Safety, efficacy, and pharmacokinetics of pradefovir for the treatment of chronic hepatitis B infection

Pradefovir is a liver targeted novel prodrug of adefovir (PMEA) developed to provide higher antiviral activity with reduced systemic toxicities. This study evaluated the tolerability, pharmacokinetics, and antiviral activity of pradefovir in patients with chronic hepatitis B (CHB) virus infection. Non-cirrhotic, treatment-naïve subjects with CHB were divided into five groups (10 patients each) and randomized within each group in a ratio of 6:2:2 to receive an ascending dose of 30, 60, 75, 90, or 120 mg pradefovir, 10 mg adefovir dipivoxil (ADV), or 300 mg tenofovir disoproxil fumarate (TDF) once a day for 28 days. A total of 51 subjects were randomized and 49 subjects completed the study. The groups were well matched and included 39 males, of whom 71% were hepatitis B e-antigen-negative with a mean hepatitis B virus (HBV) DNA level of 6.4–7.16 log10 IU/mL. No subject experienced a serious adverse event or nephrotoxicity. The most frequently reported adverse event was asymptomatic reduction in blood cholinesterase levels in the pradefovir group which recovered without any treatment about 13 ± 7 days after drug discontinuation. This adverse event was not observed in the ADV and TDF groups. The mean changes in serum HBV DNA were −2.78, −2.77, −3.08, −3.18, −3.44, −2.34, and −3.07 log10 IU/mL at 30, 60, 75, 90, and 120 mg pradefovir, 10 mg ADV and 300 mg TDF, respectively, with plateau levels reached with 60 mg pradefovir. Pradefovir and its metabolite PMEA showed linear pharmacokinetics proportional to the dose. The half-life of PMEA in the pradefovir group was 11.47–17.63 h. Short-term use of pradefovir was well tolerated. A decline in HBV DNA levels was superior to TDF at higher doses of pradefovir. 30–60 mg pradefovir is recommended for CHB treatment. CTR20150224.