Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model▿

In vitro selection studies and data from large genotype databases from clinical studies have demonstrated that tenofovir disoproxil fumarate and abacavir sulfate select for the K65R mutation in the human immunodeficiency virus type 1 polymerase region. Furthermore, other novel non-thymine nucleoside reverse transcriptase (RT) inhibitors also select for this mutation in vitro. Studies performed in vitro and in humans suggest that viruses containing the K65R mutation remained susceptible to zidovudine (ZDV) and other thymine nucleoside antiretroviral agents. Therefore, ZDV could be coformulated with these agents as a “resistance repellent” agent for the K65R mutation. The approved ZDV oral dose is 300 mg twice a day (b.i.d.) and is commonly associated with bone marrow toxicity thought to be secondary to ZDV-5′-monophosphate (ZDV-MP) accumulation. A simulation study was performed in silico to optimize the ZDV dose for b.i.d. administration with K65R-selecting antiretroviral agents in virtual subjects using the population pharmacokinetic and cellular enzyme kinetic parameters of ZDV. These simulations predicted that a reduction in the ZDV dose from 300 to 200 mg b.i.d. should produce similar amounts of ZDV-5′-triphosphate (ZDV-TP) associated with antiviral efficacy (>97% overlap) and reduced plasma ZDV and cellular amounts of ZDV-MP associated with toxicity. The simulations also predicted reduced peak and trough amounts of cellular ZDV-TP after treatment with 600 mg ZDV once a day (q.d.) rather than 300 or 200 mg ZDV b.i.d., indicating that q.d. dosing with ZDV should be avoided. These in silico predictions suggest that 200 mg ZDV b.i.d. is an efficacious and safe dose that could delay the emergence of the K65R mutation

Lack of Pharmacokinetic Interaction between Amdoxovir and Reduced- and Standard-Dose Zidovudine in HIV-1-Infected Individuals▿

Amdoxovir (AMDX) inhibits HIV-1 containing the M184V/I mutation and is rapidly absorbed and deaminated to its active metabolite, β-d-dioxolane guanosine (DXG). DXG is synergistic with zidovudine (ZDV) in HIV-1-infected primary human lymphocytes. A recent in silico pharmacokinetic (PK)/enzyme kinetic study suggested that ZDV at 200 mg twice a day (b.i.d.) may reduce toxicity without compromising efficacy relative to the standard 300-mg b.i.d. dose. Therefore, an intense PK clinical study was conducted using AMDX/placebo, with or without ZDV, in 24 subjects randomized to receive oral AMDX at 500 mg b.i.d., AMDX at 500 mg plus ZDV at 200 or 300 mg b.i.d., or ZDV at 200 or 300 mg b.i.d. for 10 days. Full plasma PK profiles were collected on days 1 and 10, and complete urine sampling was performed on day 9. Plasma and urine concentrations of AMDX, DXG, ZDV, and ZDV-5′-O-glucuronide (GZDV) were measured using a validated liquid chromatography-tandem mass spectrometry method. Data were analyzed using noncompartmental methods, and multiple comparisons were performed on the log-transformed parameters, at steady state. Coadministration of AMDX with ZDV did not significantly change either of the plasma PK parameters or percent recovery in the urine of AMDX, DXG, or ZDV/GZDV. Larger studies with AMDX/ZDV, with a longer duration, are warranted

Pharmacokinetics of the Antiviral Agent β-l-3′-Fluoro-2′,3′-Didehydro-2′,3′-Dideoxycytidine in Rhesus Monkeys

β-l-3′-Fluoro-2′,3′-didehydro-2′,3′-dideoxycytidine (l-3′-Fd4C) is a potent and selective antiretroviral nucleoside with activity against lamivudine-resistant human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) in vitro. The pharmacokinetics of l-3′-Fd4C were characterized in three rhesus monkeys given single intravenous and oral doses. A two-compartment open model was fitted to the plasma and urine data. Plasma concentrations declined in a biexponential fashion with an average beta half-life of 12.45 h and central and steady-state volumes of distribution of 0.43 and 1.90 liters/kg, respectively. The average systemic and renal clearance values were 0.23 and 0.08 liters/kg, respectively, and the apparent mean terminal half-life of the oral dose was 12.5 h. The serum concentrations exceeded the 90% effective concentration value for lamivudine-resistant and wild-type HIV-1 after oral administrations. A large variation was observed in the oral bioavailability, which ranged from 15 to 31%. To determine whether the bioavailability may be improved by using a basic buffer solution, the oral dose was repeated to the same animals in a sodium bicarbonate solution. The bioavailability of l-3′-Fd4C administered with sodium bicarbonate was not significantly different from the bioavailability when the oral dose was administered in the absence of buffer (P = 0.49), suggesting that further development of this compound may warrant other approaches, such as development of a prodrug to improve its oral absorption

Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(β-d-Dioxolane)Thymine in Rhesus Monkeys▿ †

β-d-Dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h−1; fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted

Pharmacology and Pharmacokinetics of the Antiviral Agent β-d-2′,3′-Dideoxy-3′-Oxa-5-Fluorocytidine in Cells and Rhesus Monkeys

β-d-2′,3′-Dideoxy-3′-oxa-5-fluorocytidine (d-FDOC) is an effective inhibitor of human immunodeficiency virus 1 (HIV-1) and HIV-2, simian immunodeficiency virus, and hepatitis B virus (HBV) in vitro. The purpose of this study was to evaluate the intracellular metabolism of d-FDOC in human hepatoma (HepG2), human T-cell lymphoma (CEM), and primary human peripheral blood mononuclear (PBM) cells by using tritiated compound. By 24 h, the levels of d-FDOC-triphosphate (d-FDOC-TP) were 2.8 ± 0.4, 6.7 ± 2.3, and 2.0 ± 0.1 pmol/10(6) cells in HepG2, CEM, and primary human PBM cells, respectively. Intracellular d-FDOC-TP concentrations remained greater than the 50% inhibitory concentration for HIV-1 reverse transcriptase for up to 24 h after removal of the drug from cell cultures. In addition to d-FDOC-monophosphate (d-FDOC-MP), -diphosphate (d-FDOC-DP), and -TP, d-FDOC-DP-ethanolamine and d-FDOC-DP-choline were detected in all cell extracts as major intracellular metabolites. d-FDOC was not a substrate for Escherichia coli thymidine phosphorylase. No toxicity was observed in mice given d-FDOC intraperitoneally for 6 days up to a dose of 100 mg/kg per day. Pharmacokinetic studies in rhesus monkeys indicated that d-FDOC has a t(1/2) of 2.1 h in plasma and an oral bioavailability of 38%. The nucleoside was excreted unchanged primary in the urine, and no metabolites were detected in plasma or urine. These results suggest that further safety and pharmacological studies are warranted to assess the potential of this nucleoside for the treatment of HIV- and HBV-infected individuals

Antiviral Effect of Orally Administered (−)-β-d-2-Aminopurine Dioxolane in Woodchucks with Chronic Woodchuck Hepatitis Virus Infection▿

(−)-β-d-2-Aminopurine dioxolane (APD) is a nucleoside prodrug that is efficiently converted to 9-(β-d-1,3-dioxolan-4-yl)guanine (DXG). DXG has antiviral activity in vitro against hepatitis B virus (HBV) but limited aqueous solubility, making it difficult to administer orally to HBV-infected individuals. APD is more water soluble than DXG and represents a promising prodrug for the delivery of DXG. A placebo-controlled, dose-ranging efficacy and pharmacokinetic study was conducted with woodchucks that were chronically infected with woodchuck hepatitis virus (WHV). APD was efficiently converted to DXG after oral and intravenous administrations of APD, with serum concentrations of DXG being higher following oral administration than following intravenous administration, suggestive of a considerable first-pass intestinal and/or hepatic metabolism. APD administered orally at 1, 3, 10, and 30 mg/kg of body weight per day for 4 weeks produced a dose-dependent antiviral response. Doses of 3 and 10 mg/kg/day reduced serum WHV viremia by 0.4 and 0.7 log10 copies/ml, respectively. The 30-mg/kg/day dose resulted in a more pronounced, statistically significant decline in serum WHV viremia of 1.9 log10 copies/ml and was associated with a 1.5-fold reduction in hepatic WHV DNA. Individual woodchucks within the highest APD dose group that had declines in serum WHV surface antigen levels, WHV viremia, and hepatic WHV DNA also had reductions in hepatic WHV RNA. There was a prompt recrudescence of WHV viremia following drug withdrawal. Therefore, oral administration of APD for 4 weeks was safe in the woodchuck model of chronic HBV infection, and the effect on serum WHV viremia was dose dependent