PAXLOVID™ Clinical Pharmacology

(nirmatrelvir tablets; ritonavir tablets)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nirmatrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug [see Microbiology (12.4)].

Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.

12.2 Pharmacodynamics

Cardiac Electrophysiology

At 3 times the steady state peak plasma concentration (Cmax) at the recommended dose, nirmatrelvir does not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

The pharmacokinetics of nirmatrelvir/ritonavir were similar in healthy subjects and in subjects with mild-to-moderate COVID-19.

Nirmatrelvir AUC increased in a less than dose proportional manner over a single dose range from 250 mg to 750 mg (0.83 to 2.5 times the approved recommended dose) and multiple dose range from 75 mg to 500 mg (0.25 to 1.67 times the approved recommended dose), when administered in combination with 100 mg ritonavir. Nirmatrelvir steady state was achieved on Day 2 following administration of the approved recommended dosage and the mean accumulation ratio was approximately 2-fold.

The pharmacokinetic properties of nirmatrelvir/ritonavir are displayed in Table 3.

Table 3: Pharmacokinetic Properties of Nirmatrelvir and Ritonavir in Healthy Subjects
Nirmatrelvir (When Given With Ritonavir) Ritonavir
Abbreviations: CL/F=apparent clearance; hr=hour; L/hr=liters per hour; T½=terminal elimination half-life; Tmax=the time to reach Cmax; Vz/F=apparent volume of distribution.
*
Represents data after a single dose of 300 mg nirmatrelvir (2 × 150 mg tablet formulation) administered together with 100 mg ritonavir tablet in healthy subjects.
†
Following a single oral dose of nirmatrelvir 300 mg boosted ritonavir 100 mg at -12 hours, 0 hours and 12 hours, administered under fed (high fat and high calorie meal) or fasted conditions.
‡
Red blood cell to plasma ratio.
§
300 mg nirmatrelvir (oral suspension formulation) co-administered with 100 mg ritonavir (tablet formulation) twice daily for 3 days.
Determined by 19F-NMR analysis following 300 mg nirmatrelvir oral suspension administered at 0 hr enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours, and 24 hours.
#
Determined by 14C analysis following 600 mg 14C-ritonavir oral solution (6 times the approved ritonavir dose).

Absorption

  Tmax (hr), median

3.00*

3.98*

  Food effect

Test/reference (fed/fasted) ratios of adjusted geometric means (90% CI) AUCinf and Cmax for nirmatrelvir were 119.67 (108.75, 131.68) and 161.01 (139.05, 186.44), respectively.†

Distribution

  % bound to human plasma proteins

69%

98–99%

  Blood-to-plasma ratio

0.60

0.14‡

  Vz/F (L), mean

104.7§

112.4§

Elimination

  Major route of elimination

Renal elimination

Hepatic metabolism

  Half-life (T½) (hr), mean

6.05*

6.15*

  Oral clearance (CL/F) (L/hr), mean

8.99§

13.92§

Metabolism

  Metabolic pathways

Nirmatrelvir is a CYP3A substrate but when dosed with ritonavir, metabolic clearance is minimal.

Major CYP3A, Minor CYP2D6

Excretion

  % drug-related material in feces

35.3%

86.4%#

  % of dose excreted as total (unchanged drug) in feces

27.5%

33.8%#

  % drug-related material in urine

49.6%

11.3%#

  % of dose excreted as total (unchanged drug) in urine

55.0%

3.5%#

The predicted Day 5 nirmatrelvir exposure parameters in adult subjects with mild-to-moderate COVID-19 who were treated with PAXLOVID in EPIC-HR are presented in Table 4.

Table 4: Predicted Day 5 Nirmatrelvir Exposure Parameters Following Administration of Nirmatrelvir/Ritonavir 300 mg/100 mg Twice Daily in Subjects with Mild-to-Moderate COVID-19
Pharmacokinetic Parameter (units)* Nirmatrelvir†
Abbreviations: Cmax=predicted maximal concentration; Cmin=predicted minimal concentration (Ctrough).
*
Data presented as geometric mean (10th and 90th percentile).
†
Based on 1,017 subjects with their post hoc PK parameters.
‡
AUCtau=predicted area under the plasma concentration-time profile from time 0 to 12 hours for twice-daily dosing.

Cmax (µg/mL)

3.29 (1.93, 5.40)

AUCtau (µg*hr/mL)‡

28.3 (12.5, 52.5)

Cmin (µg/mL)

1.40 (0.48, 3.45)

Effect of Food

No clinically significant differences in the pharmacokinetics of nirmatrelvir were observed following administration of a high fat meal (800-1,000 calories; 50% fat) to healthy subjects.

Specific Populations

There were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on age (18 to 86 years), sex, or race/ethnicity.

Pediatric Patients

The pharmacokinetics of nirmatrelvir/ritonavir in patients less than 18 years of age have not been established.

Patients with Renal Impairment

The pharmacokinetics of nirmatrelvir in subjects with renal impairment following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg were determined. Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in subjects with mild renal impairment was 30% and 24% higher, in subjects with moderate renal impairment was 38% and 87% higher, and in subjects with severe renal impairment was 48% and 204% higher, respectively.

