Pharmacokinetics of Adefovir after Oral Administration of Adefovir Dipivoxil 10 mg in Healthy Japanese Males and Japanese Patients with Chronic Hepatitis B

抄録

The pharmacokinetics of adefovir dipivoxil, a novel reverse transcriptase inhibitor for the treatment of chronic hepatitis B, were investigated in healthy Japanese subjects (n=12) and Japanese patients with chronic hepatitis B (n=11).
Healthy males received single and multiple doses (once daily for 5 days) of adefovir dipivoxil 10 mg. After the first and final doses, blood and urine samples were collected over 48 hours and concentrations of adefovir, the hydrolysed active metabolite, measured by LC-MS/MS. Adefovir pharmacokinetic parameters (mean±SD) were comparable after single and multiple dosing: C_max 22.9±3.3 and 24.5±3.8 ng/mL, respectively. The single dose AUC _0-∞ (239.4±35.7 ng·hr/mL) and half-life (6.89±1.21 hr) were also similar to AUC _0-24 (249.3±32.9 ng·hr/mL) and t _1/2 (7.73±0.73 hr) after multiple dosing. The steadystate accumulation ratio was 1.05±0.12, indicating a lack of appreciable accumulation during multiple dosing. Approximately 60% of the dose was recovered in urine as adefovir.
Chronic hepatitis B patients with evidence of abnormal liver function associated with YMDD mutant hepatitis B virus and taking lamivudine 100 mg once daily were also studied. The results were similar to those in healthy subjects. C_max and AUC _0-∞ after the first dose of adefovir dipivoxil 10 mg in chronic hepatitis B patients were 20.1±3.3 ng/mL and 272.8±51.3 ng·hr/mL, respectively. Furthermore, the pharmacokinetics of adefovir were comparable in patients with and without cirrhosis. Adefovir pharmacokinetics in Japanese subjects with normal renal function are therefore not altered by chronic hepatitis B infection, lamivudine co-administration or the severity of hepatic disease. These Japanese results are consistent with those in Western subjects and a major inter-ethnic difference is not observed.