Dose-dependent pharmacokinetics (PK) of short IV infusions of selodenoson (DTI-0009), a novel adenosine (A1-) receptor agonist, in healthy subjects

Abstract

Purpose To study the PK of DTI-0009, a selective A1-receptor agonist currently in phase II clinical testing for ventricular rate control in atrial fibrillation. Methods Ten healthy young volunteers (age: 21-35) received a 30–minute infusion of 1 íg/kg, 5 íg/kg of DTI-0009 or saline on three different occasions. The subjects were hydrated by a saline infusion (200 ml/min) for one hour prior to and five hours after the start of study drug. Serial plasma and urine samples were taken over 24 hours to measure DTI-0009 concentrations (as well as glucuronide, in urine only) by validated LC-MS assays (LOQ: 100 pg/ml). Noncompartmental PK analysis was performed, and instantaneous renal clearance (CLreninst) was estimated as function of urine flow (UF), and creatinine clearance (CLCrea). Results About 42% of DTI-0009 was eliminated unchanged in urine, and 3.7% as glucuronide. CLtot and CLren were reduced with increasing dose by 25% and 29%, respectively; CLnonren appeared unchanged. CLreninst paralleled DTI-0009-induced, transient reductions in UF and CLCrea. Vdss approached body weight. Conclusions DTI-0009 is largely eliminated by renal tubular secretion, which is temporarily reduced by DTI-0009-induced renal A1-receptor activation. This leads to dose- and time-dependent PK. Population variability is moderate. Clinical Pharmacology & Therapeutics (2004) 75, P28–P28; doi: 10.1016/j.clpt.2003.11.107