Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS clinical trials group protocol 062)

The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over an 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 ± 192 ng · h/ml), maximum concentration of drug in serum (1,751 ± 180 ng/ml), and half-life (2.04 ± 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 ± 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 ± 1,222 ng · h/ml) and maximum concentration of drug in serum (5,220 ± 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2,79 ± 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 ± 0.15 in HIV-infected patients with mild hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy- proven cirrhosis, our results suggest that ZDV could accumulate in HIV- infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.