GI effects in the 26-week rat and 39-week dog oral toxicity studies were limited to mild, reversible, fecal alterations in both species and mucosal basophilia/hypertrophy (minimal to slight) in the large intestine in rats.”
Route in tox
Oral (gavage)
“Study Number/ Title: GSK2330672B: 13-Week Oral Gavage Toxicity Study in Rats Followed by 4-Week Off-Dose Period (Study R43264G)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosome aberration and in vivo rat micronucleus assays
“Linerixibat did not cause gene mutation or chromosomal damage in a bacterial mutagenicity assay (Ames test), a chromosomal aberration assay using Chinese hamster ovary cells, or an in vivo rat bone marrow micronucleus assay”
Carcinogenicity
2-year rat and 26-week rasH2 mouse: no drug-related tumors
“Linerixibat was not tumorigenic in a 2-year oral carcinogenicity study in rats with oral administration of up to 1,000 mg/kg/day (approximately 3,900 times the recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice, no drug-related tumors were observed following administration of linerixibat up to 160 mg/kg/day.”
Reproductive & developmental
Oral rat fertility, rat and rabbit EFD, and rat pre/postnatal development studies
“Reproductive and developmental toxicology studies using oral administration of linerixibat included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Safety pharmacology
No hERG inhibition up to the solubility limit (253.73 μM)
“Linerixibat, at concentrations up to the limit of solubility (253.73 μM, 138.71 μg/mL) did not inhibit human ether-a go-go-related gene (hERG) current recorded from human embryonic kidney cells (HEK293) expressing the hERG ion channel.”
Genotox: Ames
Negative
“Linerixibat did not cause gene mutation or chromosomal damage in a bacterial mutagenicity assay (Ames test), a chromosomal aberration assay using Chinese hamster ovary cells, or an in vivo rat bone marrow micronucleus assay”
Genotox: in vitro mammalian
Chromosomal aberration assay in CHO cells: negative
“Linerixibat did not cause gene mutation or chromosomal damage in a bacterial mutagenicity assay (Ames test), a chromosomal aberration assay using Chinese hamster ovary cells, or an in vivo rat bone marrow micronucleus assay”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Linerixibat did not cause gene mutation or chromosomal damage in a bacterial mutagenicity assay (Ames test), a chromosomal aberration assay using Chinese hamster ovary cells, or an in vivo rat bone marrow micronucleus assay”
Carcinogenicity model
2-year rat; 26-week Tg rasH2 mouse; no drug-related tumors
“Linerixibat was not tumorigenic in a 2-year oral carcinogenicity study in rats with oral administration of up to 1,000 mg/kg/day (approximately 3,900 times the recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice, no drug-related tumors were observed following administration of linerixibat up to 160 mg/kg/day.”
Carcinogenicity timing
2-year Wistar Han rat and transgenic rasH2 mouse studies completed in support of the marketing application
“A two-year carcinogenicity study in Wistar Han rats was conducted in support of the marketing authorization for linerixibat.”
hERG / QT
No hERG inhibition up to the solubility limit (253.73 μM)
“Linerixibat, at concentrations up to the limit of solubility (253.73 μM, 138.71 μg/mL) did not inhibit human ether-a go-go-related gene (hERG) current recorded from human embryonic kidney cells (HEK293) expressing the hERG ion channel.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Lynavoy don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Findings non-adverse; NOAELs were the highest doses: 1000 mg/kg/day (26-week rat), 500 mg/kg/day (39-week dog) (FDA integrated review, p. 96)
NOAEL / key findings
Findings non-adverse; NOAELs were the highest doses: 1000 mg/kg/day (26-week rat), 500 mg/kg/day (39-week dog)
“The findings in these studies were not considered adverse and the no observed adverse effect level (NOAEL) in the 26-week rat and 39-week dog studies were the highest doses administered (1000 and 500 mg/kg/day, respectively).”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Radiolabel studies: drug-related material almost exclusively confined to the GI tract after oral dosing
“Tissue distribution studies using radiolabeled linerixibat revealed that drug-related material was almost exclusively confined to the gastrointestinal tract following oral administration.”
Modality-specific risk
Gastrointestinal effects in rats and dogs; adrenal cortical hypertrophy in rats
“The principal toxicology findings associated with linerixibat administration were gastrointestinal effects (minimal to slight, reversible) in rats and dogs, and hypertrophy (minimal to mild) in the adrenal cortex in rats.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not applicable
“14.4. Immunogenicity Assessment—Impact of PK/PD, Efficacy, and Safety Not applicable.”
