Idvynso
doravirine and islatravir
Sources:FDA multi-discipline review ↗
Species
MonkeyRatMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and rhesus monkey (islatravir), plus mouse up to 3 months
“repeat-dose toxicology studies in mice, rats, and monkeys for durations up to 3, 6, and 9 months, respectively”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound (islatravir) was tested
“repeat-dose toxicology studies in mice, rats, and monkeys for durations up to 3, 6, and 9 months, respectively”
Species: general tox
Islatravir: mouse, rat and monkey (up to 3, 6 and 9 months)
“repeat-dose toxicology studies in mice, rats, and monkeys for durations up to 3, 6, and 9 months, respectively;”
Species: DART
Islatravir: rat and rabbit (complete reproductive toxicology battery)
“a complete battery of reproductive toxicology studies in rats and rabbits;”
Species: carcinogenicity
Islatravir: rat (2-year) and rasH2 transgenic mouse (6-month)
“2-year rat and 6-month rasH2 transgenic mouse carcinogenicity studies;”
Surrogate used in
No surrogate used; islatravir tested directly
“The nonclinical safety profile of ISL was characterized through a comprehensive program that included in vitro assays and in vivo studies in mice, rats, guinea pigs, rabbits, and rhesus monkeys.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“repeat-dose toxicology studies in mice, rats, and monkeys for durations up to 3, 6, and 9 months, respectively”
Pivotal GLP studies
6-month rat and 9-month monkey islatravir studies; 3-month mouse
“repeat-dose toxicology studies in mice, rats, and monkeys for durations up to 3, 6, and 9 months, respectively”
Route in tox
Oral gavage (monkeys every 3 days)
“Dose and frequency of dosing: 0, 5, 20, and 100 mg/kg, every 3 days Route of administration: Oral gavage”
Skipped studiesopen answer page →
Genotoxicity
Islatravir: in vitro CHO chromosomal aberrations (mitigated by inosine); negative Ames and in vivo rat micronucleus
“While ISL induced chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, this effect was mitigated by the addition of inosine, suggesting it may be related to a perturbation of nucleoside/nucleotide pools rather than direct DNA interaction. Negative results in both a bacterial reverse mutation (Ames) test and an in vivo rat micronucleus assay support this interpretation.”
Carcinogenicity
Islatravir: 2-year rat and 26-week rasH2 mouse: not carcinogenic
“Consistent with this profile, ISL was non-carcinogenic in a 2-year study in rats and in a 26-week study in rasH2 transgenic mice.”
Reproductive & developmental
No fertility effects in rats (~1000x); rat skeletal malformations only at ~5100x, developmental NOEL ~500x
“ISL had no effect on the fertility of male or female rats at exposures ~1000 times the human exposure at the RHD. In rats, skeletal malformations were noted only at very high exposures (~5100 times the exposure at the RHD), with a developmental no-observed-effect level (NOEL) established at exposures ~500 times the human exposure at the RHD.”
Safety pharmacology
Transient heart rate and blood pressure increases in rats and monkeys at >1,000-fold clinical Cmax; no QTc prolongation
“While high doses produced transient increases in heart rate (HR) and blood pressure (BP) in rats and monkeys, no QTc prolongation was observed, and effects occurred only at exposures (Cmax) >1,000-fold the clinical exposure at the RHD.”
Genotox: Ames
Islatravir: negative
“Negative results in both a bacterial reverse mutation (Ames) test and an in vivo rat micronucleus assay support this interpretation.”
Genotox: in vitro mammalian
Islatravir: CHO chromosomal aberration positive, mitigated by inosine (nucleotide pool perturbation)
“While ISL induced chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, this effect was mitigated by the addition of inosine, suggesting it may be related to a perturbation of nucleoside/nucleotide pools rather than direct DNA interaction.”
Genotox: in vivo
Islatravir: rat micronucleus negative
“Negative results in both a bacterial reverse mutation (Ames) test and an in vivo rat micronucleus assay support this interpretation.”
Carcinogenicity model
Islatravir: 2-year rat and 26-week rasH2 mouse; not carcinogenic
“Consistent with this profile, ISL was non-carcinogenic in a 2-year study in rats and in a 26-week study in rasH2 transgenic mice.”
Carcinogenicity timing
Islatravir 2-year rat and 26-week rasH2 mouse studies completed before the marketing application
“Consistent with this profile, ISL was non-carcinogenic in a 2-year study in rats and in a 26-week study in rasH2 transgenic mice.”
hERG / QT
Islatravir: weak hERG inhibition (IC50 >291 μM); no QTc prolongation in rats or monkeys
“While high doses produced transient increases in heart rate (HR) and blood pressure (BP) in rats and monkeys, no QTc prolongation was observed, and effects occurred only at exposures (Cmax) >1,000-fold the clinical exposure at the RHD. ISL showed weak hERG inhibition (IC50 >291 μM) and no significant effects on other cardiac ion channels”
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 Idvynso 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: Islatravir NOAEL 3 mg/kg/day in rats (119x) and 20 mg/kg Q3D in monkeys (539x) (FDA multi-discipline review, p. 193)
NOAEL / key findings
Islatravir NOAEL 3 mg/kg/day in rats (119x) and 20 mg/kg Q3D in monkeys (539x)
“The no-observed-adverse-effect levels (NOAELs) are 3 mg/kg/day in rats and 20 mg/kg every three days (Q3D) in monkeys, at exposures (based on AUC0-24h) 119 and 539 times higher than human exposure at the RHD, respectively.”
