Pharmacokinetics, safety and tolerance of single- and multiple-dose adefovir dipivoxil in healthy Chinese subjects

Abstract

Aims: To assess the pharmacokinetics, safety and tolerance of single- and multiple-dose adefovir dipivoxil (ADV) in healthy Chinese subjects. Methods: Forty-two healthy subjects were randomized into 5, 10, 20, 40 and 60-mg dose groups for safety assessment. Nine and 10 healthy males were enrolled for a single-dose pharmacokinetic profile and assessment of the effect of food on the pharmacokinetics of adefovir (PMEA), respectively. Another 10 healthy subjects were enrolled for a multiple-dose safety assessment and pharmacokinetic profile. Safety and tolerance were evaluated by monitoring adverse events and laboratory parameters, and pharmacokinetics were assessed by determining PMEA concentrations with a validated LC-MS/MS method. Results: No serious adverse events occurred. The pharmacokinetic parameters of PMEA following ADV 10, 20 and 40 mg were: geometric mean [95% confidence interval (CI)] for AUC 0-24 h 227 (205, 253), 423 (361, 506) and 686 (585, 828) μg l -1 h, Cmax 23.0 (20.7, 27.3), 47.4 (42.8, 53.2) and 83.6 (72.6, 97.4) μg l-1, arithmetic mean (95% CI) for t1/2 6.8 (6.3, 7.3), 7.4 (6.7, 8.1) and 7.7 (6.5, 8.9) h, median value (range) for tmax 1.00 (1.00-2.00), 0.75 (0.75-2.50) and 1.00 (0.75-2.00) h, respectively. The steady-state pharmacokinetics parameters were similar to those following a single dose. The AUC of PMEA was unaffected by food. Conclusion: ADV is safe and well tolerated in healthy Chinese subjects. The mean C max of PMEA is proportional to dose, but the linearity of AUC needs further study. There is no accumulation following multiple doses of ADV and the extent of absorption of PMEA is unaffected by food. © 2006 The Authors.