The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.

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 (Cmin) values at steady state were above the in vitro minimum inhibitory concentrations (MICs) for most fungal pathogens (Cmin > 0.8 micro g ml-1). The use of a loading dose in Study B resulted in a shorter time to steady-state Cmin 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 (Cmax) 3621 and 3063 ng ml-1; areas under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCtau) 16 535 and 13 245 ng.h ml-1, and terminal elimination phase half-lives (t1/2) 6.5 and 6.7 h, respectively. On multiple dosing, voriconazole accumulated (AUCtau 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.

Effect of food on the pharmacokinetics of multiple-dose oral voriconazole.

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 AUCtau and Cmax 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 tmax values; the mean difference for tmax on day 7 was 1.1 h. The terminal phase rate constant was unchanged by administering voriconazole with food. The fasted terminal phase half-life was 7.3 h compared with 6.6 h for the fed state. Visual inspection of Cmin values suggests that steady state was achieved after 5 days in both dietary states. Voriconazole accumulation, as assessed by ratios of Cmax and AUCtau on days 1 and 7, was statistically significantly greater when administered with food (Cmax, P = 0.010, AUCtau, P = 0.006). Mean Cmax accumulation in the fasted state was 2.1-fold compared with 3.5-fold in the fed state. AUCtau 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 AUCtau after multiple dosing when taken with food, compared with fasting.

Voriconazole potentiates warfarin-induced prothrombin time prolongation.

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 Cmax, AUCtau and tmax 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 warfarin-induced prothrombin time prolongation. Regular monitoring of prothrombin time is recommended if these drugs are coadministered, with appropriate adjustment of the dose of warfarin.

No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers.

AIMS: The antibiotic erythromycin is a potent inhibitor of cytochrome P450 CYP3A4 metabolism. As CYP isozymes, including CYP3A4, are involved in the metabolism of the new triazole voriconazole, this study investigated the effects of multiple-dose erythromycin or azithromycin on the steady-state pharmacokinetics of voriconazole in healthy male subjects. METHODS: In an open, randomized, parallel-group, single-centre study, 30 healthy male subjects aged 20-41 years received oral voriconazole 200 mg twice daily for 14 days plus either erythromycin (1 g twice daily on days 8-14), azithromycin (500 mg once daily on days 12-14) or placebo (twice daily on days 8-14). Only morning doses were administered on day 14. Plasma concentrations of voriconazole were measured up to 12 h postdose on days 7 and 14, and plasma pharmacokinetic parameters were calculated. Adverse events and standard laboratory test results were recorded before and throughout the study. RESULTS: Comparison of the voriconazole Cmax day 14/day 7 ratio for the voriconazole + erythromycin group with that of the voriconazole + placebo group yielded a ratio of 107.7%[90% confidence interval (CI) 90.6, 128.0]; for the voriconazole + azithromycin group, the ratio was 117.5% (90% CI 98.8, 139.7). Comparison of the voriconazole AUCtau day 14/day 7 ratios of the voriconazole + erythromycin and voriconazole + azithromycin groups with that of the voriconazole + placebo group showed ratios of 101.2% (90% CI 89.1, 114.8) and 107.9% (90% CI 95.1, 122.4), respectively. For voriconazole tmax, the differences between the day 14-day 7 calculations for the voriconazole + erythromycin or the voriconazole + azithromycin groups and that of the voriconazole + placebo group were - 0.2 h (90% CI - 0.8, 0.3) and - 0.1 h (90% CI - 0.7, 0.5), respectively. None of these changes was considered clinically relevant. The study drugs were well tolerated by subjects in all groups; the most common study drug-related adverse events were visual disturbances, reported in all groups, and abdominal pain, present in the voriconazole + erythromycin group. CONCLUSIONS: Coadministration of erythromycin or azithromycin does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner in healthy male subjects.

Voriconazole does not affect the steady-state pharmacokinetics of digoxin.

