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Dose‐dependent pharmacokinetics (PK) of short IV infusions of selodenoson (DTI‐0009), a novel adenosine (A1‐) receptor agonist, in healthy subjects
Author(s) -
Venitz J.,
Men A. Y.,
Townsend R. W.,
Dessimoz M.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.107
Subject(s) - medicine , renal function , pharmacokinetics , urine , agonist , pharmacology , population , endocrinology , receptor , environmental health
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