The pharmacokinetics of nirmatrelvir in subjects with mild-to-moderate COVID-19 and severe renal impairment (eGFR<30 mL/min) either requiring intermittent hemodialysis (n=12) or not requiring hemodialysis (n=2) were evaluated after administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 for a total of 5 doses.

The administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 in subjects with severe renal impairment, either requiring intermittent hemodialysis or not requiring hemodialysis resulted in comparable exposures on Day 1 and at steady-state (AUC0-24 and Cmax) compared to those observed in subjects with normal renal function receiving 300 mg/100 mg nirmatrelvir/ritonavir twice daily for 5 days. During a 4-hour hemodialysis session, approximately 6.9% of nirmatrelvir dose was cleared through dialysis. Hemodialysis clearance was 1.83 L/h.

Patients with Hepatic Impairment

The pharmacokinetics of nirmatrelvir were similar in patients with moderate (Child-Pugh Class B) hepatic impairment compared to healthy subjects following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg. The impact of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of nirmatrelvir or ritonavir has not been studied.

Clinical Drug Interaction Studies

Table 5 describes the effect of other drugs on the Cmax and AUC of nirmatrelvir.

Table 5: The Effect of Other Drugs on the Pharmacokinetic Parameters of Nirmatrelvir
Co-administered Drug Dose (Schedule) N Percent Ratio (in combination with co-administered drug/alone) of Nirmatrelvir Pharmacokinetic Parameters (90% CI);
No Effect=100
Co-administered Drug Nirmatrelvir/ Ritonavir Cmax AUC*
Abbreviations: AUC=area under the plasma concentration-time curve; AUCinf=area under the plasma concentration-time profile from time zero extrapolated to infinite time; AUCtau=area under the plasma concentration-time profile from time zero to time tau (τ), the dosing interval. CI=confidence interval; Cmax=observed maximum plasma concentrations.
*
For carbamazepine, AUC=AUCinf; for itraconazole, AUC=AUCtau.
†
Carbamazepine titrated up to 300 mg twice daily on Day 8 through Day 15 (e.g., 100 mg twice daily on Day 1 through Day 3 and 200 mg twice daily on Day 4 through Day 7).

Carbamazepine†

300 mg twice daily
(16 doses)

300 mg/100 mg once daily
(2 doses)

10

56.82
(47.04, 68.62)

44.50
(33.77, 58.65)

Itraconazole

200 mg once daily
(8 doses)

300 mg/100 mg twice daily
(5 doses)

11

118.57
(112.50, 124.97)

138.82
(129.25, 149.11)

Table 6 describes the effect of nirmatrelvir/ritonavir on the Cmax and AUCinf of other drugs.

Table 6: Effect of Nirmatrelvir/Ritonavir on Pharmacokinetics of Other Drugs
Co-administered Drug Dose (Schedule) N Percent Ratio of Test/Reference of Geometric Means (90% CI);
No Effect=100
Co-administered Drug Nirmatrelvir/ Ritonavir Cmax AUCinf
Abbreviations: AUCinf=area under the plasma concentration-time curve from time zero extrapolated to infinite time; CI=confidence interval; Cmax=observed maximum plasma concentrations; CYP3A4=cytochrome P450 3A4; OATP1B1=organic anion transporter polypeptide 1B1; P-gp=p-glycoprotein.
*
For midazolam, Test=nirmatrelvir/ritonavir plus midazolam, Reference=Midazolam. Midazolam is an index substrate for CYP3A4. For dabigatran, Test=nirmatrelvir/ritonavir plus dabigatran, Reference=Dabigatran. Dabigatran is an index substrate for P-gp. For rosuvastatin, Test=nirmatrelvir/ritonavir plus rosuvastatin, Reference=Rosuvastatin. Rosuvastatin is an index substrate for OATP1B1.

Midazolam*

2 mg
(1 dose)

300 mg/100 mg twice daily
(9 doses)

10

368.33
(318.91, 425.41)

1430.02
(1204.54, 1697.71)

Dabigatran*

75 mg
(1 dose)

300 mg/100 mg twice daily
(4 doses)

24

233.06
(172.14, 315.54)

194.47
(155.29, 243.55)

Rosuvastatin*

10 mg

(1 dose)

300 mg/100 mg twice daily
(3 doses)

12

212.44

(174.31, 258.90)

131.18

(115.89, 148.48)

In Vitro Studies

Cytochrome P450 (CYP) Enzymes:

•
Nirmatrelvir is a reversible and time-dependent inhibitor of CYP3A, but not an inhibitor CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Nirmatrelvir is an inducer of CYP2B6, 2C8, 2C9, and 3A4, but there is minimal risk for pharmacokinetic interactions arising from induction of these CYP enzymes at the proposed therapeutic dose.
•
Ritonavir is a substrate of CYP2D6 and CYP3A. Ritonavir is an inducer of CYP1A2, CYP2C9, CYP2C19, CYP2B6, and CYP3A.

Transporter Systems: Nirmatrelvir is an inhibitor of P-gp and OATP1B1. Nirmatrelvir is a substrate for P-gp, but not BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, OATP1B1, OATP1B3, OATP2B1, or OATP4C1.

