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Remofovir, new HBV drug: prodrug of PMEA
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Reported by Jules Levin
"SAFETY, TOLERANCE, PHARMACOKINETICS AND PHARMACODYNAMICS OF REMOFOVIR, A LIVER-TARGETING PRODRUG OF PMEA IN HBV PATIENTS FOLLOWING DAILY DOSING FOR 28 DAYS"
Chin-Chung Lin, Valeant Pharmaceuticals International, Costa Mesa, CA; You-Chen Chao, Tri-Service General Hospital, Taipei, Taiwan Republic of China; Ming-Yang Lai, National Taiwan University Hospital, Taipei, Taiwan Republic of China; Ting-Tsung Chang, National Cheng Kung University Hospital, Tainan, Taiwan Republic of China; Wan-Long Chuang, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Republic of China; Sien-Sing Yang, Cathy General Hospital, Taipeh, Taiwan Republic of China; Rene Braeckman, Valeant Pharmaceuticals International, Costa Mesa, CA; Ding-Shinn Chen, National Taiwan University Hospital, Taipei, Taiwan Republic of China
Adeofovir dipivoxil, an esterase-activated prodrug of PMEA has a recommended dose of 10 mg QD, which is sub-optimized due to dose-limiting nephrotoxicity. Remofovir is a CYP3A4-activated prodrug of PMEA with excellent liver-target properties in rats and better safety than adeofovir dipivoxil in one-month monkey toxicity study. Thus, remofovir may optimize its clinical efficacy with lower nephrotoxicity potential than adeofovir dipivoxil.
The aims of this study are to evaluate safety, tolerance, pharmacokinetics and pharmacodynamics of remofovir in HBV patients following daily dosing for 28 days.
Forty-five adult Asian patients with compensated HBV infection completed this study. All patients had a HBV DNA viral load of >=3,000,000 copies/mL at screening. Eight to ten patients were randomized to each dose group of remofovir (5, 10, 20 and 30 mg daily) or placebo and were dosed for 28 days. Safety assessment included adverse events, physical examination, vital signs and safety laboratory tests. Serum samples were analyzed for remofovir and PMEA by validated LC-MS/MS methods. Predose serum HBV DNA levels in all patients on Days 1, 8, 15, 21 and 28 after the first dose and Weeks 4, 8 and 12 after the last dose were determined using the COBAS Amplicor assay (LOQ: 200 copies/mL).
Results
Following oral doses of remofovir up to 30 mg/day for 28 days in HBV patients, no unexpected adverse events were reported. The majority of events were mild in severity and similar between the placebo and remofovir groups. The most frequently reported event among all study patients was upper respiratory infection (30%). No dose related trends regarding safety were identified and no events resulted in a patient being withdrawn prematurely from treatment.
Remofovir was rapidly absorbed and converted to PMEA with a Tmax of 1 hr or less for both remofovir and PMEA. On Days 1 and 28, Cmax and AUC for remofovir and PMEA increased with dose. T 1/2 for PMEA (43-53 hr) was longer than that for remofovir (6.8-11 hr).
At all doses, serum HBV DNA levels decreased with time. After 4 weeks of remofovir treatment, the median log HBV decline from baseline (Day 1 predose) was 1.64 at 5 mg dose, 2.48 at 10 mg dose, 2.72 at 20 mg dose and 2.66 at 30 mg dose.
The authors concluded: (1) Remofovir was rapidly absorbed in HBV patients, and rapidly converted into PMEA. (2) Remofovir was well tolerated in patients up to doses of 30 mg/day for 28 days. (3) Cmax and AUC increased with dose for both remofovir and PMEA. (4) After 4 weeks of treatment, daily doses of 10, 20 and 30 mg of remofovir yielded clinical significant median declines in log HBV.
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