Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients

Infection remains a major complication in patients with malignant disease. There are many factors predisposing to infection in this patient population, including local factors due to the tumor, specific deficiencies in host defense mechanisms due to certain malignant processes, and deficiencies in host defense mechanisms secondary to cancer chemotherapy. Neutropenia is probably the most important factor predisposing to infection in cancer patients. These patients require prompt broad-spectrum antibiotic therapy when fever develops. The majority of infections occurring in this patient population are caused by gram-negative bacilli and cure rates usually are between 65 and 75 percent. The most important prognostic factor is whether or not the neutrophil count recovers during the course of infection. Fungal infections have increased in frequency in neutropenic patients and often present as fevers of unknown origin. Increasingly, neutropenic patients are receiving antifungal agents as empiric therapy for persistent fever that fails to respond to antibacterial antibiotics. The most critical factor in recovery from fungal infection is remission of the underlying malignant disease.

The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 micrograms/ml in mice, rats, dogs, and humans, respectively. The volumes of distribution ranged between 1.1 liter/kg in mice and 0.7 liter/kg in humans, which are approximate to the values for total body water. Whole body autoradiography studies in mice following intravenous administration of [14C]UK-49,858 demonstrated that the drug was evenly distributed throughout the tissues, including the central nervous system and the gastrointestinal tract. Plasma protein binding was low (11 to 12%) in all species. Marked species differences were observed in elimination half-lives, with mean values of 4.8, 4.0, 14, and 22 h in mice, rats, dogs, and humans, respectively. The major route of elimination of the drug was renal clearance, with about 70% of the dose being excreted unchanged in the urine in each species. Studies with [14C]UK-49,858 on metabolism and excretion (intravenous and oral) in mice and dogs showed that about 90% of the dose was recovered as unchanged drug in urine and feces, confirming the metabolic stability of the drug. This pharmacokinetic profile is markedly different from that of imidazole antifungal drugs and undoubtedly contributes to the excellent efficacy of UK-49,858 in vivo.