Oral Fluconazole as Suppressive Therapy of Disseminated Cryptococcosis in Patients with Acquired Immunodeficiency Syndrome

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...

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confidence: 99%

Pharmacokinetics and bioavailability of fluconazole in patients with AIDS

DeMuria

Forrest

Rich

et al. 1993

“…Even with standard therapy, the relapse rate of this fungal infection in patients with AIDS is high, approaching 34% within 4 months (2,6). Thus most patients are given suppressive therapy to help control the infection, but relapses still occur (9,10,12).…”

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confidence: 99%

“…The use of fluconazole as suppressive therapy for cryptococcosis in patients with AIDS has already been investigated (10,11). One study reported that two of nine patients on maintenance fluconazole had relapses with doses of no more than 200 mg daily (11).…”

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confidence: 99%

Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS

Berry

Rinaldi

Graybill

1992

“…Amphotericin B (AmB) is the "gold standard" for their treatment (19), but triazole compounds, such as fluconazole or itraconazole, are less toxic than AmB and have proven to be effective in several types of infections (13,36,47,49 We review herein the contribution of in vitro models to the study of the toxicity of polyenes, imidazoles, and triazoles in mammals. …”

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confidence: 99%

In vitro models for studying toxicity of antifungal agents

Joly

Bolard

Yéni

1992

Systemic fungal infections are an important cause of morbidity and mortality among immunocompromised patients (57, 58). Amphotericin B (AmB) is the "gold standard" for their treatment (19), but triazole compounds, such as fluconazole or itraconazole, are less toxic than AmB and have proven to be effective in several types of infections (13,36,47,49 We review herein the contribution of in vitro models to the study of the toxicity of polyenes, imidazoles, and triazoles in mammals. POLYENESPolyene antibiotics are produced by several different species of Streptomyces and have in common a macrocyclic lactone ring with a series of conjugated double bonds. About 100 polyene antibiotics have been described; they differ in the number of double bonds in the molecule and the substituents on the ring. AmB is the only polyene available for systemic administration, but its use is limited by systemic side effects (fever, chills) and renal toxicity. Indeed, its nephrotoxicity often limits the duration of therapy.All polyenes alter the membrane permeability of eukaryotic cells anid lead to cell lysis (16). Although some studies question the role of sterol in the effects of AmB, especially on artificial membranes, there is an extensive amount of data supporting the sterol hypothesis: it is generally admitted that cell sensitivity to polyene antibiotics is determined by the presence of sterol in the membrane and that the greater activity of AmB against fungi than against mammalian cells results from the drug's greater avidity for ergosterol-containing membranes than for cholesterol-containing membranes (52,53).In vitro models of toxicity might help elucidate the stilldebated relationship between permeability alterations and cell death (for a review, see reference 3) and might also help in the study of