600    

Background:  Tenofovir DF (TDF) is a nucleotide analogue HIV-1 reverse transcriptase inhibitor that also has activity against hepatitis B virus (HBV). Hepatic impairment is a frequent co-morbidity in patients with HIV, particularly when co-infection with HBV or hepatitis C virus (HCV) is present. Therefore, the effect of hepatic impairment on tenofovir PK was evaluated. In addition, the drug interaction potential of TDF on agents used to treat HBV (adefovir dipivoxil, ADV) or HCV (ribavirin, RBV) was studied. 

Methods:  We conducted 3 pharmacokinetic studies. The single-dose pharmacokinetics of tenofovir was evaluated in 24 subjects with hepatic impairment stratified into 3 groups; those with normal liver function and otherwise healthy subjects with moderate or severe hepatic impairment using the Child-Pugh-Turcotte (CPT) scoring system. The single-dose pharmacokinetics of ADV (n = 22) and RBV (n = 22) were studied following single doses when given alone and with multiple doses of TDF. Study drugs were administered in the morning with blood and urine sampling performed over 24 to 72 hours. Drug concentrations were determined in serum/plasma using LC/MS/MS and pharmacokinetic parameters calculated by noncompartmental methods. In drug interaction studies, pharmacokinetic equivalence was defined as a 90% confidence interval for the geometric mean ratio between 80 to 125% for C_max and AUC.

Results:  Tenofovir pharmacokinetics were similar in subjects with moderate or severe hepatic impairment relative to healthy controls and consistent with historical data in HIV⁺ patients (see the table). In drug interaction studies ADV and RBV exposure met the definition of pharmacokinetic equivalence when dosed with or without TDF with mean differences in C_max and AUC for either drug of <7% and <12%, respectively. In all 3 studies adverse events were generally mild, except for 1 subject in the RBV study who developed a serious adverse event (cholecystitis/pancreatitis) that was unrelated to study drug.

^*Mean ± SD (range) ^**Median (range)

Conclusions:  Tenofovir pharmacokinetics are not significantly altered with hepatic impairment. TDF does not alter the pharmacokinetics of adefovir or RBV, 2 medications used to treat viral hepatitis.

Keywords: Drug Interaction; Hepatitis; Tenofovir DF