Livtencity
maribavir
Species
MonkeyRatMouse
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (plus 13-week mouse)
“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”
Why that species
Main human metabolite VP 44469 present in mice, rats and monkeys; common toxicity species
“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.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 52-week monkey study, 2 males at 400/300 mg/kg/day (two dose levels indicate dose adjustment during the study) and 1 male at 200 mg/kg/day were euthanized in extremis.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week monkey)
“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”
Pivotal GLP studies
52-week cynomolgus monkey, 26-week rat and 13-week mouse GLP studies
“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”
Route in tox
Oral (once daily in rodents, twice daily in monkeys)
“Maribavir was applied orally once a day to mice and rats, and according to the clinical treatment schedule twice a day to monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and in vivo rat micronucleus; mutagenic without metabolic activation in mouse lymphoma assay; overall not genotoxic
“Although maribavir demonstrated mutagenic potential in the absence of metabolic activation in the mouse lymphoma assay, given the negative results of the in vivo rat micronucleus assay and the negative bacterial mutation assay, the weight of evidence indicates that maribavir does not exhibit genotoxic potential.”
Carcinogenicity
Mouse: hemangiosarcoma in males at 150 mg/kg/day; rat: not carcinogenic (exposures below human RHD)
“Maribavir was not carcinogenic in rats at any dose tested, corresponding to maribavir exposures less than human exposure at the RHD. At 150 mg/kg/day in male mice only, an increased incidence of hemangiosarcoma and combined hemangioma/ hemangiosarcoma was observed across multiple tissues at exposures less than the human exposure at the RHD.”
Reproductive & developmental
Fewer viable fetuses, more early resorptions and post-implantation loss at ≥100 mg/kg/day (about half human exposure)
“A decrease in the number of viable fetuses, and increase in early resorptions and post-implantation losses were observed at ≥100 mg/kg/day (at exposures approximately half the human exposure at the RHD).”
Safety pharmacology
No hERG effect up to 1500 µg/mL, >4000-fold the clinical unbound Cmax
“Maribavir had no effect on the hERG current at concentrations of up to 1500 µg/mL (measured concentration 1250 µg/mL), providing a wide safety margin of more than 4000-fold the anticipated clinical plasma unbound Cmax of 0.344 µg/mL (0.91 µM), at the maximum proposed clinical dose of 400 mg BID.”
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 Livtencity 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: Regenerative anemia and gastrointestinal effects in the 52-week monkey and 26-week rat studies (FDA integrated review, p. 75)
NOAEL / key findings
Regenerative anemia and gastrointestinal effects in the 52-week monkey and 26-week rat studies
“The major findings in the 52-week study in monkeys and 26-week study in rats were regenerative anemia and gastrointestinal effects”
Risksopen answer page →
Immune & cytokine safety
Not immunotoxic in rats up to 100 mg/kg/day
“Maribavir was not immunotoxic in rats at up to 100 mg/kg/day.”
Biodistribution & persistence
Melanin binding: uveal tract radioactivity ~6-fold higher in pigmented rats, retained beyond 504 h
“In pigmented rats, concentrations of radioactivity in the uveal tract were approximately 6-fold higher than those observed for albino rats, and were measurable through the last timepoint, indicating retention of DRM beyond 504 hours postdose.”
Modality-specific risk
Low or no exposure margins: NOAEL/LOAEL exposures below human exposure at the recommended dose
“The exposures at the no observed adverse effect levels/lowest observed adverse effect levels in the 52-week monkey study, 26-week rat study, and 13-week mouse study were less than the human exposures at the recommended human dose (RHD).”