Clinical trial NCT01030653
Conditions: Healthy
Keywords: Voriconazole Pharmacokinetics Obese Healthy Volunteer
Sponsor: Manjunath Prakash Pai
Start date: 2009-11-01; Completion date: 2010-05-01
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Obese subjects may require a higher fixed oral maintenance dosing regimen of voriconazole compared to normal weight subjects to achieve comparable plasma exposures. The current study is designed to address this issue.

Detailed description:
The prevalence of obesity has increased tremendously in the past two decades. An estimated 1 out of 5 persons in the United States are classified as obese. Under representation of obese patients in pharmacokinetic trials grossly limit generalizability of drug dosing recommendations in this emerging population. No published pharmacokinetic studies of voriconazole dosing in patients with obesity currently exist in the literature. Specifically,voriconazole pharmacokinetic data from subjects with a body mass index (BMI) ≥ 35 kg/m2(Class II and III obesity) are limited.

Voriconazole is available as both an intravenous and oral formulation. Anecdotal experience suggest that the use of oral voriconazole to be significantly more prevalent that that of intravenous therapy. The current oral recommended dosing regimen for voriconazole includes use of 200 mg every 12 hours for patients who are over 40 kg. The dosage can be increased to 300 mg by mouth every 12 hours in situations where a sufficient clinical response is not noted. A weight based dosing strategy is also utilized in patients with more serious infections (3-6 mg/kg IV Q 12 hours) such as invasive aspergillosis. Voriconazole demonstrates non-linear pharmacokinetics and so dosing based on total body weight may result in non-dose proportional exposure. For example, a 1.5 fold dose increment in voriconazole from 200 mg to 300 mg every 12 hours results in a 2.5 fold increase in exposure. The most appropriate body size descriptor is unknown (i.e. ideal body weight, fat free weight, lean body weight, etc.) for most antimicrobials, including voriconazole. As a consequence, the appropriateness of weight-based voriconazole dosage selection in obese patients is not known. Intuitively, weight based dosing (on total body weight) in this population could lead to higher than expected exposures (non-linear pharmacokinetics) and lead to potential adverse events. Therapeutic drug monitoring is increasingly advocated as a system to improve voriconazole dosing. However, an assay to measure voriconazole concentrations in the clinic is not routinely available. Hence, the current pilot study proposes to characterize the pharmacokinetic profile of voriconazole in obese subjects using two fixed dose regimens.

Arms: arm 1: Voriconazole administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (200 mg Every 12 Hours x 7 Doses) followed by 7 day washout followed by Loading Dose (400 mg x 2 Doses, Day 1) and a Maintenance Doses (300 mg Every 12 Hours x 7 Doses) arm 2: Voriconazole administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (300 mg Every 12 Hours x 7 Doses) followed by 7 day washout followed by Loading Dose (400 mg x 2 Doses, Day 1) and a Maintenance Doses (200 mg Every 12 Hours x 7 Doses)
Interventions: intervention 1: Voriconazole low dose intervention 2: Voriconazole high dose
Intervention descriptions: intervention 1: Voriconazole 400 mg po x 2 doses (loading dose)then 200 mg po twice daily x 7 doses intervention 2: Voriconazole 400 mg po x 2 doses (loading dose)then 300 mg po twice daily x 7 doses

Protocol documents: