Paxlovid
nirmatrelvir and ritonavir
Species
MonkeyRat
Longest study
4 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
“Pivotal repeat-dose toxicology studies were conducted in rats (2-week and 1-month durations) up to 1000 mg/kg/day and in monkeys (15-day and 1-month durations) up to 600 mg/kg/day.”
Why that species
PK profile similar to human; no pharmacologically relevant species because the target is a viral protein
“The species used for the GLP compliant pivotal studies included rats and monkeys based on similar PK profile seen in these species compared to human. Furthermore, the pharmacological target of PF-07321332 is an exogenous entity (virus-specific protein) and therefore there are no pharmacologically relevant species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Pivotal repeat-dose toxicology studies were conducted in rats (2-week and 1-month durations) up to 1000 mg/kg/day and in monkeys (15-day and 1-month durations) up to 600 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
4 (1-month rat and monkey)
“Pivotal repeat-dose toxicology studies were conducted in rats (2-week and 1-month durations) up to 1000 mg/kg/day and in monkeys (15-day and 1-month durations) up to 600 mg/kg/day.”
Pivotal GLP studies
2-week and 1-month rat and 15-day and 1-month monkey oral studies with nirmatrelvir
“Pivotal repeat-dose toxicology studies were conducted in rats (2-week and 1-month durations) up to 1000 mg/kg/day and in monkeys (15-day and 1-month durations) up to 600 mg/kg/day.”
Route in tox
Oral
“The oral route of administration was selected as it is the route of clinical administration.”
Skipped studiesopen answer page →
Genotoxicity
Nirmatrelvir negative in Ames, in vitro TK6 micronucleus and in vivo rat micronucleus assays
“Nirmatrelvir was negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli , the in vitro micronucleus assay using human lymphoblastoid TK6 cells, and the in vivo rat micronucleus assays.”
Carcinogenicity
Not conducted for nirmatrelvir (5-day treatment duration)
“No carcinogenicity studies have been performed. Considering that the duration of treatment is limited to 5 days, the absence of carcinogenicity studies is in-line with the recommendations of ICH S1A.”
Reproductive & developmental
Rat and rabbit EFD: only lower fetal body weight (9%) in rabbits at 1000 mg/kg/day, without significant maternal toxicity
“In the rabbit EFD study, lower fetal body weights (9% decrease) were observed at 1,000 mg/kg/day in the absence of significant maternal toxicity findings.”
Safety pharmacology
Monkey telemetry: small transient BP, heart rate and RR/PR/QT changes at 150 mg/kg/day; no arrhythmias
“In a cardiovascular safety pharmacology study in cynomolgus monkeys, small transient effects such as increased systolic, diastolic, and mean blood pressure (BP), heart rate (HR) decreases, and associated RR, PR, and QT interval increases were observed following oral administration of 150 (75 BID) mg/kg/day nirmatrelvir.”
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 Paxlovid 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: NOAELs were the highest doses tested (rat 1000, monkey 600 mg/kg/day); all findings non-adverse (FDA integrated review, p. 125)
NOAEL / key findings
NOAELs were the highest doses tested (rat 1000, monkey 600 mg/kg/day); all findings non-adverse
“Pivotal repeat-dose toxicology studies were conducted in rats (2-week and 1-month durations) up to 1000 mg/kg/day and in monkeys (15-day and 1-month durations) up to 600 mg/kg/day. All the findings discussed below are considered drug-related but non-adverse.”
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
Rat QWBA: highest levels in liver, kidney, pancreas and adrenal; no quantifiable brain penetration
“The tissues with the highest Cmax values (Tmax = 4 hours for most tissues) excluding the gastrointestinal tract were observed in the liver, kidney, pancreas, and adrenal gland. [14C]nirmatrelvir-derived radioactivity did not cross the blood:brain barrier to a quantifiable extent.”
Modality-specific risk
QT prolongation; hERG and monkey QT data indicated low risk
“In vitro hERG assays and an in vivo QT study in monkeys suggested that nirmatrelvir has a low risk for QT prolongation.”