(M-086) Population Pharmacokinetic (Pop PK) Modeling of Nirmatrelvir/Ritonavir in Severe Renal Impaired Participants with COVID-19 either on or not on Hemodialysis

Phylinda Chan, PhD – Pharmacometrics Group Lead, Pfizer R&D UK Ltd

Objectives: A recent study (NCT05487040)¹ investigated the PK of nirmatrelvir co-administered with ritonavir (RTV) in severe renal impaired (SRI) adults with COVID-19 who may or may not require hemodialysis (HD). This analysis aimed to characterize the PK of nirmatrelvir co-administered with RTV in SRI adults with COVID-19 and to simulate nirmatrelvir exposures to support dose recommendation in SRI patients requiring intermittent HD or not yet requiring HD.

Methods: Pop PK analysis was performed by updating a previous model based on pooled 12 phase 1/2/3 studies² with SRI data¹ using NONMEM 7.5 with first-order conditional estimation method with interaction. The Pop PK model was a 2-compartment model with first-order absorption including allometric scaling of body weight with fixed exponents (0.75 for clearances and 1 for volumes) and dose-dependent absorption (power function on relative bioavailability [F1]). The effect of baseline body surface area-normalized creatinine clearance (nCLCR) on clearance (CL) was modeled using a breakpoint model where nirmatrelvir CL increased with nCLCR up to the estimated breakpoint of 70 mL/min/1.73 m² and was independent of nCLCR above the estimated breakpoint. The model also included the effects of co-administration of CYP3A inhibitors and inducers and COVID-19 infection on CL, formulation (nirmatrelvir 150 mg tablet) on F1, and age on central volume of distribution. Residual random effects were described with separate proportional errors for Phase 1 (serial sampling) and Phase 2/3 (sparse sampling) data.
A simulation dataset with 5000 sample size was created for each renal function category (normal, mild, moderate, non-HD severe, severe on HD) to simulate nirmatrelvir exposures. Covariates were sampled from a multivariate normal density based on the covariance of age, weight and nCLCR observed in the Pop PK dataset. Dose recommendation was based on nirmatrelvir exposures matching adults with COVID-19 and with normal renal function following nirmatrelvir/RTV 300 mg/100 mg twice daily (BID) given orally for 5 days.

Results: The SRI study contains 14 adults including 2 non-HD participants and 12 HD participants with COVID-19. There were 33 plasma and 61 venous port evaluable observations. The SRI PK data were adequately described by the Pop PK model with a separate CL estimated for PK samples collected during HD. At a studied dose of 300 mg on day 1 followed by 150 mg on days 2-5 once daily (QD), adults with SRI showed similar exposure compared to adults with normal renal function (nirmatrelvir/RTV 300 mg/100 mg BID). For HD and non-HD, >90% of simulated subjects achieved Cmin≥EC90 of 292 ng/mL after the first dose and on day 5.

Conclusion: Simulation results support a nirmatrelvir dose of 300 mg with RTV 100 mg on day 1 followed by nirmatrelvir 150 mg with RTV 100 mg on days 2-5 QD orally for COVID-19 adult patients with SRI (non-HD or HD).

Citations: [1] A Study to measure the Amount of Study Medicine in Blood in Adult Participants with COVID-19 and Severe Kidney Disease. https://classic.clinicaltrials.gov/ct2/show/NCT05487040.

[2] Chan PLS, et al. Dosing recommendation of nirmatrelvir/ritonavir using an integrated population pharmacokinetic analysis. CPT Pharmacometrics Syst Pharmacol. 2023; 12: 1897-1910.