Pharmacokinetics, safety and bioavailability of HPMPC (cidofovir) in human immunodeficiency virus-infected subjects

• Published in: Antiviral research Vol. 29; no. 2; pp. 153 - 161
• Main Authors: Wachsman, M., Petty, B.G., Cundy, K.C., Jaffe, H.S., Fisher, P.E., Pastelak, A., Lietman, P.S.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.03.1996; Elsevier
• Subjects: Adolescent; Adult; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Bioavailability; Biological and medical sciences; Biological Availability; Cidofovir; Clinical trial; Cytomegalovirus; Cytosine - adverse effects; Cytosine - analogs & derivatives; Cytosine - pharmacokinetics; Double-Blind Method; Drug Administration Routes; Female; HIV Infections - drug therapy; HIV Infections - metabolism; HIV Infections - urine; human immunodeficiency virus; Humans; Male; Medical sciences; Middle Aged; Organophosphonates; Organophosphorus Compounds - adverse effects; Organophosphorus Compounds - pharmacokinetics; Pharmacology. Drug treatments; Zidovudine - pharmacokinetics; Cytomegalovirus; Antiviral; Clinical trial; Cidofovir; Bioavailability; Human; Immunopathology; Intravenous administration; Oral administration; AIDS; Immune deficiency; Infection; Chemotherapy; Treatment; Viral disease; Phase I trial; Double blind study; Subcutaneous administration; Pharmacokinetics; Pyrimidine nucleotide
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/0166-3542(95)00829-2

We conducted a single-center, double-blind, placebo-controlled phase I study in HIV-positive subjects to ascertain the safety, tolerance, bioavailability, pharmacokinetics, and maximum tolerated dose of HPMPC (cidofovir). Five subjects were randomized to receive drug and two to receive 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 received 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 AUC values were determined before and then with HPMPC administration for each route. The AUC values of HPMPC were dose-proportional. Subcutaneous bioavailability was essentially equivalent to that of the intravenous route, but the development of transient local fibrosis and the volumes needed for subcutaneous dosing precluded higher subcutaneous dosing than 3 mg/kg. Oral bioavailability was poor, estimated to be less than 5%. Drug elimination was predominantly renal. Nephrotoxicity in one subject was the only serious adverse event observed. This subject had a significant lag period prior to oral absorption and also had the highest AUC values for both HPMPC and zidovudine. We found no consistent effect on zidovudine AUC by concomitant HPMPC.