Single-Dose Pharmacokinetics and Metabolism of [ ¹⁴ C]Remofovir in Rats and Cynomolgus Monkeys

Abstract

Single-dose pharmacokinetics and metabolism of [14 C]remofovir was studied in rats and monkeys following intravenous (i.v.) and oral administration (30 mg/kg of body weight). Oral absorption and bioavailability were 29.7 and 5.42% in rats and 65.6 and 19.4% in monkeys, respectively. Following i.v. administration, the elimination half-life for remofovir was 0.7 h in both rats and monkeys. Total body clearance was 5.85 liters/h/kg in rats and 2.60 liters/h/kg in monkeys; apparent volume of distribution was 5.99 liters/kg in rats and 2.70 liters/kg in monkeys. Following oral administration, remofovir was extensively converted to 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and other metabolites in both species. In rats, excretion of total radioactivity in urine accounted for 61.8% of the i.v. dose and 12.9% of the oral dose, while in monkeys it accounted for 43.3% of the i.v. dose and 34.9% of the oral dose. Following i.v. dosing of [ 14 C]remofovir, fecal excretion of radioactivity accounted for 37.5% of the dose in rats and 17.4% of the dose in monkeys, indicating significant biliary excretion of the drug in animals. PMEA and metabolite A were the major urinary metabolites in both species after i.v. and oral administration of remofovir.Adefovir, 9-(2-phosphonylmethoxyethyl)adenine (or PMEA), is an acyclic phosphonate analogue of adenine which has been shown to be effective against hepatitis B virus (HBV) in stably transfected human hepatocellular carcinoma cell lines and primary duck hepatocytes infected with duck HBV and in the duck model of hepatitis B (5, 6). PMEA is phosphorylated to PMEA diphosphate by cellular kinases which inhibit HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate dATP and by causing DNA chain termination after its incorporation into viral DNA (9). Cerny et al.(1) reported that PMEA was converted to four metabolites, including PMEA monophosphate and PMEA diphosphate. However, PMEA is poorly absorbed in a number of species, including rats, monkeys, and humans (2, 3, 11). The low oral bioavailability of PMEA appears to be in part a consequence of the limited intestinal permeability of phosphonate, which is ionized at a physiological pH (10).Adefovir dipivoxil is an oral prodrug of PMEA. In clinical trials, at week 48, serum HBV DNA levels had decreased by a median of 3.52 log copies per ml in the group given 10 mg of adefovir dipivoxil and 4.76 log copies per ml in the 30-mg group, compared with 0.55 log copies per ml in the placebo group (P Ͻ 0.001 for each comparison). Twenty-one percent of the patients in the 10-mg group and 39% of those in the 30-mg group had undetectable serum levels of HBV DNA, compared with 0% of the patients in the placebo group (P Ͻ 0.001 for each comparison) (8). It is clear that 30 mg of adefovir dipivoxil had better efficacy than 10 mg of the drug. However, dose-limiting kidney toxicity was an undesired side effect for adefovir dipivoxil. The incidence of serum creatinine increase (0.3 to Ͻ0.5 mg/dl from baseline) was significantly h...

Prodrugs of Phosphates and Phosphonates

“…Because adefovir dipivoxil is approved for use at a suboptimal dose for efficacy because of kidney toxicity, pradefovir was advanced into human clinical trials with the aim of achieving superior efficacy with similar or better safety. Its pharmacokinetics in humans have been reported, as well as in rats and cynomolgus monkeys . In a phase 2 clinical trial at doses of 10–30 mg, antiviral efficacy superior to adefovir dipivoxil was achieved along with lower plasma exposure to adefovir .…”

“…Its pharmacokinetics in humans have been reported, 130 as well as in rats and cynomolgus monkeys. 131 In a phase 2 clinical trial at doses of 10-30 mg, antiviral efficacy superior to adefovir dipivoxil was achieved along with lower plasma exposure to adefovir. 132 A review surrounding pradefovir has recently appeared, 133 and extension of HepDirect prodrug technology to the hepatitis B antiviral agent lamivudine has been described.…”

Metabolic Activation of Pradefovir by CYP3A4 and Its Potential as an Inhibitor or Inducer

“…However, it is known that P450 is also present in the gastrointestinal tract (12). In order to elucidate whether pradefovir may already be converted to PMEA by gastrointestinal P450 prior to entry into the liver, a study was carried out with portal vein-cannulated rats.…”