12.4 Microbiology

Mechanism of Action

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nonstructural protein 5 (nsp5) protease. Inhibition of SARS-CoV-2 Mpro renders it incapable of processing the viral polyproteins pp1a and pp1ab, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro 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 Mpro active site by X-ray crystallography.

Antiviral Activity

Cell Culture Antiviral Activity

Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 (USA-WA1/2020 isolate) infection of differentiated normal human bronchial epithelial (dNHBE) cells with EC50 and EC90 values of 62 nM (31 ng/mL) and 181 nM (90 ng/mL), respectively, after 3 days of drug exposure.

The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7, BQ.1, BQ.1.11, XBB.1.5, EG.5, and JN.1 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC50 value of 88 nM (range: 39-146 nM) against the Omicron sub-variants, reflecting EC50 value fold changes ≤1.8 relative to the USA-WA1/2020 isolate.

In addition, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1 variants was assessed in Vero E6 P-gp knockout cells. Nirmatrelvir had a median EC50 value of 25 nM (range: 16-141 nM). The Beta variant was the least susceptible variant tested, with an EC50 value fold change of 3.7 relative to USA-WA1/2020. The other variants had EC50 value fold changes ≤1.1 relative to USA-WA1/2020.

Clinical Antiviral Activity

In clinical trial EPIC-HR, which enrolled subjects who were primarily infected with the SARS-CoV-2 Delta variant, PAXLOVID treatment was associated with a 0.83 log10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5 (mITT1 analysis set, all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment); similar results were observed in the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days). In the EPIC-SR trial, which included subjects who were infected with SARS-CoV-2 Delta (79%) or Omicron (19%) variants, PAXLOVID treatment was associated with a 1.05 log10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5, with similar declines observed in subjects infected with Delta or Omicron variants. The degree of reduction in viral RNA levels relative to placebo following 5 days of PAXLOVID treatment was similar between unvaccinated high-risk subjects in EPIC-HR and vaccinated high-risk subjects in EPIC-SR.

Antiviral Resistance

In Cell Culture and Biochemical Assays

SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with Mpro substitutions, and biochemical assays with recombinant SARS-CoV-2 Mpro containing amino acid substitutions. Table 7 indicates Mpro substitutions and combinations of Mpro substitutions that have been observed in SARS-CoV-2 under nirmatrelvir selective pressure in cell culture. Individual Mpro substitutions are listed regardless of whether they occurred alone or in combination with other Mpro substitutions. Note that the Mpro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of Mpro. Substitutions at other Mpro cleavage sites have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown.

Abbreviation: ND=no data.
*
EC50 value fold change ranges are shown in instances where multiple data points have been reported.

Table 7: SARS-CoV-2 Mpro Amino Acid Substitutions Selected by Nirmatrelvir in Cell Culture*

Single Substitutions

(EC50 value fold change in cell culture)

T21I (1.1-4.8), S46F (ND), L50F (1.2-4.2), P108S (ND), T135I (ND), F140L (4.1), S144A (2.2-5.3), C160F (2.1), E166A (3.3), E166V (25‑288), L167F (1.9-2.5), T169I (ND), H172Y (15), A173V (0.9-2.3), V186A (ND), R188G (ND), A191V (0.7-1.5), A193P (ND), P252L (5.9), S301P (ND), and T304I (1.4-5.5).

≥2 Substitutions

(EC50 value fold change in cell culture)

T21I+S144A (9.4), T21I+E166V (83-250), T21I+A173V (3.1-8.9), T21I+T304I (3.0-7.9), L50F+E166V (34-175), L50F+T304I (5.9), T135I+T304I (3.8), F140L+A173V (10-17), H172Y+P252L (ND), A173V+T304I (5.8-20), T21I+L50F+A193P+S301P (29), T21I+S144A+T304I (11-28), T21I+C160F+A173V+V186A+T304I (28-29), T21I+A173V+T304I (15-16), and L50F+F140L+L167F+T304I (43-55).

Table 8 indicates Mpro substitutions and combinations of Mpro substitutions that have been found to reduce nirmatrelvir activity ≥3-fold (based on IC50 or Ki values) in biochemical assays using recombinant SARS-CoV-2 Mpro. Note that these Mpro substitutions were laboratory engineered and most were not observed in PAXLOVID-treated subjects in clinical trials. In addition, according to public sequence databases, most of these substitutions have not been observed in clinical isolates or have been observed but with global cumulative frequencies ≤0.002%. Thus, the clinical relevance of these substitutions is unclear. The following Mpro substitutions and combinations of Mpro substitutions emerged in cell culture in the presence of nirmatrelvir but conferred <3-fold reduced nirmatrelvir activity in biochemical assays: T21I, S46F, L50F, P108S, T135I, C160F, T169I, V186A, A191V, A193P, P252L, S301P, T304I, T21I+T304I, and L50F+T304I.