AIMS: Voriconazole is a triazole antifungal agent with potent fungicidal activity against Aspergillus species. Digoxin is a commonly prescribed cardiac glycoside with a narrow therapeutic index. This aim of this study was to investigate the effect of multiple-dose voriconazole on the steady-state pharmacokinetics of digoxin in healthy male volunteers. METHODS: This was a double-blind, randomized, placebo-controlled, parallel-group study. All subjects received daily administration of oral digoxin for a total of 22 days (0.5 mg twice daily on day 1, 0.25 mg twice daily on day 2 and 0.25 mg once daily on days 3-22). In addition, on days 11-22 the subjects were randomized to receive either voriconazole (200 mg twice daily) or matching placebo. RESULTS: Concomitant administration with voriconazole did not significantly alter the Cmax, AUCtau, tmax or CLR of digoxin at steady state. The ratios between groups for Cmax and AUCtau at day 22, corrected for baseline (day 10) were 109.8%[90% confidence interval (CI) 97.1, 124.1] and 100.5% (90% CI 91.4, 110.5), respectively. In addition, group mean Cmin values were similar in both treatment groups throughout the study. There were no significant differences between treatments with respect to the incidence of adverse events, all of which were classified as mild and transient in nature. CONCLUSIONS: The steady-state pharmacokinetics of digoxin are not affected in a clinically relevant manner by the concomitant administration of voriconazole.

Histamine H2-receptor antagonists have no clinically significant effect on the steady-state pharmacokinetics of voriconazole.

AIMS: Voriconazole, a new triazole antifungal agent, is metabolized mainly by cytochrome P450s CYP2C19 and CYP2C9, and also by CYP3A4. The aim of this open-label, placebo-controlled, randomized, three-way crossover study was to determine the effects of cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole. METHODS: Twelve healthy male subjects received oral voriconazole 200 mg twice daily plus cimetidine 400 mg twice daily, voriconazole 200 mg twice daily plus ranitidine 150 mg twice daily, and voriconazole 200 mg twice daily plus placebo twice daily. Treatment periods were separated by at least 7 days. RESULTS: When cimetidine was administered with voriconazole, the maximum plasma voriconazole concentration (Cmax) and the area under the plasma concentration-time curve of voriconazole (AUCtau) was increased by 18.3%[90% confidence interval (CI) 6.0, 32.0] and 22.5% (90% CI 13.3, 32.5), respectively. Concomitant ranitidine had no significant effect on voriconazole Cmax or AUCtau. Time of Cmax (tmax) elimination half-life (t 1/2) or terminal phase rate constant (kel) for voriconazole were similar in all three treatment groups. Most adverse events were mild and transitory; two subjects were withdrawn due to adverse events. CONCLUSIONS: Coadministration of the histamine H2-receptor antagonists cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner.

Effect of omeprazole on the steady-state pharmacokinetics of voriconazole.

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 Cmax and AUCtau of voriconazole were increased by 15%[90% confidence interval (CI) 5, 25] and 41% (90% CI 29, 55), respectively, with no effect on tmax during coadministration of omeprazole. Visual inspection of predose plasma concentrations (Cmin) 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.

Evaluation of Pulsincap to provide regional delivery of dofetilide to the human GI tract.

Pulsincap formulations designed to deliver a dose of drug following a 5-h delay were prepared to evaluate the capability of the formulation to deliver dofetilide to the lower gastrointestinal (GI) tract. By the expected 5-h release time, the preparations were well dispersed throughout the GI tract, from stomach to colon. Plasma analysis permitted drug absorption to be determined as a function of GI tract site of release. Dofetilide is a well-absorbed drug, but showed a reduction in observed bioavailability when delivered from the Pulsincap formulations, particularly at more distal GI tract sites. Dispersion of the drug from the soluble excipient used in this prototype formulation relies on a passive diffusion mechanism and the relevance of this factor to the reduced extent and consistency of absorption from the colon is discussed. In these studies the effects of the degree of dispersion versus the site of dispersion could not be ascertained; nevertheless the scintigraphic analysis demonstrated good in vitro-in vivo correlation for time of release from Pulsincap preparations. The combination of scintigraphic and pharmacokinetic analysis permits identification of the site of drug release from the dosage form and pharmacokinetic parameters to be studied in man in a non-invasive manner.