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”
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.”
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.”