Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 3C-like protease main protease (Mpro), also referred to as 3CLpro or NSP5 protease. Inhibition of the SARS-CoV-2 3CL protease renders it incapable of processing polyprotein precursors, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS CoV-2 3CL protease in a biochemical assay with a Ki value of 3.1 nM and an IC50 value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 3CL protease active site by X-ray crystallography.
Ritonavir is an HIV-1 protease inhibitor but is not active against the SARS-CoV-2 3CL protease. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.
Current non-clinical and clinical data do not suggest a risk of QT prolongation, but QT prolongation has not been fully evaluated in humans.
The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy subjects and in participants with mild to moderate COVID-19.
Ritonavir is administered with nirmatrelvir as a pk (pharmacokinetic) enhancer resulting in higher systemic concentrations and longer half-life of nirmatrelvir. In healthy participants in the fasted state, the mean half‑life (t1/2) of a single dose of 150 mg nirmatrelvir administered alone was approximately 2 hours compared to 7 hours after administration of a single dose of 250 mg/100 mg nirmatrelvir/ritonavir thereby supporting a twice daily administration regimen.
Upon administration of single dose of nirmatrelvir/ritonavir 250 mg/100 mg to healthy participants in the fasted state, the geometric mean (CV%) maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to the time of last measurement (AUClast) was 2.88 ug/mL (25%) and 27.6 ug*hr/mL (13%), respectively.
Upon repeat-dose of nirmatrelvir/ritonavir 75 mg/100 mg, 250 mg/100 mg, and 500 mg/100 mg administered twice daily, the increase in systemic exposure at steady-state appears to be less than dose proportional. Multiple dosing over 10 days achieved steady-state on Day 2 with approximately 2-fold accumulation. Systemic exposures on Day 5 were similar to Day 10 across all doses.. The pharmacokinetic properties of nirmatrelvir; ritonavir are displayed in Table 7.
Table 7: Pharmacokinetic Properties of Nirmatrelvir and Ritonavir in Healthy Subjects
Nirmatrelvir (When Given with Ritonavir)
Tmax (h), median
Test/Reference (fed/fasted) ratios of geometric means (90% Confidence Interval) AUClast and Cmax for nirmatrelvir were 120.9 (109.3 – 133.7) and 161.0 (139.1 – 186.4), respectivelyb
% bound to human plasma proteins
Vz/F (L), mean
Major route of elimination
Half-life (t1/2) (hr), mean
Oral clearance (CL/F), mean
Major CYP3A4, Minor CYP2D6
% drug-related material in feces
% drug-related material in urine
a. Represents data after a single dose of 300 mg nirmatrelvir (2 x 150 mg tablet formulation) administered together with 100 mg ritonavir tablet in healthy subjects.
b. Following a single oral dose of nirmatrelvir 300 mg boosted with ritonavir 100 mg at -12 hours, 0 hours, and 12 hours, administered under fed (high fat, high calorie meal) (Test) or fasted (Reference) conditions.
c. 300 mg nirmatrelvir (oral suspension formulation) and 100 mg ritonavir (tablet formulation) administered together twice a day for 3 days.
d. Red blood cell to plasma ratio.
e. Nirmatrelvir is a CYP3A4 substrate but when dosed with ritonavir metabolic clearance is minimal.
f. Determined by 19F-NMR analysis following 300 mg oral suspension enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours, and 24 hours.
g. Determined by 14C analysis following 600 mg 14C-ritonavir oral solution.
The Single dose pharmacokinetic data of PAXLOVID in healthy subjects is depicted below in Table 8.
Table 8: Single Dose Pharmacokinetics of Nirmatrelvir Following Dosing with 300 mg/100 mg Nirmatrelvir/Ritonavir in Healthy Subjects
PK Parameter (units)
6.05 ± 1.79
Represents data from 2 x 150 mg tablets of nirmatrelvir. Values are presented as geometric mean (geometric % CV) except median (range) for Tmax and arithmetic mean ± SD for T1/2.
Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir (CV%) Cmax and area under the plasma concentration-time curve from 0 to infinity (AUCinf) was 2.21 µg/mL (33) and 23.01 µg*hr/mL (23), respectively. The median (range) time to Cmax (Tmax) was 3.00 hrs (1.02-6.00). The arithmetic mean (+SD) terminal elimination half-life was 6.1 (1.8) hours. Following oral administration of nirmatrelvir /ritonavir 300 mg/100 mg after a single dose, the geometric mean ritonavir (CV%) Cmax and AUCinf was 0.36 µg/mL (46) and 3.60 µg*hr/mL (47), respectively. The median (range) time to Cmax (Tmax) was 3.98 hrs (1.48-4.20). The arithmetic mean (+SD) terminal elimination half-life was 6.1 (2.2) hours.
Effect of food on oral absorption:
In healthy subjects, administration of a single oral dose of nirmatrelvir 300 mg (2 x 150 mg tablets) boosted with ritonavir 100 mg (1 x 100 mg tablet) at -12 hours, 0 hours, and 12 hours, under fed conditions (high fat and high calorie meal) increased the exposure of nirmatrelvir relative to fasting conditions. There was an approximate 61% increase in nirmatrelvir mean Cmax and a 21% increase in nirmatrelvir mean AUClast relative to fasting conditions. There was a delay in the median Tmax by 0.21 hours when dosed with the high fat, high calorie meal compared to fasting conditions. PAXLOVID can be taken orally with or without food.
The protein binding of nirmatrelvir in human plasma is approximately 69%. The protein binding of ritonavir in human plasma is approximately 98-99%.
In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir is primarily metabolized by CYP3A4. Nirmatrelvir is not an inducer or substrate of other CYP enzymes. Administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In plasma, the only drug-related entity observed was unchanged nirmatrelvir. Minor oxidative metabolites were observed in the feces and urine.
In vitro studies utilising human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of oxidation metabolite M-2.
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolized by CYP3A4) and other protease HIV inhibitors may influence the pharmacokinetics of ritonavir.
The primary route of elimination of nirmatrelvir when administered with ritonavir was renal excretion of intact drug. Approximately 49.6% and 35.3% of the administered dose of nirmatrelvir 300 mg was recovered in urine and feces, respectively. Nirmatrelvir was the predominant drug-related entity with small amounts of metabolites arising from hydrolysis reactions in excreta. In plasma, the only drug related entity quantifiable was unchanged nirmatrelvir.
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir.
Special Populations and Conditions
Table 9: Impact of Hepatic Impairment on Nirmatrelvir Pharmacokinetics
Normal Hepatic Function
Moderate Hepatic Impairment (n=8)
2.0 (0.6 - 2.1)
1.5 (1.0 - 2.0)
7.21 ± 2.10
5.45 ± 1.57
Values are presented as geometric mean (geometric % CV) except Median (Range) for Tmax and arithmetic mean ± SD for t1/2.
Table 10: Impact of Renal Impairment on Nirmatrelvir/Ritonavir Pharmacokinetics
Normal Renal Function
Mild Renal Impairment
Moderate Renal Impairment
Severe Renal Impairment
2.0 (1.0 - 4.0)
2.0 (1.0 – 3.0)
2.50 (1.0 – 6.0)
3.0 (1.0 - 6.1)
7.73 ± 1.82
6.60 ± 1.53
9.95 ± 3.42
13.37 ± 3.32
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