Table 8: SARS-CoV-2 Mpro Amino Acid Substitutions That Reduce Nirmatrelvir Activity ≥3-Fold in Biochemical Assays

Single Substitutions

(IC50/Ki value fold change in biochemical assay)

Y54A/C (3.0-25), F140A/L/S (1.2-230), G143S (3.6-148), S144A/F/G/M/W/Y (1.2-76), S144D/E/H/Q/T/V (81-480), S144K/L/P/R (1,165->5,319), H164N (1.9-6.7), M165D/F/G/T (5.7-51), M165H/K/P/R/W (>384), M165Y (3,838), E166A/G/K/L/Q (4.5-77), E166D/H/I/N/V/Y (143-708), E166R/V (>1,538-7,700), L167F (1.4-4.5), P168del (4.5-9.3), H172D/F/G/K/Q/Y (10-91), H172A/C/E/M/N/R/V/Y (114-858), H172I/L/S/T (1,172-6,740), A173S/V (4.1-52), R188G (38), Q189E/K (1.6-16), Q192A/C/D/E/F/G/H/I/K/L/P/R/S/T/V/W (5.0-61), Q192Y (>384), A260V (0.6-3.3), and V297A (3.0).

≥2 Substitutions

(IC50/Ki value fold change in biochemical assay)

T21I+S144A (20), T21I+E166V (120-11,000), T21I+A173V (15), L50F+E166V (100-4,500), T135I+T304I (5.1), F140L+A173V (95), S144A+T304I (28), E166V+L232R (5,700), P168del+A173V (170-536), H172Y+P252L (180), A173V+T304I (28), T21I+S144A+T304I (51), T21I+A173V+T304I (55), L50F+E166A+L167F (52-180), T21I+L50F+A193P+S301P (7.3), L50F+F140L+L167F+T304I (190), and T21I+C160F+A173V+V186A+T304I (28).

In Clinical Trials

Treatment-emergent substitutions were evaluated among subjects in clinical trials EPIC-HR/SR with sequence data available at both baseline and post-baseline visits (n=907 PAXLOVID-treated subjects, n=946 placebo-treated subjects). SARS-CoV-2 Mpro amino acid changes were classified as PAXLOVID treatment-emergent substitutions if they occurred at the same amino acid position in 3 or more PAXLOVID-treated subjects and were ≥2.5-fold more common in PAXLOVID-treated subjects than placebo-treated subjects. The following PAXLOVID treatment-emergent Mpro substitutions were observed: T98I/R/del(n=4), E166V (n=3), and W207L/R/del (n=4). In biochemical assays, the T98I and W207L/R substitutions did not affect nirmatrelvir activity (Ki value fold changes were 0.3 and 0.7/0.3, respectively), whereas the E166V substitution (which occurs at a Mpro-nirmatrelvir contact residue) reduced nirmatrelvir activity 187-7,700-fold. Within the Mpro cleavage sites, the following PAXLOVID treatment-emergent substitutions were observed: A5328S/V(n=7) and S6799A/P/Y (n=4). These cleavage site substitutions were not associated with the co-occurrence of any specific Mpro substitutions. In a cell culture replicon assay, the A5328S/V and S6799A substitutions did not affect nirmatrelvir activity (EC50 value fold changes were 0.3/0.2 and 0.7, respectively).

None of the treatment-emergent substitutions listed above in Mpro or Mpro cleavage sites occurred in PAXLOVID-treated subjects who experienced hospitalization. Thus, the clinical significance of these substitutions is unknown.

Viral RNA Rebound and Treatment-Emergent Substitutions

EPIC-HR and EPIC-SR were not designed to evaluate COVID-19 rebound; exploratory analyses were conducted to assess the relationship between PAXLOVID use and rebound in viral RNA shedding levels.

Post-treatment increases in SARS-CoV-2 RNA shedding levels in nasopharyngeal samples were observed on Day 10 and/or Day 14 in a subset of PAXLOVID and placebo recipients in EPIC-HR and EPIC-SR, irrespective of COVID-19 symptoms. The frequency of detection of post-treatment viral RNA rebound varied according to analysis parameters, but was generally similar among PAXLOVID and placebo recipients. A similar or smaller percentage of placebo recipients compared to PAXLOVID recipients had nasopharyngeal viral RNA results < lower limit of quantitation (LLOQ) at all study timepoints in both the treatment and post-treatment periods.

In EPIC-HR, of 59 PAXLOVID-treated subjects identified with post-treatment viral RNA rebound and with available viral sequence data, treatment-emergent substitutions in Mpro potentially reducing nirmatrelvir activity were detected in 2 (3%) subjects, including E166V in 1 subject and T304I in 1 subject. Both subjects had viral RNA shedding levels <LLOQ by Day 14.

Post-treatment viral RNA rebound was not associated with the primary clinical outcome of COVID-19 related hospitalization or death from any cause through Day 28 following the single 5-day course of PAXLOVID treatment. The clinical relevance of post-treatment increases in viral RNA following PAXLOVID or placebo treatment is unknown.

Cross-Resistance

Cross-resistance is not expected between nirmatrelvir and remdesivir or any other anti-SARS-CoV-2 agents with different mechanisms of action (i.e., agents that are not Mpro inhibitors).

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Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nirmatrelvir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral drug [see Microbiology (12.4)].

Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.

12.2 Pharmacodynamics

Cardiac Electrophysiology

At 3 times the steady state peak plasma concentration (Cmax) at the recommended dose, nirmatrelvir does not prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

The pharmacokinetics of nirmatrelvir/ritonavir were similar in healthy subjects and in subjects with mild-to-moderate COVID-19.

Nirmatrelvir AUC increased in a less than dose proportional manner over a single dose range from 250 mg to 750 mg (0.83 to 2.5 times the approved recommended dose) and multiple dose range from 75 mg to 500 mg (0.25 to 1.67 times the approved recommended dose), when administered in combination with 100 mg ritonavir. Nirmatrelvir steady state was achieved on Day 2 following administration of the approved recommended dosage and the mean accumulation ratio was approximately 2-fold.

The pharmacokinetic properties of nirmatrelvir/ritonavir are displayed in Table 3.

Table 3: Pharmacokinetic Properties of Nirmatrelvir and Ritonavir in Healthy Subjects
Nirmatrelvir (When Given With Ritonavir) Ritonavir
Abbreviations: CL/F=apparent clearance; hr=hour; L/hr=liters per hour; T½=terminal elimination half-life; Tmax=the time to reach Cmax; Vz/F=apparent volume of distribution.
*
Represents data after a single dose of 300 mg nirmatrelvir (2 × 150 mg tablet formulation) administered together with 100 mg ritonavir tablet in healthy subjects.
†
Following a single oral dose of nirmatrelvir 300 mg boosted ritonavir 100 mg at -12 hours, 0 hours and 12 hours, administered under fed (high fat and high calorie meal) or fasted conditions.
‡
Red blood cell to plasma ratio.
§
300 mg nirmatrelvir (oral suspension formulation) co-administered with 100 mg ritonavir (tablet formulation) twice daily for 3 days.
Determined by 19F-NMR analysis following 300 mg nirmatrelvir oral suspension administered at 0 hr enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours, and 24 hours.
#
Determined by 14C analysis following 600 mg 14C-ritonavir oral solution (6 times the approved ritonavir dose).

Absorption

  Tmax (hr), median

3.00*

3.98*

  Food effect

Test/reference (fed/fasted) ratios of adjusted geometric means (90% CI) AUCinf and Cmax for nirmatrelvir were 119.67 (108.75, 131.68) and 161.01 (139.05, 186.44), respectively.†

Distribution

  % bound to human plasma proteins

69%

98–99%

  Blood-to-plasma ratio

0.60

0.14‡

  Vz/F (L), mean

104.7§

112.4§

Elimination

  Major route of elimination

Renal elimination

Hepatic metabolism

  Half-life (T½) (hr), mean

6.05*

6.15*

  Oral clearance (CL/F) (L/hr), mean

8.99§

13.92§

Metabolism

  Metabolic pathways

Nirmatrelvir is a CYP3A substrate but when dosed with ritonavir, metabolic clearance is minimal.

Major CYP3A, Minor CYP2D6

Excretion

  % drug-related material in feces

35.3%

86.4%#

  % of dose excreted as total (unchanged drug) in feces

27.5%

33.8%#

  % drug-related material in urine

49.6%

11.3%#

  % of dose excreted as total (unchanged drug) in urine

55.0%

3.5%#

The predicted Day 5 nirmatrelvir exposure parameters in adult subjects with mild-to-moderate COVID-19 who were treated with PAXLOVID in EPIC-HR are presented in Table 4.

Table 4: Predicted Day 5 Nirmatrelvir Exposure Parameters Following Administration of Nirmatrelvir/Ritonavir 300 mg/100 mg Twice Daily in Subjects with Mild-to-Moderate COVID-19
Pharmacokinetic Parameter (units)* Nirmatrelvir†
Abbreviations: Cmax=predicted maximal concentration; Cmin=predicted minimal concentration (Ctrough).
*
Data presented as geometric mean (10th and 90th percentile).
†
Based on 1,017 subjects with their post hoc PK parameters.
‡
AUCtau=predicted area under the plasma concentration-time profile from time 0 to 12 hours for twice-daily dosing.

Cmax (µg/mL)

3.29 (1.93, 5.40)

AUCtau (µg*hr/mL)‡

28.3 (12.5, 52.5)

Cmin (µg/mL)

1.40 (0.48, 3.45)

Effect of Food

No clinically significant differences in the pharmacokinetics of nirmatrelvir were observed following administration of a high fat meal (800-1,000 calories; 50% fat) to healthy subjects.

Specific Populations

There were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on age (18 to 86 years), sex, or race/ethnicity.

Pediatric Patients

The pharmacokinetics of nirmatrelvir/ritonavir in patients less than 18 years of age have not been established.

Patients with Renal Impairment

The pharmacokinetics of nirmatrelvir in subjects with renal impairment following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg were determined. Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in subjects with mild renal impairment was 30% and 24% higher, in subjects with moderate renal impairment was 38% and 87% higher, and in subjects with severe renal impairment was 48% and 204% higher, respectively.

