Voriconazole, a novel wide‐spectrum triazole: oral pharmacokinetics and safety

Abstract

Aims Voriconazole is a potent new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing. Methods Sixty-four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg -1 twice daily, 4 mg kg -1 once daily, 2 mg kg -1 three times daily, or 3 mg kg -1 twice daily. Eleven subjects received 1.5 mg kg -1 three times daily, and 21 subjects were administered placebo. Results Voriconazole exhibited nonlinear (dose-and time-dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing k el values on multiple dosing, with a consequent increase in the terminal phase t 1/2 . There was also notable intersubject variability in C max and AUC t . The absorption of voriconazole was rapid (mean t max = 0.9-1.7 h) after single and multiple dosing and the decline in plasma concentration-time curves after t max was generally biphasic. By day 12, the C max , AUC t , t max , and t 1/2 values for the 3 mg kg -1 twice-daily group were 2356 ng ml -1 , 11 170 ng·h ml -1 , 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single-dose data. Accumulation ratios for C max and AUC t , which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg -1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of C min values together with statistical analyses of C max and AUC t values suggest that steady-state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens ( C min > 0.8 m g ml -1 ). Voriconazole was well tolerated: most treatmentrelated adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing. Conclusions The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg -1 twice daily.

Voriconazole Therapeutic Drug Monitoring

“…Voriconazole is a triazole antifungal with enhanced activity against a broad spectrum of fungal pathogens, including Aspergillus and Candida species (11, 26). We provide a succinct review of voriconazole's pharmacokinetics (PK) and present new PK-pharmacodynamic (PD) data relating drug concentration to therapeutic response.The pharmacokinetics of voriconazole in volunteers and patients have shown that voriconazole exhibits a nonlinear pharmacokinetic profile, secondary to saturable clearance (6,16,24,25). Voriconazole is metabolized by the cytochrome P450 system, with less than 2% of the dose excreted unchanged (12,13,24,25).…”

“…The proportions of CYP2C19 extensive metabolizers in the U.S. population are estimated to be 2% homozygous extensive and 26% heterozygous extensive. Homozygous extensive metabolizers have a twofold lower exposure than heterozygous extensive metabolizers and fourfold lower drug exposure than poor metabolizers (12, 13).In 10 trials, the median values for the average and maximum voriconazole plasma concentrations in individual patients (n ϭ 1,121) were 2.51 g/ml and 3.79 g/ml, respectively (6,16,23,24,25). The values for area under the plasma concentrationtime curve on day 10 in 200-and 300-mg administration groups were approximately 5.8 and 3.8 times higher, respectively, among the poor metabolizers than among the extensive metabolizers.…”

Farmacología de los azoles

“…La absorción oral más elevada se obtiene con voriconazol, fármaco que administrado en ayunas alcanza una biodisponibilidad próxima al 100% [25][26][27], cifra que es inferior a su vez en el caso de itraconazol en solución (70%) [21], y que se reduce cuando este fármaco se administra en forma de cápsulas, hasta situarse en el 55%, cifra que es inferior cuando este fármaco se administra junto con una suspensión de alcalinos [18]. La biodisponibilidad de posaconazol, solo comercializado en solución para uso por vía oral, se sitúa en torno al 60% [10].…”

Triazole Use in the Nursery: Fluconazole, Voriconazole, Posaconazole, and Ravuconazole

“…Studies in both healthy volunteers [85][86][87] and critically ill adults [88,89] have demonstrated non-linear PK that is thought to be due to saturable first-pass metabolism and decreased systemic clearance. Consequently small changes in dose may affect large changes in serum drug levels.…”