Label warnings
- Liver Test Elevations
- Diarrhea
- Fat-Soluble Vitamin Deficiency
HepatotoxicityGastrointestinalMetabolic & endocrine
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Lynavoy don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Findings non-adverse; NOAELs were the highest doses: 1000 mg/kg/day (26-week rat), 500 mg/kg/day (39-week dog) (FDA integrated review, p. 96)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral); recovery phase not stated
“In dogs, 500 mg/kg/day (maximum tested dose) was tolerated for 39 weeks, although minimal body weight loss was observed during the first two weeks of the 39-week dog study.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“GI effects in the 26-week rat and 39-week dog oral toxicity studies were limited to mild, reversible, fecal alterations in both species and mucosal basophilia/hypertrophy (minimal to slight) in the large intestine in rats.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies using oral administration of linerixibat included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Reproductive & developmental
Oral rat fertility, rat and rabbit EFD, and rat pre/postnatal development studies
“Reproductive and developmental toxicology studies using oral administration of linerixibat included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
PPND / ePPND: when
PPND in rat completed and reviewed before the marketing application
“In a pre- and postnatal development study in pregnant rats with maternal dosing (oral) performed during organogenesis through lactation, treatment with up to 1000 mg/kg/day (1138 times the anticipated human exposure at the recommended dose) produced a few clinical signs in the mothers with no adverse effects on the F1 offspring’s growth, sexual maturation, neurobehavioral functions, or reproductive performance.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“Linerixibat was not tumorigenic in a 2-year oral carcinogenicity study in rats with oral administration of up to 1,000 mg/kg/day (approximately 3,900 times the recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice, no drug-related tumors were observed following administration of linerixibat up to 160 mg/kg/day.”
Carcinogenicity model
2-year rat; 26-week Tg rasH2 mouse; no drug-related tumors
“Linerixibat was not tumorigenic in a 2-year oral carcinogenicity study in rats with oral administration of up to 1,000 mg/kg/day (approximately 3,900 times the recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice, no drug-related tumors were observed following administration of linerixibat up to 160 mg/kg/day.”
Carcinogenicity timing
2-year Wistar Han rat and transgenic rasH2 mouse studies completed in support of the marketing application
“A two-year carcinogenicity study in Wistar Han rats was conducted in support of the marketing authorization for linerixibat.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat and dog NOAEL AUC 140- to 145-fold above exposure in moderate hepatic impairment at 40 mg
“The exposure parameters (Cmax and AUC) in participants with moderate HI following a 40- mg dose were significantly lower than the exposures for the no observed adverse effect level dose in GLP toxicology studies (140- to 145-fold lower AUC and 1198- to 1226-fold lower Cmax gender-averaged exposure in GLP toxicology rat and dog studies, respectively).”
NOAEL / key findings
Findings non-adverse; NOAELs were the highest doses: 1000 mg/kg/day (26-week rat), 500 mg/kg/day (39-week dog)
“The findings in these studies were not considered adverse and the no observed adverse effect level (NOAEL) in the 26-week rat and 39-week dog studies were the highest doses administered (1000 and 500 mg/kg/day, respectively).”
Efficacy evidenceopen answer page →
Efficacy evidence
Fecal bile acid excretion in healthy mice and dogs; rat necrotizing enterocolitis model; no PBC model
“The Applicant therefore evaluated the ability of linerixibat to decrease serum bile acids and increase fecal excretion of bile acids (resulting from inhibition of enterohepatic recirculation) in healthy mice and dogs and in a rat model of necrotizing enterocolitis (NEC).”
Why that model
No established animal model of PBC
“PBC is a cholestatic liver disease for which animal models have not been established.”
Reviewer's view of the efficacy data
Mechanistic/pharmacodynamic evidence was not accepted as confirmatory evidence of effectiveness
“For this application, mechanistic/pharmacodynamic evidence does not constitute confirmatory evidence.”
Flexibilityopen answer page →
Flexibility accepted
Efficacy modelVerdict not stated
No PBC or cholestatic pruritus model; bile acid excretion in healthy mice and dogs and a rat NEC model instead
Why: No established animal model of PBC
“PBC is a cholestatic liver disease for which animal models have not been established. The Applicant therefore evaluated the ability of linerixibat to decrease serum bile acids and increase fecal excretion of bile acids (resulting from inhibition of enterohepatic recirculation) in healthy mice and dogs and in a rat model of necrotizing enterocolitis (NEC).”
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