A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir

Abstract

Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC₉₀), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir's cytochrome P450 (CYP) 3A4-mediated metabolism which results in renal elimination becoming the primary route of nirmatrelvir elimination when dosed concomitantly. Nirmatrelvir exhibits absorption-limited nonlinear pharmacokinetics. When coadministered with ritonavir in patients with mild-to-moderate COVID-19, nirmatrelvir reaches a maximum concentration of 3.43 µg/mL (11.7× EC₉₀) in approximately 3 h on day 5 of dosing, with a geometric mean day 5 trough concentration of 1.57 µg/mL (5.4× EC₉₀). Drug interactions with nirmatrelvir/ritonavir (PAXLOVID^TM) are primarily attributed to ritonavir-mediated CYP3A4 inhibition, and to a lesser extent CYP2D6 and P-glycoprotein inhibition. Population pharmacokinetics and quantitative systems pharmacology modeling support twice daily dosing of 300 mg/100 mg nirmatrelvir/ritonavir for 5 days, with a reduced 150 mg/100 mg dose for patients with moderate renal impairment. Rapid clinical development of nirmatrelvir/ritonavir in response to the emerging COVID-19 pandemic was enabled by innovations in clinical pharmacology research, including an adaptive phase 1 trial design allowing direct to pivotal phase 3 development, fluorine nuclear magnetic resonance spectroscopy to delineate absorption, distribution, metabolism, and excretion profiles, and innovative applications of model-informed drug development to accelerate development.

Fig. 1

Nirmatrelvir acts on the proteolysis step of the SARS-CoV-2 coronavirus inside the host cell¹. ¹Reprinted from Alzyoud et al. [61]. Drug Design, Development and Therapy 2022:16 2463–2478 Originally published by and used with permission from Dove Medical Press Ltd. ACE2, angiotensin-converting enzyme 2; M^pro, main protease; PL^pro, papain-like protease; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2

Fig. 2

QSP-predicted viral load decline versus time with various dose durations of 300 mg/100 mg nirmatrelvir/ritonavir¹. Simulation of a virtual population (n = 502) to predict viral load effect for nirmatrelvir/ritonavir 300 mg/100 mg twice daily in symptomatic patients with COVID-19. ¹Reprinted from Singh et al. [24]. BID, twice daily; PI, prediction interval; QSP, quantitative systems pharmacology model

Fig. 3

Viral load CFB versus nirmatrelvir C_trough on day 5. Blue dots represent individual data from patients enrolled in EPIC-HR, the pivotal nirmatrelvir/ritonavir phase 2/3 study, who received 300 mg/100 mg nirmatrelvir/ritonavir twice daily for 5 days [50]. Data from patients in the active treatment arm of EPIC-HR who were hospitalized are represented by red dots. Median PopPK-predicted nirmatrelvir day C_trough is shown as a black dashed line, and nirmatrelvir concentration relative to EC₉₀ (292 ng/mL) reference lines are shown as blue dashed lines. A linear regression is shown as a solid blue line with an associated 95% confidence interval shaded in gray. CFB, change from baseline; C_min, minimum observed concentration; C_trough, trough concentration; EC₉₀, 90% effective concentration; EPIC-HR, Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients; PopPK, population pharmacokinetic model

Fig. 4

Nirmatrelvir CL/F versus eGFR following a single 100 mg nirmatrelvir dose enhanced with 100 mg ritonavir¹. The bold line is the predicted linear regression line; the shaded area represents the 90% confidence interval. The vertical lines represent the boundary criteria of the renal function groups. ¹Reprinted from Toussi et al. [47]. CKD–EPI, Chronic Kidney Disease Epidemiology Collaboration equation; CL/F, apparent oral clearance; eGFR, estimated glomerular filtration rate

Fig. 5

PopPK-predicted nirmatrelvir C_trough on day 5 of twice daily nirmatrelvir with 100 mg ritonavir dosing for simulated patients with varying degrees of renal impairment¹. Open circles represent predicted C_trough; red symbols represent group means; blue lines represent 10th and 90th percentiles; the red-dashed line is the EC₉₀ (292 ng/mL). (A) 150 mg/100 mg nirmatrelvir/ritonavir every 12 h, with clearance reduced by one-half (i.e., moderate renal impairment); (B) 300 mg/100 mg nirmatrelvir/ritonavir every 12 h, with clearance reduced by one-third (i.e., mild renal impairment); (C) 300 mg/100 mg nirmatrelvir/ritonavir every 12 h, with no reduction in clearance (reference group). ¹Reprinted from Toussi et al. [47]. C_trough, trough concentration; EC₉₀, 90% effective concentration; PopPK, population pharmacokinetic model