PHARMACOKINETICS, SAFETY AND BIOAVAILABILITY OF HPMPC (CIDOFOVIR) IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED SUBJECTS

We conducted a single-center, double-blind, placebo-controlled phase I study in HIV-positive subjects to ascertain the safety, tolerance, bi oavailability, pharmacokinetics, and maximum tolerated dose of HPMPC ( cidofovir). Five subjects were randomized to receive drug and two to r eceive placebo at each of three dosage tiers (1, 3, and 10 mg/kg) with a 2-week washout period between doses. Subjects at 1 and 3 mg/kg rece ived single doses of HPMPC by subcutaneous (s.c.), intravenous (i.v.), and oral (p.o.) routes, while subjects at 10 mg/kg received only i.v. and p.o. doses. For subjects already taking zidovudine, zidovudine AU C values were determined before and then with HPMPC administration for each route. The AUC values of HPMPC were dose-proportional. Subcutane ous bioavailability was essentially equivalent to that of the intraven ous route, but the development of transient local fibrosis and the vol umes needed for subcutaneous dosing precluded higher subcutaneous dosi ng than 3 mg/kg. Oral bioavailability was poor, estimated to be less t han 5%. Drug elimination was predominantly renal. Nephrotoxicity in on e subject was the only serious adverse event observed. This subject ha d a significant lag period prior to oral absorption and also had the h ighest AUC values for both HPMPC and zidovudine. We found no consisten t effect on zidovudine AUC by concomitant HPMPC.