PAXLOVID 10 Clinical Pharmacology

10.1 Mechanism of Action

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.

10.2 Pharmacodynamics

Current non-clinical and clinical data do not suggest a risk of QT prolongation, but QT prolongation has not been fully evaluated in humans.

10.3 Pharmacokinetics

The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy subjects.

Ritonavir is administered with nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemic concentrations and longer half-life of nirmatrelvir, thereby supporting a twice daily administration regimen.

Upon oral administration of nirmatrelvir/ritonavir, the increase in systemic exposure appears to be less than dose proportional up to 750 mg as a single dose and up to 500 mg twice daily as multiple doses. Twice daily dosing over 10 days achieved steady-state on Day 2 with approximately 2-fold accumulation. The pharmacokinetic properties of nirmatrelvir; ritonavir are displayed in Table 6.

The Single dose pharmacokinetic data of PAXLOVID in healthy subjects is depicted below in Table 6.

Absorption

Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir (CV%) C_max and area under the plasma concentration-time curve from 0 to infinity (AUC_inf) was 2.21 µg/mL (33) and 23.01 µg*hr/mL (23), respectively. The median (range) time to C_max (T_max) 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%) C_max and AUC_inf was 0.36 µg/mL (46) and 3.60 µg*hr/mL (47), respectively. The median (range) time to C_max (T_max) 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:  

An exploratory study in 4 healthy volunteers showed that dosing with a high-fat high-calorie meal modestly increased the exposure of nirmatrelvir (approximately 15% increase in mean C_max and 1.6% increase in mean AUC_last) relative to fasting conditions following administration of a suspension formulation (250mg) of nirmatrelvir co-administered with ritonavir (100 mg) tablets.

Distribution

The protein binding of nirmatrelvir in human plasma is approximately 69%. The protein binding of ritonavir in human plasma is approximately 98-99%. metabolized.

Metabolism

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.

Elimination

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

• Age/Gender The pharmacokinetics of nirmatrelvir/ritonavir based on age and gender have not been evaluated.
• Pediatrics The pharmacokinetics of nirmatrelvir/ritonavir in patients less than 18 years of age have not been evaluated.
• Ethnic Origin Systemic exposure in Japanese participants was numerically lower but not clinically meaningfully different than those in Western participants
• Hepatic Insufficiency The pharmacokinetics of nirmatrelvir/ritonavir have not been evaluated in Covid-19 patients with hepatic impairment. A single oral dose of 100 mg nirmatrelvir administered at 0 hours enhanced with 100 mg ritonavir administered at -12 hours, 0 hours, 12 hours and 24 hours in subjects with moderate hepatic impairment resulted in similar nirmatrelvir exposures compared to subjects with normal hepatic function (see Table 8). Adjusted geometric mean ratio (90% CI) of AUC_inf and C_max of nirmatrelvir comparing moderate hepatic impairment (test) to normal hepatic function (reference) were 98.78% (70.65%, 138.12%) and 101.96% (74.20%, 140.11%), respectively. Ritonavir mean C_max and AUC₁₂ were increased by 84% and 68%, respectively, after the second dose in subjects with moderate hepatic impairment compared to subjects with normal hepatic function. Nirmatrelvir/ritonavir has not been studied in subjects with severe hepatic impairment.

• Renal Insufficiency An open-label study compared nirmatrelvir/ritonavir pharmacokinetics in healthy adult subjects and subjects with mild (eGFR 60 - <90 mL/min), moderate (eGFR ≥30 to <90 mL/min), and severe (eGFR <30 mL/min) renal impairment following administration of a single oral dose of nirmatrelvir 100 mg enhanced with ritonavir 100 mg administered at -12, 0, 12, and 24 hours. Compared to healthy controls with no renal impairment, the C_max and AUC of nirmatrelvir in patients with mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was 38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher, respectively.