tetano
Editor, Senior Moderator
Clin Pharmacokinet
. 2024 Jan 4.
doi: 10.1007/s40262-023-01339-y. Online ahead of print. A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir
Jacqueline Gerhart[SUP] 1 [/SUP], Donna S Cox[SUP] 2 [/SUP], Ravi Shankar P Singh[SUP] 3 [/SUP], Phylinda L S Chan[SUP] 4 [/SUP], Rohit Rao[SUP] 3 [/SUP], Richard Allen[SUP] 3 [/SUP], Haihong Shi[SUP] 5 [/SUP], Joanna C Masters[SUP] 6 [/SUP], Bharat Damle[SUP] 7 [/SUP]
Affiliations
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 (EC[SUB]90[/SUB]), 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× EC[SUB]90[/SUB]) in approximately 3 h on day 5 of dosing, with a geometric mean day 5 trough concentration of 1.57 µg/mL (5.4× EC[SUB]90[/SUB]). Drug interactions with nirmatrelvir/ritonavir (PAXLOVID[SUP]TM[/SUP]) 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.
. 2024 Jan 4.
doi: 10.1007/s40262-023-01339-y. Online ahead of print. A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir
Jacqueline Gerhart[SUP] 1 [/SUP], Donna S Cox[SUP] 2 [/SUP], Ravi Shankar P Singh[SUP] 3 [/SUP], Phylinda L S Chan[SUP] 4 [/SUP], Rohit Rao[SUP] 3 [/SUP], Richard Allen[SUP] 3 [/SUP], Haihong Shi[SUP] 5 [/SUP], Joanna C Masters[SUP] 6 [/SUP], Bharat Damle[SUP] 7 [/SUP]
Affiliations
- PMID: 38177893
- DOI: 10.1007/s40262-023-01339-y
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 (EC[SUB]90[/SUB]), 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× EC[SUB]90[/SUB]) in approximately 3 h on day 5 of dosing, with a geometric mean day 5 trough concentration of 1.57 µg/mL (5.4× EC[SUB]90[/SUB]). Drug interactions with nirmatrelvir/ritonavir (PAXLOVID[SUP]TM[/SUP]) 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.