Tolerability and safety profile of posaconazole: evaluation of 18 controlled studies in healthy volunteers.

Background And Objectives: Antifungal agent utility can be limited by safety and tolerability concerns. Posaconazole is an extended-spectrum triazole antifungal agent for the treatment and prophylaxis of invasive fungal infection. The aim was to analyse the overall safety profile of posaconazole in healthy volunteers.

Methods: Safety data from all 18 clinical pharmacology single- and multiple-dose trials of posaconazole conducted in healthy volunteers plus 2 additional healthy subsets from other pharmacology trials were pooled and analysed. Four hundred and forty-nine healthy volunteers (354 men; 95 women) were enrolled. Three hundred and twenty-seven were white, and the mean age and weight of subjects were similar across all dosing groups. The population evaluated had no confounding factors of underlying disease or concomitant medications. Safety evaluations included spontaneously reported adverse events, clinical laboratory test results, electrocardiograms and vital sign measurements.

Results: A total of 448 subjects received posaconazole, 50-1200 mg/day administered as single or multiple doses for up to 14 days. Two hundred and seventeen subjects received >or=800 mg/day posaconazole, and 188 subjects received multiple doses of posaconazole at 800 mg/day. Two hundred and thirty-one subjects received <800 mg/day. Forty-eight subjects from three studies received placebo. The incidence of treatment-emergent adverse events reported with posaconazole was similar to that seen with placebo (57% vs. 63% respectively) and unrelated to dose. The most common treatment-related adverse events (posaconazole vs. placebo) were headache (17% vs. 13%), dry mouth (9% vs. 0%) and dizziness (6% vs. 2%). No clinically significant changes in vital signs or laboratory test parameters were observed, except for transient, mild to moderate elevations in liver function test results. Posaconazole also demonstrated minimal potential to prolong corrected QT interval.

Conclusions: The safety profile analysis found posaconazole to be well tolerated, and results were similar across sex, age and race.