Pharmacokinetics of Voriconazole in Obese Subjects

Manjunath Prakash Pai

Status and phase: Completed; Phase 4

Conditions: Healthy

Treatments: Drug: Voriconazole low dose; Drug: Voriconazole high dose

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01030653

09010

Details and patient eligibility

About

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.

Full 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.

Enrollment: 10 patients

Sex: All

Ages: 18 to 50 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

1. males and females, 18 to 50 years of age;
2. non-smoking or light-smoking (≤5 cigarettes per day) volunteers;
3. BMI ≥ 35 kg/m2;
4. female subjects of childbearing potential either surgically sterilized, using an effective method of contraception (diaphragm, cervical cap, condom) or agree to abstain from sex from time of prestudy screening, during entire study period and 1 week following the study period.

Exclusion criteria

1. History of significant hypersensitivity reaction or intolerance to voriconazole, fluconazole,itraconazole, posaconazole, or ketoconazole ;
2. history of significant clinical illness requiring pharmacological management;
3. abnormal serum electrolyte or complete blood count requiring further clinical work-up;
4. transaminases (AST or ALT) >2.5 x upper limit of normal;
5. estimated creatinine clearance <50 mL/min (Cockcroft-Gault equation);
6. positive urine pregnancy test (if female);
7. abnormal electrocardiogram (ECG) as judged by study physician;
8. unable to tolerate venipuncture and multiple blood draws;
9. clinically significant abnormal physical examination defined as a physical finding requiring further clinical work-up.

Trial design

Primary purpose: Health Services Research

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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10 participants in 2 patient groups

Voriconazole low dose first then high dose

Experimental group

Description:

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)

Treatment:

Drug: Voriconazole high dose

Drug: Voriconazole low dose

Voriconazole high dose first then low dose

Experimental group

Description:

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)

Treatment:

Drug: Voriconazole high dose

Drug: Voriconazole low dose