Zokinvy
lonafarnib
Species
MonkeyRat
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“The Sprague Dawley rat and cynomolgus monkey were selected as the main rodent and non-rodent species in the general toxicity studies.”
Why that species
Farnesyltransferase sequence highly conserved between humans and rat, mouse, rabbit and monkey
“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.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The results of the 1-year oral toxicity study in monkeys indicated that treatment with lonafarnib resulted in histological changes in the male reproductive tract at all doses (10, 20, and 40 mg/kg/day), and in the eye at 40 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
52 (1-year monkey)
“The nonclinical safety profile of lonafarnib was evaluated in cardiovascular safety pharmacology studies in monkeys, repeated dose oral toxicology studies in rats for up to 6 months and in monkeys for up to 1 year”
Pivotal GLP studies
Repeat-dose studies up to 6 months in rats and 12 months in cynomolgus monkeys
“Overall, the toxicity profile of lonafarnib has been characterized via single-dose toxicity studies in mice and rats, repeat-dose toxicity studies (up to 6 months in Sprague Dawley rats and 12 months in cynomolgus monkeys)”
Route in tox
Oral
“The oral route of administration was utilized in all pivotal toxicity studies to match the intended clinical administration route.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosomal aberration and mouse micronucleus assays
“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”
Carcinogenicity
Not conducted; postmarketing requirement
“The Applicant will be required to conduct a carcinogenicity study postapproval.”
Reproductive & developmental
Rat EFD: post-implantation loss at ~human exposure; rabbit EFD: skeletal malformations below human exposure
“In pregnant rats, post-implantation loss (resorptions) was seen at plasma drug exposures approximately equal to that achieved in humans. In pregnant rabbits, skeletal malformations were seen at plasma drug exposures lower than human exposures.”
Safety pharmacology
hERG IC50 1.3 µM, about 3-fold below total clinical Cmax
“The hERG IC50 was 1.3 µM (0.83 µg/mL), which is approximately 3 times below the clinical Cmax (2.64 µg/mL).”
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 Zokinvy 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: 6-month rat: renal toxicity (inner medulla necrosis, mineralization) at 30 and 60 mg/kg/day; NOAEL 15 mg/kg/day (FDA integrated review, p. 66)
NOAEL / key findings
6-month rat: renal toxicity (inner medulla necrosis, mineralization) at 30 and 60 mg/kg/day; NOAEL 15 mg/kg/day
“The results of the 6-month oral toxicity study in rats indicated that treatment with lonafarnib (at doses of 30 and 60 mg/kg/day) produced renal toxicity, including necrosis and mineralization in the inner medulla and mononuclear cell infiltrates. The no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid hypocellularity in spleen, thymus and mesenteric lymph node after 3 months in rats
“In rats, toxicity was seen after 3-months administration of lonafarnib and were attributed as lymphoid hypocellularity and with corresponding weight loss and the affected organs/tissues included spleen, thymus and mesenteric lymph node”
Biodistribution & persistence
Low to moderate brain penetration (brain:plasma AUC ~6.5%)
“The AUC ratio of brain to plasma was about 6.5% at each dose level, indicating a low to moderate brain penetration of Lonafarnib.”
Modality-specific risk
Nephrotoxicity, retinal toxicity, impaired fertility and embryo-fetal toxicity
“Nephrotoxicity, retinal toxicity, impaired fertility, and embryo-fetal toxicity were observed in nonclinical studies.”