Risksopen answer page →
Immune & cytokine safety
Dose- and duration-dependent lymphocyte decreases in two mouse strains
“The most clinically relevant finding was dose- and duration-dependent decreases in lymphocytes, which was consistently observed in two mouse strains.”
Biodistribution & persistence
Strong melanin binding (uveal tract) in pigmented rats; crosses placenta with significant fetal exposure
“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.”
Modality-specific risk
Lymphocyte decreases; the clinical lymphocyte-effect dose gives ~25-fold higher ISL-TP exposure than the recommended dose
“An in vitro PK/PD model using human PBMCs established that the clinical dose associated with lymphocyte decreases (0.75 mg QD) corresponds to an ISL-TP exposure approximately 25-fold higher than the RHD.”
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 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.
Label warnings
- Skin and Hypersensitivity Reactions
- Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
Hypersensitivity & infusion reactionsSkin reactions
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 Idvynso 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: Islatravir NOAEL 3 mg/kg/day in rats (119x) and 20 mg/kg Q3D in monkeys (539x) (FDA multi-discipline review, p. 193)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Islatravir 9-month rhesus monkey oral study; findings reversible by end of recovery period
“Nine-month oral toxicity study in rhesus monkeys / Study No. TT #14-1068 Key Study Findings • Dose-limiting toxicities were observed at 100 mg/kg, leading to early termination of dosing and euthanasia of seven animals. All findings were reversible and absent at the end of the recovery period.”
Pivotal GLP studies
6-month rat and 9-month monkey islatravir studies; 3-month mouse
“repeat-dose toxicology studies in mice, rats, and monkeys for durations up to 3, 6, and 9 months, respectively”
DART package
Species: DART
Islatravir: rat and rabbit (complete reproductive toxicology battery)
“a complete battery of reproductive toxicology studies in rats and rabbits;”
Reproductive & developmental
No fertility effects in rats (~1000x); rat skeletal malformations only at ~5100x, developmental NOEL ~500x
“ISL had no effect on the fertility of male or female rats at exposures ~1000 times the human exposure at the RHD. In rats, skeletal malformations were noted only at very high exposures (~5100 times the exposure at the RHD), with a developmental no-observed-effect level (NOEL) established at exposures ~500 times the human exposure at the RHD.”
PPND / ePPND: when
Islatravir PPND in rat completed before the marketing application
“Pre- and postnatal development studies in rats showed no effects on maternal parameters or F₁ offspring development, behavior, or reproductive performance at doses up to 10 mg/kg/day”
Carcinogenicity
Species: carcinogenicity
Islatravir: rat (2-year) and rasH2 transgenic mouse (6-month)
“2-year rat and 6-month rasH2 transgenic mouse carcinogenicity studies;”
Carcinogenicity model
Islatravir: 2-year rat and 26-week rasH2 mouse; not carcinogenic
“Consistent with this profile, ISL was non-carcinogenic in a 2-year study in rats and in a 26-week study in rasH2 transgenic mice.”
Carcinogenicity timing
Islatravir 2-year rat and 26-week rasH2 mouse studies completed before the marketing application
“Consistent with this profile, ISL was non-carcinogenic in a 2-year study in rats and in a 26-week study in rasH2 transgenic mice.”
Safety marginopen answer page →
Safety margin at NOAEL
Islatravir NOAEL: rat 119x and monkey 539x human AUC at the recommended dose
“The no-observed-adverse-effect levels (NOAELs) are 3 mg/kg/day in rats and 20 mg/kg every three days (Q3D) in monkeys, at exposures (based on AUC0-24h) 119 and 539 times higher than human exposure at the RHD, respectively.”
NOAEL / key findings
Islatravir NOAEL 3 mg/kg/day in rats (119x) and 20 mg/kg Q3D in monkeys (539x)
“The no-observed-adverse-effect levels (NOAELs) are 3 mg/kg/day in rats and 20 mg/kg every three days (Q3D) in monkeys, at exposures (based on AUC0-24h) 119 and 539 times higher than human exposure at the RHD, respectively.”
Efficacy evidenceopen answer page →
Efficacy evidence
Islatravir anti-HIV-1 activity in human PBMCs (IC50 0.21 nM)
“This active form inhibits HIV-1 replication, and the parent drug exhibited an IC50 of 0.21 nM in human PBMCs.”
Why that model
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.
Reviewer's view of the efficacy data
Nonclinical and clinical virology data support approval
“Overall, the nonclinical and clinical virology data support approval of NDA 216964 for DOR/ISL.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAcceptedBeyond the letter
Islatravir positive for chromosomal aberrations in vitro (CHO cells); accepted on mechanism and negative Ames and in vivo micronucleus
Why: Effect mitigated by inosine, suggesting nucleotide pool perturbation; negative Ames and in vivo rat micronucleus · Pharmacology or kinetics · Weight of evidence
“While ISL induced chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, this effect was mitigated by the addition of inosine, suggesting it may be related to a perturbation of nucleoside/nucleotide pools rather than direct DNA interaction.”
“ISL is not considered genotoxic or carcinogenic at clinically relevant exposures.”
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