Pharmacokinetics and tolerability of single oral doses of 882C87, a potent, new anti-varicella-zoster virus agent, in healthy volunteers.
882C87 is a nucleoside analog with potent, specific activity against varicella-zoster virus. It is approximately seven times as potent as acyclovir with an in vitro 50% inhibitory concentration of 1 to 2 microM. The tolerability and pharmacokinetics of single doses of 882C87 have been investigated in a series of studies with healthy young and elderly adult volunteers. The young received 50 to 1,600 mg, and the elderly received 50 and 100 mg. Concentrations of 882C87 and its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5PU), in plasma and urine were assayed by an automated sequential trace enrichment of dialysate-high-performance liquid chromatography procedure, and noncompartmental pharmacokinetic parameters were derived from the data. Concentrations of 882C87 in plasma increased proportionally for doses of up to 400 mg, but after higher doses the increase was less than dose proportional. In young adults, after 200, 400, and 1,600 mg, the maximum concentrations of the drug in plasma were 9.0, 16.3, and 34.7 microM, respectively, and the areas under the concentration-time curve (AUC) from 0 h to infinity were 166.6, 333.7, and 822.9 microM.h, respectively. Elimination half-life was 11.3 to 13.0 h after 50 to 400 mg, increasing to 15.3 h after 1,600 mg, associated with a small decrease in renal clearance. In healthy elderly volunteers concentrations of 882C87 in plasma after 50 and 100 mg were similar to those in young adults after twice the dose; apparent clearance and renal clearance were significantly reduced, and half-life was significantly longer at 15 h. Administration of 882C87 with food produced a small, nonsignificant reduction in mean AUC from 0 h to infinity, but in subjects with a low fasting AUC there was an increase after food and in subjects with a high fasting AUC there was a decrease. Concentrations of 5PU in plasma were one-third to one-half those of 882C87 and, in most subjects, were not dose proportional. There was a lag of at least 5 h after dosing with 882C87 before 5PU was detectable in plasma.
Peck
R W
RW
Department of Clinical Pharmacology, Wellcome Foundation Limited, Beckenham, United Kingdom.
Weatherley
B C
BC
Wootton
R
R
Crome
P
P
Holdich
T A
TA
Posner
J
J
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001086:Arabinofuranosyluracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D005215:Fasting / Q000378:metabolism; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D008297:Male; D016037:Single-Blind Method
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; C067854:5-propynylarabinofuranosyluracil