Pharmacokinetics and bioavailability of fluconazole in patients with AIDS

Abstract

Fluconazole pharmacokinetics were evaluated for 10 volunteers with AIDS who had no clinical evidence of gastroenteritis. Single 100-mg intravenous (i.v.) and oral (p.o.) doses were administered in a randomized, crossover design. i.v. doses were delivered by a constant-rate infusion over 30 min. Serum fluconazole concentrations were measured by gas-liquid chromatography. The i.v. and p.o. studies were modelled simultaneously by iterative two-stage analysis, which provided individual parameter estimates and a population pharmacokinetic model. Median areas under the concentration-time curves for i.v. and p.o. studies did not differ (90.6 and 99.3 ,ug/ml. h, respectively). Consistent with this finding, the median fractional bioavailability was 1.1 (range, 0.45 to 1.3), comparable to those in healthy subjects. Serum pharmacokinetics in these AIDS patients were generally similar to published data for healthy volunteers. However, foliowing p.o. dosing, we observed a slightly delayed and highly variable time to maximum concentration in serum (median, 2 h; range, 15 min to 8 h). Data were well described by a linear, two-compartment pharmacokinetic model with first-order absorption and elimination. Repeated-measures analysis ofvariance found no significant differences among any of the pharmacokinetic parameters between i.v. and p.o. studies. On the basis of our findings, we suggest no change in dosage of p.o. fluconazole in patients with AIDS who show no clinical signs of enteropathy.Oral (p.o.) fluconazole is frequently administered to persons with AIDS for the treatment of commonly occurring fungal infections, including oropharyngeal and esophageal candidiasis (31) and cryptococcal meningitis (32). Frequently, AIDS patients have hypochlorhydria (23) and other physiologic and anatomic disturbances of the alimentary tract (17,22,25), although gastroenteral symptoms may be absent. Potentially, these factors could interfere with the overall absorption of p.o. administered agents, alter drug transit time, and influence efficacy (11,29).To our knowledge, the absorption of p.o. fluconazole in patients with AIDS has not been investigated. The recommended dosage of p.o. fluconazole for the treatment of fungal infections in patients with AIDS is based upon pharmacokinetic data derived from healthy volunteers (4,14,21). The objective of this study was to determine the p.o. bioavailability and pharmacokinetics of fluconazole in patients with AIDS.(Results of this investigation were presented at the VIIIth International Conference on AIDS/IIIrd STD World Congress, Amsterdam, The Netherlands, July 1992.) MATERIALS AND METHODSPatients and selection criteria. The study population consisted of ambulatory patients who were served by the Brigham and Women's Hospital and the Harvard Community Health Plan (Boston, Mass.). The study protocol was approved by the institutional review boards for human investigation of both institutions. Written informed consent was obtained from each subject.Volunteers who had AIDS (5) were eligible for the stu...

Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients

“…The mean population pharmacokinetic parameter estimates were in the same range as those already reported [14,15,16,17]. Although a previous study reported no e ect of BW on¯uconazole pharmacokinetics [16], in this study BW signi®cantly in¯uenced¯uconaz-ole CL and V d .…”

Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus

“…Since the pharmacokinetics of ddI in dogs are similar to those from limited observations in humans, similarities in metabolic profiles of these two species (i.e., xanthine oxidase) may explain the lack of interaction found in this trial (see below). Like other azoles, fluconazole is an inhibitor of multiple hepatic P-450 enzymes; it also appears to inhibit some non-P-450 enzymes, such as uridine diphosphate-glucurosyl transferase, which is responsible for the metabolism of ZDV (6,9,19). However, we found that the pharmacokinetics of ddI are not altered by fluconazole when both are given at commonly prescribed dosages.…”

“…Fluconazole is well absorbed in the HIV population and is frequently prescribed for prophylaxis and treatment of fungal infections (6). However, fluconazole inhibits a number of hepatic P-450 enzymes that are responsible for the metabolism of many drugs, such as theophylline, phenytoin, cyclosporin, and rifabutin (9,16,21).…”

Pharmacokinetics and bioavailability of fluconazole in two groups of males with human immunodeficiency virus (HIV) infection compared with those in a group of males without HIV infection

“…One paper described the bioavailability (of a tablet formulation) and pharmacokinetics of fluconazole in people with AIDS (11). Single 100-mg intravenous and oral doses of fluconazole were administered.…”