Aims To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildena®l citrate. Methods Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildena®l (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildena®l and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildena®l (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildena®l were also assessed in all of these studies. Results The calculated absolute oral bioavailability of sildena®l was 41% (90% CI: 36 ±47). Food slowed the rate of absorption, delaying mean t max by approximately 1 h and reducing C max by 29% (90% CI: 19±38). Systemic exposure, as assessed by the mean area under the plasma concentration±time curve (AUC), was reduced by 11% (90% CI: 6±16). These food effects were not considered to be of clinical signi®cance. There was statistical evidence of nonproportionality in C max and AUC over the dose range 25±200 mg. However the degree of nonproportionality was small, with predicted increases in C max and AUC of 2.2-and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsigni®cant. Sildena®l was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions Sildena®l had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical signi®cance. Across the dose range of 25±200 mg, systemic exposure increased in a slightly greater than dose-proportional manner.

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.

Aims Voriconazole, a novel triazole antifungal agent, is metabolized by the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and to a lesser extent by CYP3A4. Omeprazole, a proton pump inhibitor used widely for the treatment of gastric and duodenal ulcers, is predominantly metabolized by CYP2C19 and CYP3A4. The aim of this study was to determine the effects of omeprazole on the steady-state pharmacokinetics of voriconazole. A secondary objective was to characterize the pharmacokinetic profile of an oral loading dose regimen of 400 mg twice-daily voriconazole on day 1. Methods This was an open, randomized, placebo-controlled, two-way crossover study of 18 healthy male volunteers. Subjects received oral voriconazole (400 mg twice daily on day 1 followed by 200 mg twice daily on days 2-9 and a single 200-mg dose on day 10) with either omeprazole (40 mg once daily) or matched placebo for 10 days. There was a minimum 7-day washout between treatment periods. Results Mean C max and AUC t of voriconazole were increased by 15% [90% confidence interval (CI) 5, 25] and 41% (90% CI 29, 55), respectively, with no effect on t max during coadministration of omeprazole. Visual inspection of predose plasma concentrations ( C min ) indicated that steady-state plasma concentrations were achieved following the second loading dose. One subject withdrew from the study during the voriconazole + omeprazole treatment period because of treatment-related abnormal liver function test values. All other treatment-related adverse events resolved without intervention. Conclusions Omeprazole had no clinically relevant effect on voriconazole exposure, suggesting that no voriconazole dosage adjustment is necessary for patients in whom omeprazole therapy is initiated. Administration of a 400-mg twice-daily oral loading dose regimen on day 1 resulted in steady-state plasma levels of voriconazole being achieved following the second loading dose.

Aims Voriconazole is a novel triazole with broad-spectrum antifungal activity. It is likely that some patients receiving voriconazole may also require treatment with the anticoagulant warfarin. Cytochrome P450 isoenzymes are important in the metabolism of both these drugs. This study investigated the effect of voriconazole on the pharmacodynamics of warfarin by measuring prothrombin time, and also evaluated the safety and tolerability of the coadministered drugs. Methods This was a double-blind, placebo-controlled, two-way crossover study in which healthy male subjects received either 300 mg voriconazole or placebo twice daily on days 1-12, plus a single oral dose of 30 mg warfarin on day 7 of each study period. Volunteers were randomized to one of the following treatment sequences: voriconazole + warfarin followed by placebo + warfarin or placebo + warfarin followed by voriconazole + warfarin. There was a washout of at least of 7 days between treatment periods. Results The mean C max , AUC t and t max for voriconazole were 3736 ng ml -1 , 25 733 ng·h ml -1 , and 1.66 h, respectively. Both the mean maximum change from baseline prothrombin time and the mean area under the effect curve (AUEC) for prothrombin time during coadministration with voriconazole (17 s and 3211 s·h, respectively) were statistically significantly greater than the mean values observed during the placebo period (8 s and 2282 s·h). Prothrombin times were still increased by a mean value of 5.4 s 144 h post warfarin dose following coadministration with voriconazole compared with a mean value of 0.6 s in the placebo treatment period. Conclusions Coadministration of voriconazole and warfarin potentiates warfarininduced prothrombin time prolongation. Regular monitoring of prothrombin time is recommended if these drugs are coadministered, with appropriate adjustment of the dose of warfarin.