The pharmacokinetics of nirmatrelvir in subjects with mild-to-moderate COVID-19 and severe renal impairment (eGFR<30 mL/min) either requiring intermittent hemodialysis (n=12) or not requiring hemodialysis (n=2) were evaluated after administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 for a total of 5 doses.

The administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 in subjects with severe renal impairment, either requiring intermittent hemodialysis or not requiring hemodialysis resulted in comparable exposures on Day 1 and at steady-state (AUC0-24 and Cmax) compared to those observed in subjects with normal renal function receiving 300 mg/100 mg nirmatrelvir/ritonavir twice daily for 5 days. During a 4-hour hemodialysis session, approximately 6.9% of nirmatrelvir dose was cleared through dialysis. Hemodialysis clearance was 1.83 L/h.

Patients with Hepatic Impairment

The pharmacokinetics of nirmatrelvir were similar in patients with moderate (Child-Pugh Class B) hepatic impairment compared to healthy subjects following administration of a single oral dose of nirmatrelvir 100 mg (0.33 times the approved recommended dose) co-administered with ritonavir 100 mg. The impact of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of nirmatrelvir or ritonavir has not been studied.

Clinical Drug Interaction Studies

Table 5 describes the effect of other drugs on the Cmax and AUC of nirmatrelvir.

Table 5: The Effect of Other Drugs on the Pharmacokinetic Parameters of Nirmatrelvir
Co-administered Drug Dose (Schedule) N Percent Ratio (in combination with co-administered drug/alone) of Nirmatrelvir Pharmacokinetic Parameters (90% CI);
No Effect=100
Co-administered Drug Nirmatrelvir/ Ritonavir Cmax AUC*
Abbreviations: AUC=area under the plasma concentration-time curve; AUCinf=area under the plasma concentration-time profile from time zero extrapolated to infinite time; AUCtau=area under the plasma concentration-time profile from time zero to time tau (τ), the dosing interval. CI=confidence interval; Cmax=observed maximum plasma concentrations.
*
For carbamazepine, AUC=AUCinf; for itraconazole, AUC=AUCtau.
†
Carbamazepine titrated up to 300 mg twice daily on Day 8 through Day 15 (e.g., 100 mg twice daily on Day 1 through Day 3 and 200 mg twice daily on Day 4 through Day 7).

Carbamazepine†

300 mg twice daily
(16 doses)

300 mg/100 mg once daily
(2 doses)

10

56.82
(47.04, 68.62)

44.50
(33.77, 58.65)

Itraconazole

200 mg once daily
(8 doses)

300 mg/100 mg twice daily
(5 doses)

11

118.57
(112.50, 124.97)

138.82
(129.25, 149.11)

Table 6 describes the effect of nirmatrelvir/ritonavir on the Cmax and AUCinf of other drugs.

Table 6: Effect of Nirmatrelvir/Ritonavir on Pharmacokinetics of Other Drugs
Co-administered Drug Dose (Schedule) N Percent Ratio of Test/Reference of Geometric Means (90% CI);
No Effect=100
Co-administered Drug Nirmatrelvir/ Ritonavir Cmax AUCinf
Abbreviations: AUCinf=area under the plasma concentration-time curve from time zero extrapolated to infinite time; CI=confidence interval; Cmax=observed maximum plasma concentrations; CYP3A4=cytochrome P450 3A4; OATP1B1=organic anion transporter polypeptide 1B1; P-gp=p-glycoprotein.
*
For midazolam, Test=nirmatrelvir/ritonavir plus midazolam, Reference=Midazolam. Midazolam is an index substrate for CYP3A4. For dabigatran, Test=nirmatrelvir/ritonavir plus dabigatran, Reference=Dabigatran. Dabigatran is an index substrate for P-gp. For rosuvastatin, Test=nirmatrelvir/ritonavir plus rosuvastatin, Reference=Rosuvastatin. Rosuvastatin is an index substrate for OATP1B1.

Midazolam*

2 mg
(1 dose)

300 mg/100 mg twice daily
(9 doses)

10

368.33
(318.91, 425.41)

1430.02
(1204.54, 1697.71)

Dabigatran*

75 mg
(1 dose)

300 mg/100 mg twice daily
(4 doses)

24

233.06
(172.14, 315.54)

194.47
(155.29, 243.55)

Rosuvastatin*

10 mg

(1 dose)

300 mg/100 mg twice daily
(3 doses)

12

212.44

(174.31, 258.90)

131.18

(115.89, 148.48)

In Vitro Studies

Cytochrome P450 (CYP) Enzymes:

•
Nirmatrelvir is a reversible and time-dependent inhibitor of CYP3A, but not an inhibitor CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Nirmatrelvir is an inducer of CYP2B6, 2C8, 2C9, and 3A4, but there is minimal risk for pharmacokinetic interactions arising from induction of these CYP enzymes at the proposed therapeutic dose.
•
Ritonavir is a substrate of CYP2D6 and CYP3A. Ritonavir is an inducer of CYP1A2, CYP2C9, CYP2C19, CYP2B6, and CYP3A.

Transporter Systems: Nirmatrelvir is an inhibitor of P-gp and OATP1B1. Nirmatrelvir is a substrate for P-gp, but not BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, OATP1B1, OATP1B3, OATP2B1, or OATP4C1.

