In this study, the safety, tolerability, and pharmacokinetics of intravenous (i.v.)-to oral-dose regimens of voriconazole were evaluated with a group of 42 healthy men, 41 of whom completed the study. Two cohorts of subjects participated in the study. Cohort 1 (n ؍ 28) took part in two study periods, each consisting of 14 days separated by a minimum 7-day washout. In one of the periods, 14 subjects received 6 mg/kg i. 1-fold increases in C max and AUC , respectively. Similarly, a 2-fold increase in oral dosing resulted in 2.8-and 3.9-fold increases in C max and AUC , respectively. The mean values for C max observed following oral dosing were lower than those obtained after i.v. administration, ranging from 62.7 to 89.6% of the i.v. value. After the switch from i.v. to oral dosing, most subjects achieved steady state by day 4, and mean minimum concentrations in plasma remained above clinically important MICs. The pharmacokinetic profiles for saliva followed a pattern similar to those observed for plasma; there was a highly significant correlation between plasma and saliva voriconazole concentrations (P < 0.0001). Voriconazole was well tolerated; the most commonly reported adverse events in voriconazole-treated subjects were mild to moderate headache, rash, and abnormal vision. Visual function tests detected no further abnormalities during voriconazole treatment.
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.
Aims Voriconazole is a new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. These studies evaluated the pharmacokinetics and safety of intravenous voriconazole in healthy male volunteers. Methods Two single-blind, placebo-controlled studies were conducted. In Study A, 12 subjects were randomized to voriconazole (3 mg kg -1 ) or placebo, administered once daily on days 1 and 12, and every 12 h on days 3-11. In Study B, 18 subjects were randomized to voriconazole or placebo, with voriconazole being administered as a loading dose at 6 mg kg -1 twice on day 1, then at 3 mg kg -1 twice daily on days 2-9, and once at 3 mg kg -1 on day 10. Results In both studies, the plasma concentrations of voriconazole increased rapidly following the initiation of dosing. Minimum observed plasma concentration ( C min ) values at steady state were above the in vitro minimum inhibitory concentrations (MICs) for most fungal pathogens ( C min > 0.8 m g ml -1 ). The use of a loading dose in Study B resulted in a shorter time to steady-state C min values than was observed in Study A. Values of the final day plasma pharmacokinetic parameters in Studies A and B were similar: maximum observed plasma concentration ( C max ) 3621 and 3063 ng ml -1 ; areas under the plasma concentration-time curve from time zero to the end of the dosing interval (AUC t ) 16 535 and 13 245 ng·h ml -1 , and terminal elimination phase half-lives ( t 1/2 ) 6.5 and 6.7 h, respectively. On multiple dosing, voriconazole accumulated (AUC t accumulation ratio 2.53-3.17, Study A) at a level that was not predictable from single-dose data. The mean concentration-time profiles for voriconazole in saliva were similar to those in plasma. Multiple doses of voriconazole were well tolerated and no subject discontinued from either study. Seven cases of possibly drug-related visual disturbance were reported in three subjects (Study B). Conclusions Administration of a loading dose of 6 mg kg -1 i.v. voriconazole on the first day of treatment followed by 3 mg kg -1 i.v. twice daily achieves steady state by the third day of dosing. This dosage regimen results in plasma levels of the drug that rapidly exceed the minimum inhibitory concentrations (MICs) against important fungal pathogens, including Aspergillus spp.
Aims Voriconazole is a new triazole antifungal agent with activity against a range of clinically important and emerging pathogens. This study determined the effect of food on the pharmacokinetics of voriconazole in healthy volunteers. Methods This was an open, randomized, two-way crossover, multiple-dose study in male volunteers. Twelve subjects received voriconazole 200 mg twice daily for 6.5 days. Each dose was administered either with food or in the fasted state, i.e. not within 2 h of food. Treatment periods were separated by a minimum 7-day washout period. Plasma samples were taken for the estimation of voriconazole plasma concentrations on days 1 and 7. Safety and toleration were assessed by monitoring of both laboratory safety tests and adverse events. Results Administering voriconazole with food significantly decreased both day 7 AUC t and C max by approximately 35% (9598-7520 ng·h ml -1 ; P = 0.003) and 22% (2038-1332 ng ml -1 ; P = 0.008), respectively. Administering voriconazole with food statistically significantly delayed absorption, evident from t max values; the mean difference for t max on day 7 was 1.1 h. The terminal phase rate constant was unchanged by administering voriconazole with food. The fasted terminal phase halflife was 7.3 h compared with 6.6 h for the fed state. Visual inspection of C min values suggests that steady state was achieved after 5 days in both dietary states. Voriconazole accumulation, as assessed by ratios of C max and AUC t on days 1 and 7, was statistically significantly greater when administered with food ( C max , P = 0.010, AUC t , P = 0.006). Mean C max accumulation in the fasted state was 2.1-fold compared with 3.5-fold in the fed state. AUC t accumulation in the fasted state was 3.1-fold compared with 4.2-fold in the fed state. There were no discontinuations due to adverse events or laboratory abnormalities. Treatment-related mild-to-moderate visual disturbances were experienced by six out of 12 subjects. Conclusions The bioavailability of twice-daily 200 mg voriconazole is reduced by approximately 22% as measured by AUC t after multiple dosing when taken with food, compared with fasting.
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