Model-Based Tacrolimus Dosing Using the Population Pharmacokinetic Analysis Under the Nirmatrelvir/Ritonavir Therapy

Nirmatrelvir/ritonavir is an antiviral agent used against severe acute respiratory syndrome coronavirus 2 infection and inhibits cytochrome P450 3A and P-glycoprotein. The concomitant use of nirmatrelvir/ritonavir markedly increases tacrolimus blood concentrations. Although temporary discontinuation or dose reduction of tacrolimus at the start of nirmatrelvir/ritonavir therapy is recommended in the package insert of this drug, little information is available on tacrolimus dosage adjustment when restarting. In this study, tacrolimus blood concentrations before and after nirmatrelvir/ritonavir co-administration were collected from national university hospitals across Japan, and population pharmacokinetic analysis was performed to develop an optimal dosing strategy for tacrolimus. In total, 83 tacrolimus blood concentrations from 15 patients were used in the analysis. First, the individual pharmacokinetic parameters of tacrolimus before the intake of nirmatrelvir/ritonavir were estimated by post hoc Bayesian analysis using previously reported population pharmacokinetic parameters based on a two-compartment model. The change in the relative bioavailability and clearance of tacrolimus after nirmatrelvir/ritonavir administration was estimated by population pharmacokinetic modeling. Consequently, tacrolimus clearance was considered almost completely inhibited, and relative bioavailability increased 7.99-fold with the co-administration of nirmatrelvir/ritonavir. The optimal dosing strategy based on the simulation was to withhold tacrolimus during nirmatrelvir/ritonavir therapy and to restart tacrolimus at 10% of the baseline dose on day 1, followed by 20% on day 3% and 50% on day 6, and increased to 100% on day 9 after discontinuation of nirmatrelvir/ritonavir, respectively. The proposed strategy will contribute to a safe and effective tacrolimus therapy when used in combination with nirmatrelvir/ritonavir.