12.4 Microbiology

Mechanism of Action

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nonstructural protein 5 (nsp5) protease. Inhibition of SARS-CoV-2 Mpro renders it incapable of processing the viral polyproteins pp1a and pp1ab, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro 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 Mpro active site by X-ray crystallography.

Antiviral Activity

Cell Culture Antiviral Activity

Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 (USA-WA1/2020 isolate) infection of differentiated normal human bronchial epithelial (dNHBE) cells with EC50 and EC90 values of 62 nM (31 ng/mL) and 181 nM (90 ng/mL), respectively, after 3 days of drug exposure.

The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7, BQ.1, BQ.1.11, XBB.1.5, EG.5, and JN.1 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC50 value of 88 nM (range: 39-146 nM) against the Omicron sub-variants, reflecting EC50 value fold changes ≤1.8 relative to the USA-WA1/2020 isolate.

In addition, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1 variants was assessed in Vero E6 P-gp knockout cells. Nirmatrelvir had a median EC50 value of 25 nM (range: 16-141 nM). The Beta variant was the least susceptible variant tested, with an EC50 value fold change of 3.7 relative to USA-WA1/2020. The other variants had EC50 value fold changes ≤1.1 relative to USA-WA1/2020.

Clinical Antiviral Activity

In clinical trial EPIC-HR, which enrolled subjects who were primarily infected with the SARS-CoV-2 Delta variant, PAXLOVID treatment was associated with a 0.83 log10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5 (mITT1 analysis set, all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment); similar results were observed in the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days). In the EPIC-SR trial, which included subjects who were infected with SARS-CoV-2 Delta (79%) or Omicron (19%) variants, PAXLOVID treatment was associated with a 1.05 log10 copies/mL greater median decline in viral RNA shedding levels in nasopharyngeal samples through Day 5, with similar declines observed in subjects infected with Delta or Omicron variants. The degree of reduction in viral RNA levels relative to placebo following 5 days of PAXLOVID treatment was similar between unvaccinated high-risk subjects in EPIC-HR and vaccinated high-risk subjects in EPIC-SR.

Antiviral Resistance

In Cell Culture and Biochemical Assays

SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with Mpro substitutions, and biochemical assays with recombinant SARS-CoV-2 Mpro containing amino acid substitutions. Table 7 indicates Mpro substitutions and combinations of Mpro substitutions that have been observed in SARS-CoV-2 under nirmatrelvir selective pressure in cell culture. Individual Mpro substitutions are listed regardless of whether they occurred alone or in combination with other Mpro substitutions. Note that the Mpro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of Mpro. Substitutions at other Mpro cleavage sites have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown.

Abbreviation: ND=no data.
*
EC50 value fold change ranges are shown in instances where multiple data points have been reported.

Table 7: SARS-CoV-2 Mpro Amino Acid Substitutions Selected by Nirmatrelvir in Cell Culture*

Single Substitutions

(EC50 value fold change in cell culture)

T21I (1.1-4.8), S46F (ND), L50F (1.2-4.2), P108S (ND), T135I (ND), F140L (4.1), S144A (2.2-5.3), C160F (2.1), E166A (3.3), E166V (25‑288), L167F (1.9-2.5), T169I (ND), H172Y (15), A173V (0.9-2.3), V186A (ND), R188G (ND), A191V (0.7-1.5), A193P (ND), P252L (5.9), S301P (ND), and T304I (1.4-5.5).

≥2 Substitutions

(EC50 value fold change in cell culture)

T21I+S144A (9.4), T21I+E166V (83-250), T21I+A173V (3.1-8.9), T21I+T304I (3.0-7.9), L50F+E166V (34-175), L50F+T304I (5.9), T135I+T304I (3.8), F140L+A173V (10-17), H172Y+P252L (ND), A173V+T304I (5.8-20), T21I+L50F+A193P+S301P (29), T21I+S144A+T304I (11-28), T21I+C160F+A173V+V186A+T304I (28-29), T21I+A173V+T304I (15-16), and L50F+F140L+L167F+T304I (43-55).

Table 8 indicates Mpro substitutions and combinations of Mpro substitutions that have been found to reduce nirmatrelvir activity ≥3-fold (based on IC50 or Ki values) in biochemical assays using recombinant SARS-CoV-2 Mpro. Note that these Mpro substitutions were laboratory engineered and most were not observed in PAXLOVID-treated subjects in clinical trials. In addition, according to public sequence databases, most of these substitutions have not been observed in clinical isolates or have been observed but with global cumulative frequencies ≤0.002%. Thus, the clinical relevance of these substitutions is unclear. The following Mpro substitutions and combinations of Mpro substitutions emerged in cell culture in the presence of nirmatrelvir but conferred <3-fold reduced nirmatrelvir activity in biochemical assays: T21I, S46F, L50F, P108S, T135I, C160F, T169I, V186A, A191V, A193P, P252L, S301P, T304I, T21I+T304I, and L50F+T304I.

