Physiologically‐based pharmacokinetic modelling guided dose evaluations of nirmatrelvir/ritonavir in renal impairment for the management of COVID‐19

• Published in: British journal of clinical pharmacology Vol. 91; no. 4; pp. 1041 - 1048
• Main Authors: Ng, Tat Ming, Wang, Ziteng, Chan, Eric Chun Yong
• Format: Journal Article
• Language: English
• Published: England 01.04.2025
• Subjects: Antiviral Agents - administration & dosage; Antiviral Agents - pharmacokinetics; COVID-19 Drug Treatment; COVID‐19; Cytochrome P-450 CYP3A - metabolism; Dose-Response Relationship, Drug; dosing adjustment recommendation; Drug Combinations; Female; Humans; Male; Microsomes, Liver - metabolism; Middle Aged; Models, Biological; nirmatrelvir/ritonavir; physiologically‐based pharmacokinetic model; Renal Insufficiency - complications; Renal Insufficiency - metabolism; Ritonavir - administration & dosage; Ritonavir - pharmacokinetics; severe renal impairment; nirmatrelvir/ritonavir; COVID‐19; severe renal impairment; dosing adjustment recommendation; physiologically‐based pharmacokinetic model
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.16074

We aimed to address factors contributing to the pharmacokinetic changes of nirmatrelvir/ritonavir in renal impaired (RI) patients and recommend dosing adjustment via a physiologically‐based pharmacokinetic (PBPK) modelling approach. A PBPK model of nirmatrelvir/ritonavir was developed via Simcyp® Simulator. Sensitivity analysis of the influence of hepatic CYP3A4 intrinsic clearance and abundance, as well as hepatic non‐CYP3A4 metabolism (other human liver microsomes [HLM] CLint) was performed to evaluate the effects of RI on oral clearance of nirmatrelvir. Other HLM CLint, the most sensitive parameter, was adjusted, and the simulated plasma concentration profiles of nirmatrelvir in severe RI subjects were within the therapeutic index of 292–10 000 ng/mL for dosing regimens of loading doses of 300/100 mg followed by 150/100 mg or 75/100 mg twice daily of nirmatrelvir/ritonavir. Considering that nirmatrelvir is available as a 150 mg tablet, we recommend 300/100 mg followed by 150/100 mg twice daily as the dosing regimen to be investigated in severe RI.