Clinical trial NCT01030653: Pharmacokinetics of Voriconazole in Obese Subjects
Official title: Pharmacokinetics of Voriconazole in Obese Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Healthy
Keywords: Voriconazole
Pharmacokinetics
Obese
Healthy Volunteer
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: TKL Research, Inc.
name: Pfizer
First posted: 2009-12-11
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: HEALTH_SERVICES_RESEARCH

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Steady-State Cmax and Cmin of Two Voriconazole Dosing Regimens
timeFrame: Day 5
measure: Geometric Mean Ratio of the AUC Between the High and Low Dose Voriconazole
timeFrame: 14 days
Secondary outcomes:
measure: The Area Under the Curve Over the Dosing Interval for All Participants While on the High Dose and Low Dose Interventions.
timeFrame: 12 hours
Other outcomes:
Locations:
city: Paramus
country: United States
facility: TKL Research Inc
state: New Jersey
Study officials:
affiliation: University of Michigan
name: Manjunath P Pai, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pai MP, Norenberg JP, Anderson T, Goade DW, Rodvold KA, Telepak RA, Mercier RC. Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin. Antimicrob Agents Chemother. 2007 Aug;51(8):2741-7. doi: 10.1128/AAC.00059-07. Epub 2007 Jun 4.