Pharmacokinetics of Voriconazole in Obese Subjects

NCT ID: NCT01030653

Last Updated: 2017-02-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-11-30
• Study Completion Date: 2010-05-31

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.

Conditions

Healthy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: NONE

Study Groups

Voriconazole low dose first then high dose

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)

Group Type: EXPERIMENTAL

Voriconazole low dose

Intervention Type: DRUG

Voriconazole 400 mg po x 2 doses (loading dose)then 200 mg po twice daily x 7 doses

Voriconazole high dose

Intervention Type: DRUG

Voriconazole 400 mg po x 2 doses (loading dose)then 300 mg po twice daily x 7 doses

Voriconazole high dose first then low dose

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)

Group Type: EXPERIMENTAL

Voriconazole low dose

Intervention Type: DRUG

Voriconazole 400 mg po x 2 doses (loading dose)then 200 mg po twice daily x 7 doses

Voriconazole high dose

Intervention Type: DRUG

Voriconazole 400 mg po x 2 doses (loading dose)then 300 mg po twice daily x 7 doses

Interventions

Voriconazole low dose

Voriconazole 400 mg po x 2 doses (loading dose)then 200 mg po twice daily x 7 doses

Intervention Type: DRUG

Voriconazole high dose

Voriconazole 400 mg po x 2 doses (loading dose)then 300 mg po twice daily x 7 doses

Intervention Type: DRUG

Other Intervention Names

Vfend; Vfend

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

TKL Research, Inc.

INDUSTRY

Sponsor Role: collaborator

Pfizer

INDUSTRY

Sponsor Role: collaborator

Manjunath Prakash Pai

OTHER

Sponsor Role: lead

Responsible Party

Manjunath Prakash Pai

Associate Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Manjunath P Pai, PharmD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

TKL Research Inc

Paramus, New Jersey, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 17548489 (View on PubMed)

Other Identifiers

09010

Identifier Type: -

Identifier Source: org_study_id