Table 8: SARS-CoV-2 Mpro Amino Acid Substitutions That Reduce Nirmatrelvir Activity ≥3-Fold in Biochemical Assays

Single Substitutions

(IC50/Ki value fold change in biochemical assay)

Y54A/C (3.0-25), F140A/L/S (1.2-230), G143S (3.6-148), S144A/F/G/M/W/Y (1.2-76), S144D/E/H/Q/T/V (81-480), S144K/L/P/R (1,165->5,319), H164N (1.9-6.7), M165D/F/G/T (5.7-51), M165H/K/P/R/W (>384), M165Y (3,838), E166A/G/K/L/Q (4.5-77), E166D/H/I/N/V/Y (143-708), E166R/V (>1,538-7,700), L167F (1.4-4.5), P168del (4.5-9.3), H172D/F/G/K/Q/Y (10-91), H172A/C/E/M/N/R/V/Y (114-858), H172I/L/S/T (1,172-6,740), A173S/V (4.1-52), R188G (38), Q189E/K (1.6-16), Q192A/C/D/E/F/G/H/I/K/L/P/R/S/T/V/W (5.0-61), Q192Y (>384), A260V (0.6-3.3), and V297A (3.0).

≥2 Substitutions

(IC50/Ki value fold change in biochemical assay)

T21I+S144A (20), T21I+E166V (120-11,000), T21I+A173V (15), L50F+E166V (100-4,500), T135I+T304I (5.1), F140L+A173V (95), S144A+T304I (28), E166V+L232R (5,700), P168del+A173V (170-536), H172Y+P252L (180), A173V+T304I (28), T21I+S144A+T304I (51), T21I+A173V+T304I (55), L50F+E166A+L167F (52-180), T21I+L50F+A193P+S301P (7.3), L50F+F140L+L167F+T304I (190), and T21I+C160F+A173V+V186A+T304I (28).

In Clinical Trials

Treatment-emergent substitutions were evaluated among subjects in clinical trials EPIC-HR/SR with sequence data available at both baseline and post-baseline visits (n=907 PAXLOVID-treated subjects, n=946 placebo-treated subjects). SARS-CoV-2 Mpro amino acid changes were classified as PAXLOVID treatment-emergent substitutions if they occurred at the same amino acid position in 3 or more PAXLOVID-treated subjects and were ≥2.5-fold more common in PAXLOVID-treated subjects than placebo-treated subjects. The following PAXLOVID treatment-emergent Mpro substitutions were observed: T98I/R/del(n=4), E166V (n=3), and W207L/R/del (n=4). In biochemical assays, the T98I and W207L/R substitutions did not affect nirmatrelvir activity (Ki value fold changes were 0.3 and 0.7/0.3, respectively), whereas the E166V substitution (which occurs at a Mpro-nirmatrelvir contact residue) reduced nirmatrelvir activity 187-7,700-fold. Within the Mpro cleavage sites, the following PAXLOVID treatment-emergent substitutions were observed: A5328S/V(n=7) and S6799A/P/Y (n=4). These cleavage site substitutions were not associated with the co-occurrence of any specific Mpro substitutions. In a cell culture replicon assay, the A5328S/V and S6799A substitutions did not affect nirmatrelvir activity (EC50 value fold changes were 0.3/0.2 and 0.7, respectively).

None of the treatment-emergent substitutions listed above in Mpro or Mpro cleavage sites occurred in PAXLOVID-treated subjects who experienced hospitalization. Thus, the clinical significance of these substitutions is unknown.

Viral RNA Rebound and Treatment-Emergent Substitutions

EPIC-HR and EPIC-SR were not designed to evaluate COVID-19 rebound; exploratory analyses were conducted to assess the relationship between PAXLOVID use and rebound in viral RNA shedding levels.

Post-treatment increases in SARS-CoV-2 RNA shedding levels in nasopharyngeal samples were observed on Day 10 and/or Day 14 in a subset of PAXLOVID and placebo recipients in EPIC-HR and EPIC-SR, irrespective of COVID-19 symptoms. The frequency of detection of post-treatment viral RNA rebound varied according to analysis parameters, but was generally similar among PAXLOVID and placebo recipients. A similar or smaller percentage of placebo recipients compared to PAXLOVID recipients had nasopharyngeal viral RNA results < lower limit of quantitation (LLOQ) at all study timepoints in both the treatment and post-treatment periods.

In EPIC-HR, of 59 PAXLOVID-treated subjects identified with post-treatment viral RNA rebound and with available viral sequence data, treatment-emergent substitutions in Mpro potentially reducing nirmatrelvir activity were detected in 2 (3%) subjects, including E166V in 1 subject and T304I in 1 subject. Both subjects had viral RNA shedding levels <LLOQ by Day 14.

Post-treatment viral RNA rebound was not associated with the primary clinical outcome of COVID-19 related hospitalization or death from any cause through Day 28 following the single 5-day course of PAXLOVID treatment. The clinical relevance of post-treatment increases in viral RNA following PAXLOVID or placebo treatment is unknown.

Cross-Resistance

Cross-resistance is not expected between nirmatrelvir and remdesivir or any other anti-SARS-CoV-2 agents with different mechanisms of action (i.e., agents that are not Mpro inhibitors).

Medication Guide

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