Safety, pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects

摘要

BackgroundPradefovir is efficiently converted to adefovir [9-(2-phosphonylmethoxyethyl) adenine (PMEA)], producing high hepatic PMEA concentration but low levels in the systemic circulation and kidney. The aim of this study is to evaluate the tolerability, adverse effect (AEs), pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir.MethodsFifty healthy subjects were divided into five groups and randomized within each group at a ratio of 3:1:1 to receive a single ascending dose of pradefovir (10, 30, 60, 90, or 120?mg), and 10?mg adefovir dipivoxil (ADP) or placebo. Blood and urine samples were collected and analyzed. A total of 1930 polymorphic loci were analyzed in 6 blood samples collected from the 90?mg pradefovir group.ResultsThe single oral dose of pradefovir up to 120?mg was well tolerated. A total of 29 dose-limited mild AEs were reported in 17 subjects. The peak plasma concentration (Cmax) and area under the curve (AUC)0–48 of serum pradefovir ranged from (21.41?±?12.98) to (447.33?±?79.34)?ng/mL and (46.10?±?29.45) to (748.18?±?134.15) ng?h/mL across the dose range, respectively. The Cmax and AUC0–48 of serum PMEA ranged from 18.10?±?4.96 to 312.33?±?114.19?ng/mL and 72.65?±?28.25 to 1095.48?±?248.47?ng?h/mL. Generally, no kidney impairment was observed. Pharmacogenetic analysis identified three metabolism-related single nucleotide polymorphism (SNP) locis, P450 (cytochrome) oxidoreductase [POR (rs6965343)], arylamine N-acetyltransferases [NAT1 (rs4986993)] and CYP2F1 (rs305968)], and one distribution-related loci, orosomucoid 2 [ORM2 (rs12685968)].ConclusionsThe single oral dose of pradefovir 10–120?mg was well tolerated. SNPs may be associated with variable rates of adverse events.Trial registration numberCTR20140341.