Pharmacokinetics and pharmacodynamics of peldesine (BCX-34), a purine nucleoside phosphorylase inhibitor, following single and multiple oral doses inhealthy volunteers

The pharmacokinetic parameters of peldesine (BCX-34) were investigated afte r single and multiple oral doses in two groups of healthy adult volunteers. The pharmacodynamic elevation of endogenous inosine and 2'-deoxyguanosine was simultaneously monitored. The first group of 8 subjects received an int ravenous dose (18 mg/m(2)) and five oral doses (30, 63, 108, 144, and 192 m g/m(2)) of drug A second group of 12 subjects received 360 mg/m(2) in four and in six divided doses orally Serial blood samples and total urine output s were collected during dosing and for at least 24 hours after the last dos e was administered. One set of samples was analyzed using high-pressure Liq uid chromatography/ultraviolet (LC/UV) methods, validated for intact drug i n human plasma and urine samples. Another set of samples was analyzed for t he biomarkers, inosine and 2'-deoxyguanosine, using high-pressure LC with e ither mass spectrometry (MS) or electrochemical detection (EC) methods. The pharmacokinetic parameters of inosine and 2'-deoxyguanosine were calculate d using noncompartmental methods and correlated against the pharmacokinetic parameters of BCX-34. For the single-dose study the results exhibited line ar pharmacokinetics over the dose range from 30 to 144 mg/m(2). The calcula ted terminal half-life was 3.5 +/- 1.0 h, and the absolute bioavailability of the oral formulation rt as approximately 51%. Analysis of urine in the f irst 24 hours of collection accounted for approximately 82% of the absorbed intact drug Evaluation of the multiple-dose pharmacokinetics indicated tha t steady-state blood concentrations were achieved by 24 hours when the drug was administered four or six times a day. A drug dose-related elevation of plasma 2'-deoxyguanosine was observed. This phenomenon was not seen with p lasma inosine levels. However, analysis of urine samples showed an increase in inosine output with an increase in the drug dose. The calculated termin al half-life of inosine and 2'-deoxyguanosine was 15.3 +/- 1.8 h and 1.3 +/ - 0.1 h, respectively Journal of Clinical Pharmacology, 2000;40:410-420 (C) 2000 the American College of Clinical Pharmacology.