Pharmacokinetic, Safety, and Antiviral Profiles of Oral Ganciclovir in Persons Infected with Human Immunodeficiency Virus: A Phase I/II Study

Abstract

A phase I/II study evaluated the pharmacokinetics, tolerability, and antiviral activity of oral ganciclovir in persons infected with human immunodeficiency virus (HIV). Oral bioavailability ranged from 2.6% to 7.3%. The mean maximum serum concentration achieved at 1000 mg every 8 h was 1.11 micrograms/mL, and mean trough level was 0.54 microgram/mL. The time to maximum serum drug concentration was 1.0-2.9 h, with a serum half-life of 3.0-7.3 h, suggesting prolonged oral absorption. Serious adverse events were uncommon. Decreased cytomegalovirus (CMV) shedding was observed from all sites. The median days (by dosage) to retinitis progression assessed by retinal examination after initiation of oral ganciclovir were 62 (1000 mg every 8 h), 148 (500 mg every 3 h), 75 (750 mg every 3 h), 148 (1000 mg every 3 h), and 139 (2000 mg every 8 h). Thus, oral ganciclovir has pharmacokinetic, toxicity, and antiviral profiles that may prove beneficial for both maintenance therapy of CMV retinitis and prevention of CMV disease in HIV-infected persons.

Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication

“…Problems associated with each of these therapies include toxicities, such as bone marrow suppression (granulocytopenia, anemia, and thrombocytopenia), with GCV (8,18) and nephrotoxicity with CDV (14,15) and PFA (5). In addition, emergence of drug-resistant virus in patients undergoing long-term maintenance therapy with these drugs has resulted in diminished drug efficacies (12,13).…”

Maribavir Pharmacokinetics and the Effects of Multiple-Dose Maribavir on Cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N -Acetyltransferase-2, and Xanthine Oxidase Activities in Healthy Adults

“…In human immunodeficiency virus-infected men with asymptomatic HCMV shedding, mean reductions in semen HCMV titers of 2.9 to 3.7 log 10 PFU/ml were observed among all 28-day maribavir dosing regimens (16). The decrease in mean HCMV titers reported with maribavir are comparable to the approved doses for the anti-HCMV activities of ganciclovir and cidofovir (17,24).…”

Quantification of ganciclovir in human plasma using capillary electrophoresis

“…administration of 5 mg/ L every 12 h in the therapy and prophylaxis for CMV disease were 3.03 6 2.63 mg/L [16]. After oral administration of 1000 mg every 8 h, the mean plasma concentrations were 0.54 mg/L in [17]. In general, after oral administration, the trough levels are between 0.2 and 0.5 mg/L and should be higher than 0.5 mg/L [18].…”