PHARMACOKINETICS OF NETIVUDINE, A POTENT ANTI-VARICELLA ZOSTER VIRUS DRUG, IN PATIENTS WITH RENAL IMPAIRMENT

The pharmacokinetics of a single oral 200 mg dose of netivudine 1-(bet a-D-arabinofuranosyl)-5-(1-propynyl)uracil), a nucleoside analogue und er development for use in varicella tester virus infections, were stud ied in 12 renal failure (RF) subjects (creatinine clearance 15 +/- 7 m l/min) and 12 age-matched healthy subjects with normal creatinine clea rance. Blood and urine samples were collected up to nine days after dr ug administration. Concentrations of netivudine and of its main metabo lite, the pyrimidine base 5-(1-propynyl)uracil (5 PU), were determined by a specific high performance liquid chromatography assay. The mean peak plasma concentrations of netivudine, T-max, and volume of distrib ution were not significantly affected by RF. The elimination half-life of netivudine was approximately 15 h in subjects with normal renal fu nction and 60 h in RF patients. Plasma and renal clearances of netivud ine were significantly reduced in RF patients and AUC was three to fou r times higher in these patients. C-max and AUC of 5 PU were higher in RF patients, and the half-life was also significantly longer. However , the half-life of this metabolite was much lower than that of the par ent compound. T-max and the lag time were similar in the two groups. T here were highly significant correlations for netivudine and 5 PU betw een half-life and creatinine clearance and between renal clearance and creatinine clearance. These findings suggest that netivudine dosage m ay need to be reduced in patients with severe renal failure, and confi rm that formation of the 5 PU is independent of the elimination of net ivudine from plasma.