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Journal of Antimicrobial Chemotherapy (1996) 37, 965-974
© 1996 The British Society for Antimicrobial Chemotherapy

research-article

Pharmacokinetics of netivudine, a potent anti-varicella zoster virus drug, in patients with renal impairment

J. P. Fillastrea, M. Godina, B. Legalliciera, P. Chretienb, R. Bidaultc, C. GillotiiTc, R. Wootond, J. Posnerd and R. W. Peckd

aDepartment of Nephrology, University of Rouen France bC EM AX Lab. rue Maréchal Juin Rouen France cLaboratoires Wellcome 92442 Issy-les-Moulineaux cedex, France cThe Wellcome Research Laboratories Beckenham, UK

Received 19 April 1995; returned 25 July 1995; accepted 7 November 1995

Correspondence: J. P. Fillastre, C.H.U. de Rouen, Hopital de Bois Guillaume, 76031 Rouen Cedex, France

The pharmacokinetics of a single oral 200 mg dose of netivudine (1-(ß-D-arabino-furanosyl)-5-(1-propynyl)uracil), a nucleoside analogue under development for use in varicella zoster virus infections, were studied in 12 renal failure (RF) subjects (creatinine clearance 15±7mL/min) and 12 age-matched healthy subjects with normal creatinine clearance. Blood and urine samples were collected up to nine days after drug administration. Concentrations of netivudine and of its main metabolite, 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, Tmax and volume of distribution were not significantly affected by RF. The elimination half-life of netivudine was approximately 15 h in subjects with normal renal function and 60 h in RF patients. Plasma and renal clearances of netivudine were significantly reduced in RF patients and AUC was three to four times higher in these patients. Cmax 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 parent compound. Tmax and the lag time were similar in the two groups. There were highly significant correlations for netivudine and 5 PU between half-life and creatinine clearance and between renal clearance and creatinine clearance. These findings suggest that netivudine dosage may need to be reduced in patients with severe renal failure, and confirm that formation of the 5 PU is independent of the elimination of netivudine from plasma.


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