Timothy Henkel

A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis.

Anidulafungin is a novel antifungal agent of the echinocandin class. This randomized, double-blind, double-dummy study compared the efficacy and safety of intravenous anidulafungin to that of oral fluconazole in 601 patients with endoscopically and microbiologically documented esophageal candidiasis. Patients received intravenous anidulafungin (100 mg on day 1, followed by 50 mg per day) or oral fluconazole (200 mg on day 1, followed by 100 mg per day) for 7 days beyond resolution of symptoms (range, 14-21 days). At the end of therapy, the rate of endoscopic success for anidulafungin (242 [97.2%] of 249 treated patients) was found to be statistically noninferior to that for fluconazole (252 [98.8%] of 255 treated patients; treatment difference, -1.6%; 95% confidence interval, -4.1 to 0.8). The safety profile of anidulafungin was similar to that of fluconazole; treatment-related adverse events occurred in 9.3% and 12.0% of patients, respectively. Laboratory parameters were similar between treatment arms. Anidulafungin is as safe and effective as oral fluconazole for the treatment of esophageal candidiasis, when assessed at the completion of therapy.

Phase 2, Randomized, Dose-Ranging Study Evaluating the Safety and Efficacy of Anidulafungin in Invasive Candidiasis and Candidemia

ABSTRACT This study evaluated the safety and efficacy of anidulafungin, a novel echinocandin, in patients with invasive candidiasis, including candidemia. A total of 123 eligible patients were randomized to one of three intravenous regimens, 50, 75, or 100 mg once daily. Treatment continued for 2 weeks beyond resolution or improvement of signs and symptoms. The primary efficacy criterion was a successful global response rate (i.e., clinical and microbiological success) in the evaluable population at the follow-up (FU) visit, 2 weeks after end of therapy (EOT). One hundred twenty (120) patients received at least one dose of anidulafungin; 68 were evaluable. Review of adverse events and laboratory data indicated no dose response for safety parameters. Non-albicans Candida species accounted for approximately one-half of all isolates. Success rates at EOT were 84, 90, and 89% in the 50-, 75-, and 100-mg groups, respectively. At FU, the success rates were 72, 85, and 83%. Phase 3 studies of anidulafungin for the treatment of invasive candidiasis and candidemia are warranted.

Assessment of the Safety and Pharmacokinetics of Anidulafungin When Administered With Cyclosporine

Anidulafungin is a novel antifungal agent of the echinocandin class that is intended for the treatment of invasive fungal disease. It is likely that anidulafungin will be coadministered with cyclosporine. In vitro studies and clinical studies were performed to evaluate the effect of anidulafungin on cyclosporine metabolism and to investigate the safety and pharmacokinetics of anidulafungin when concomitantly administered with cyclosporine. The potential for anidulafungin to inhibit the metabolism of cyclosporine was evaluated by pooled human hepatic microsomal protein fractions in vitro, incubating 3H‐cyclosporine with different concentrations of anidulafungin. The safety of coadministration and the effects of cyclosporine on the pharmacokinetics of anidulafungin were assessed in a multiple‐dose, open‐label clinical study of 12 healthy volunteers. Subjects received a 200‐mg intravenous loading dose of anidulafungin, followed by a daily 100‐mg intravenous maintenance dose on days 2 through 8. An oral solution of cyclosporine (Neoral oral solution; 100 mg/mL) 1.25 mg/kg was also administered to subjects twice daily on days 5 through 8. In the in vitro study, the addition of anidulafungin had no effect on cyclosporine metabolism by human hepatic microsomal protein fractions. In the clinical study, no dose‐limiting toxicities or serious adverse events occurred. A small increase in anidulafungin concentrations and drug exposure (22%) was observed after 4 days of dosing with cyclosporine and was not considered to be clinically relevant. The results support the concomitant use of anidulafungin and cyclosporine without the need for dosage adjustments of either drug.

Lack of Pharmacokinetic Interaction Between Anidulafungin and Tacrolimus

The safety and pharmacokinetics of anidulafungin coadministered with tacrolimus were investigated using a single‐sequence, open‐label design. Healthy volunteers received 5 mg tacrolimus orally on days 1 and 13 of the study. Anidulafungin (200 mg) was administered intravenously on day 4, followed by 100‐mg doses on days 5 through 13. Key pharmacokinetic parameters, including Cmax, AUC, t½, CL, and Vss, were derived from concentration‐time data. The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of anidulafungin plus tacrolimus to each drug alone were well within the 80% to 125% bioequivalence range, indicating no pharmacokinetic interaction. This ratio was 101.6 (90% CI: 92.77–111.22) for tacrolimus AUC0‐∞ and 107.2 (90% CI: 105.1–109.4) for anidulafungin AUCss. The 2 drugs were well tolerated, and no drug‐related serious adverse events were reported. Because of its lack of pharmacokinetic interaction with key immunosuppressive agents, anidulafungin is an important option for the prevention and treatment of invasive fungal infections in transplant recipients.