Understanding adefovir pharmacokinetics as a component of a transporter phenotyping cocktail

Abstract

Purpose: Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CL_R) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail.

Methods: Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination.

Results: A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h^-1 vs. 5.18 h^-1) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (K_m) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (V_max) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min.

Conclusion: The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high K_m value suggests that assessing renal OAT1 activity by CL_R has no relevant misspecification error with the cocktail doses used.

Keywords: Adefovir; Nonlinear renal elimination; OAT1-mediated drug-drug interactions; Population pharmacokinetics.