Published in:
01-07-2017 | Original Article
Safety, pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects
Authors:
Yanhua Ding, Hong Zhang, Xiaojiao Li, Cuiyun Li, Guiling Chen, Hong Chen, Min Wu, Junqi Niu
Published in:
Hepatology International
|
Issue 4/2017
Login to get access
Abstract
Background
Pradefovir 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.
Methods
Fifty 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.
Results
The 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 (C
max) 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 C
max 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)].
Conclusions
The single oral dose of pradefovir 10–120 mg was well
tolerated. SNPs may be associated with variable rates of adverse events.
Trial registration number
CTR20140341.