Pharmacokinetics of Nirmatrelvir/Ritonavir after Multiple Administration in a Phase 1, Open-Label Study in Healthy Chinese Adults and Compared with Non-Chinese Participants.

Abstract

Nirmatrelvir (PF-07321332) has demonstrated antiviral activity and an acceptable safety profile in clinical studies. This study aimed to demonstrate the pharmacokinetic (PK) profiles of Chinese participants after administration of nirmatrelvir/ritonavir, and to further evaluate the ethnic differences between different races. This Phase 1, open-label, single-site study assessed the PK, safety, and tolerability of nirmatrelvir 300 mg plus ritonavir 100 mg administered twice daily for 10 days in healthy Chinese adults. In total, 14 Chinese participants were enrolled with an age range of 24 to 43 years. Samples were collected after first-dose administration on day 1 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 h after drug administration) and last-dose administration on day 10 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after drug administration) to assess PK parameters after a single dose and multiple doses; pre-dose samples were collected on days 5, 8, and 10 to confirm that steady-state was achieved. All PK samples were assayed with a liquid chromatography-tandem mass spectrometry method to quantify plasma concentration of nirmatrelvir and ritonavir. Study participants were monitored for safety for 28-35 days after the last-dose administration. Adverse events (AEs), clinical safety laboratory tests, vital signs, and 12-lead electrocardiograms were all monitored during study. Results for Chinese participants were compared with results in healthy non-Chinese adult participants who received the same nirmatrelvir/ritonavir dose in other Phase 1 studies. All 14 healthy Chinese adults completed the study. Nirmatrelvir was rapidly absorbed, with a median t_max of approximately 2 h. Geometric mean nirmatrelvir C_max and AUC were 3.08 μg/mL and 19.66 μg·h/mL after the first dose and increased to 4.50 μg/mL and 32.01 μg·h/mL at steady state, with less than 2-fold accumulation and a mean terminal half-life of 6.84 h. Steady-state concentrations were achieved before day 5. Nirmatrelvir/ritonavir was well tolerated; 6 participants (42.9%) reported AEs, 4 of which (28.6%) were treatment-related mild dysgeusia. No serious AEs or discontinuations were reported. The results showed that the PK characteristics of nirmatrelvir/ritonavir in healthy Chinese adults were comparable with results from previous studies in non-Chinese healthy adults, with no apparent clinically significant differences observed between Chinese and non-Chinese participants. In healthy Chinese participants, the PK profile of nirmatrelvir 300 mg plus ritonavir 100 mg twice daily was comparable with that observed in non-Chinese participants, with an overall favorable safety profile, supporting the use of this dosing regimen for the Chinese population. NCT05339334.