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.”
Species: general tox
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.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Fertility and embryo-foetal development studies were evaluated in rats and rabbits with PF-07321332 (studies 21GR146, 21GR132 and 21GR126). Pre- and postnatal development was evaluated in rats (21GR149) based on the interim results.”
Species: carcinogenicity
Not conducted (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.”
Surrogate used in
No surrogate used; target is a viral protein, so no pharmacologically relevant species
“Furthermore, the pharmacological target of PF-07321332 is an exogenous entity (virus-specific protein) and therefore there are no pharmacologically relevant species.”
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.”
Genotox: Ames
Negative (S. typhimurium and E. coli)
“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.”
Genotox: in vitro mammalian
In vitro micronucleus in human TK6 cells: negative
“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.”
Genotox: in vivo
Rat micronucleus: negative
“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 model
Not conducted; 5-day treatment, in line with ICH S1A
“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.”
Carcinogenicity timing
Not required (treatment limited to 5 days, per ICH S1A)
“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.”
hERG / QT
No clinically meaningful hERG effect in vitro
“From in vitro and ex vivo data (studies 200804.QHJ, 20LJ076 and 20J075), there was no clinically meaningful effect of PF-07321332 on hERG, isolated guinea pig heart or isolated rat aorta assays.”
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.”
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
Boxed warning: Significant drug interactions with paxlovid
- Risk of Serious Adverse Reactions Due to Drug Interactions
- Hypersensitivity Reactions
- Hepatotoxicity
- Risk of HIV-1 Resistance Development
Hypersensitivity & infusion reactionsHepatotoxicity
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
1-month cynomolgus monkey (oral, twice daily) with 2-week recovery
“One-Month BID Oral Gavage Toxicity Study of PF-07321332 in Cynomolgus Monkeys with a Two-Week Recovery (Study# 21GR125)”
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.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Fertility and embryo-foetal development studies were evaluated in rats and rabbits with PF-07321332 (studies 21GR146, 21GR132 and 21GR126). Pre- and postnatal development was evaluated in rats (21GR149) based on the interim results.”
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.”
PPND / ePPND: when
Rat PPND ongoing at the EU marketing application (interim report only); final report requested after authorisation
“The pre- and postnatal development study was ongoing; the interim report has been provided. The final study report for the PPND (21GR149) is requested by 30/04/2022 (LEG).”
Carcinogenicity
Species: carcinogenicity
Not conducted (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.”
Carcinogenicity model
Not conducted; 5-day treatment, in line with ICH S1A
“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.”
Carcinogenicity timing
Not required (treatment limited to 5 days, per ICH S1A)
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL ~8.0x (rat) and ~14x (monkey) predicted human AUC24 at 300/100 mg BID
“The NOAELs were the highest doses administered 1000 mg/kg in rat and 600 mg/kg (300 BID) in monkeys and represented 11x/8.0x and 21x/14x for rats and monkeys (Cmax/AUC24), respectively, over the predicted human total PF-07321332 Cmax and AUC24 at a dose of 300/100 mg PF-07321332/ritonavir BID.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse-adapted SARS-CoV-2 (MA10) infection in BALB/c and 129 mice: reduced lung viral titres and disease
“PF-07321332 showed antiviral activity in mouse models with mouse-adapted (MA) SARS-CoV-2 infection in BALB/c and 129 mouse strains (studies 105036 and 022652).”
Why that model
Mouse-adapted virus chosen over hACE2 transgenic mice for more clinically relevant phenotypes
“SARS-CoV-2 MA exhibited more clinically relevant phenotypes than those seen in Hfh4-ACE2 transgenic mice, which expresses human ACE2, and thus SARS-CoV-2 MA is used by numerous investigators in the SARS-CoV-2 field.”
Reviewer's view of the efficacy data
EMA: in vivo proof-of-concept studies consistently support antiviral activity (lower lung titres, less disease)
“The in vivo proof of concept studies consistently support the antiviral activity of PF-07321332, as demonstrated by reduced infectious lung titres and ameliorated indicators of disease (weight loss and lung pathology) compared to placebo-treated animals”
Flexibilityopen answer page →
Flexibility accepted
OtherVerdict not stated
No combination toxicity studies of nirmatrelvir with ritonavir
Why: Ritonavir is a marketed PK enhancer with well characterised nonclinical and clinical safety profiles · Human data · Class precedent
“No combination studies with administration of PF-07321332 with ritonavir have been conducted. Ritonavir is an already marketed drug as a PK enhancer with well characterised nonclinical and clinical safety profiles.”
DARTAccepted with a conditionBeyond the letter
Pre- and postnatal development study ongoing at authorisation; only interim report submitted, final report requested post-authorisation
“The pre- and postnatal development study was ongoing; the interim report has been provided. The final study report for the PPND (21GR149) is requested by 30/04/2022 (LEG).”
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