A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of voriconazole and ketoconazole. Serial ECGs and plasma samples were obtained at specified intervals over a 24- hour post dose observation period. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of voriconazole and after ketoconazole 800 mg were all < 10 msec. Females exhibited a greater increase in QTc than males, although all mean changes were < 10 msec. Age was not found to affect the magnitude of increase in QTc. No subject in any group had an increase in QTc of ≥ 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec. However, the QT effect of voriconazole combined with drugs known to prolong the QT interval is unknown (see CONTRAINDICATIONS, PRECAUTIONS-DRUG INTERACTIONS).

Pharmacokinetics in Special Populations

Gender

In a multiple oral dose study, the mean Cmax and AUC_τ for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years), after tablet dosing. In the same study, no significant differences in the mean Cmax and AUC_τ were observed between healthy elderly males and healthy elderly females ( ≥ 65 years). In a similar study, after dosing with the oral suspension, the mean AUC for healthy young females was 45% higher than in healthy young males whereas the mean Cmax was comparable between genders. The steady state trough voriconazole concentrations (Cmin) seen in females were 100% and 91% higher than in males receiving the tablet and the oral suspension, respectively.

In the clinical program, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female subjects were similar. Therefore, no dosage adjustment based on gender is necessary.

Geriatric

In an oral multiple dose study the mean Cmax and AUC_τ in healthy elderly males ( ≥ 65 years) were 61% and 86% higher, respectively, than in young males (18-45 years). No significant differences in the mean Cmax and AUCX were observed between healthy elderly females ( ≥ 65 years) and healthy young females (18-45 years).

In the clinical program, no dosage adjustment was made on the basis of age. An analysis of pharmacokinetic data obtained from 552 patients from 10 voriconazole clinical trials showed that the median voriconazole plasma concentrations in the elderly patients ( > 65 years) were approximately 80% to 90% higher than those in the younger patients ( ≤ 65 years) after either IV or oral administration. However, the safety profile of voriconazole in young and elderly subjects was similar and, therefore, no dosage adjustment is necessary for the elderly.

Pediatric

A population pharmacokinetic analysis was conducted on pooled data from 35 immunocompromised pediatric patients aged 2 to < 12 years old who were included in two pharmacokinetic studies of intravenous voriconazole (single dose and multiple dose). Twenty- four of these patients received multiple intravenous maintenance doses of 3 mg/kg and 4 mg/kg. A comparison of the pediatric and adult population pharmacokinetic data revealed that the predicted average steady state plasma concentrations were similar at the maintenance dose of 4 mg/kg every 12 hours in children and 3 mg/kg every 12 hours in adults (medians of 1.19 ug/mL and 1.16 ug/mL in children and adults, respectively) (see PRECAUTIONS, Pediatric Use).

Hepatic Insufficiency

After a single oral dose (200 mg) of voriconazole in 8 patients with mild (Child-Pugh Class A) and 4 patients with moderate (Child-Pugh Class B) hepatic insufficiency, the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched controls with normal hepatic function. There was no difference in mean peak plasma concentrations (Cmax) between the groups. When only the patients with mild (Child-Pugh Class A) hepatic insufficiency were compared to controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic insufficiency compared to controls.

In an oral multiple dose study, AUC_τ was similar in 6 subjects with moderate hepatic impairment (Child-Pugh Class B) given a lower maintenance dose of 100 mg twice daily compared to 6 subjects with normal hepatic function given the standard 200 mg twice daily maintenance dose. The mean peak plasma concentrations (Cmax) were 20% lower in the hepatically impaired group.

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