Effect of food on the pharmacokinetics of multiple‐dose oral voriconazole

Abstract

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.

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].…”

Role of Therapeutic Drug Monitoring of Voriconazole in the Treatment of Invasive Fungal Infections

“…69 Two trials reported a possible association between high concentration of voriconazole and neurologic adverse events. 31,29 Pascual and others 29 recorded neurologic events (including confusion, agitation, pattern of toxic encephalopathy on electroencephalography, extrapyramidal signs, myoclonus, and visual and auditory hallucinations) in 5 of the 16 patients who had trough concentrations of voriconazole above 5.5 mg/L; they observed no such effects in the group with concentrations of 5.5 mg/L or below (p = 0.002). In a small retrospective study, 4 of 6 patients with neurologic adverse events (including neuropathy, hallucinations, anxiety, insomnia, irritability, and impaired concentration) had trough concentrations of voriconazole above 4 mg/L.…”

“…8, [25][26][27][28][29][30][31][32] In their recent review articles, Smith and others 33 and Hope and others 34 addressed the topic of TDM for antifungal agents, discussing voriconazole briefly. Brüggemann and others 35 and Howard and others 36 also discussed the role of TDM for voriconazole specifically, the latter focusing exclusively on invasive aspergillosis.…”

Optimizing antifungal choice and administration

“…Finally, posaconazole absorption is saturable, thus despite a long elimination half life, exposure is increased when administered as divided doses of 200 mg four times daily versus as a single 800 mg daily dose 41,42 . Interpatient variability with voriconazole is primarily due to differences in metabolism related to CYP2C19 polymorphisms, rather than absorption issues, although voriconazole absorption is modestly reduced by administration with food 43 . CYP2C19 is the major determinant of voriconazole metabolism and clearance, and patients who are homozygous extensive CYP2C19 metabolizers have markedly lower plasma concentrations than homozygous poor metabolizers or heterozygous extensive metabolizers 44,45 .…”