Understanding adefovir pharmacokinetics as a component of a transporter phenotyping cocktail

• Published in: European journal of clinical pharmacology Vol. 80; no. 7; pp. 1069 - 1078
• Main Authors: Dong, Qian, Chen, Chunli, Taubert, Max, Bilal, Muhammad, Kinzig, Martina, Sörgel, Fritz, Scherf-Clavel, Oliver, Fuhr, Uwe, Dokos, Charalambos
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2024; Springer Nature B.V
• Subjects: Adefovir; Adefovir dipivoxil; Adenine - administration & dosage; Adenine - analogs & derivatives; Adenine - pharmacokinetics; Adult; Antiviral drugs; Bioavailability; Biological Availability; Biomedical and Life Sciences; Biomedicine; Digoxin; Digoxin - administration & dosage; Digoxin - blood; Digoxin - pharmacokinetics; Drug interaction; Drug Interactions; Female; Glomerular filtration rate; Humans; Kidneys; Male; Metformin; Metformin - administration & dosage; Metformin - blood; Metformin - pharmacokinetics; Middle Aged; Models, Biological; Organic Anion Transport Protein 1 - genetics; Organic Anion Transport Protein 1 - metabolism; Organophosphonates - administration & dosage; Organophosphonates - blood; Organophosphonates - pharmacokinetics; Pharmacokinetics; Pharmacology/Toxicology; Phenotype; Phenotyping; Sitagliptin Phosphate - pharmacokinetics; Young Adult; Population pharmacokinetics; Adefovir; OAT1-mediated drug-drug interactions; Nonlinear renal elimination
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-024-03673-x

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.