Pharmacokinetics of Voriconazole in Obese Subjects

NCT01030653

Last updated date
Study Location
TKL Research Inc
Paramus, New Jersey, 07652, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Healthy
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18-50 years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


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.

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Advanced Information
Descriptive Information
Brief Title  ICMJE Pharmacokinetics of Voriconazole in Obese Subjects
Official Title  ICMJE Pharmacokinetics of Voriconazole in Obese Subjects
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Condition  ICMJE Healthy
Intervention  ICMJE
  • Drug: Voriconazole low dose
    Voriconazole 400 mg po x 2 doses (loading dose)then 200 mg po twice daily x 7 doses
    Other Name: Vfend
  • Drug: Voriconazole high dose
    Voriconazole 400 mg po x 2 doses (loading dose)then 300 mg po twice daily x 7 doses
    Other Name: Vfend
Study Arms  ICMJE
  • Experimental: 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)
    Interventions:
    • Drug: Voriconazole low dose
    • Drug: Voriconazole high dose
  • Experimental: 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)
    Interventions:
    • Drug: Voriconazole low dose
    • Drug: Voriconazole high dose
Publications * 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. Epub 2007 Jun 4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 10, 2009)
10
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2010
Actual Primary Completion Date April 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01030653
Other Study ID Numbers  ICMJE 09010
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Manjunath Prakash Pai, University of Michigan
Study Sponsor  ICMJE Manjunath Prakash Pai
Collaborators  ICMJE
  • TKL Research, Inc.
  • Pfizer
Investigators  ICMJE
Principal Investigator:Manjunath P Pai, PharmDUniversity of Michigan
PRS Account University of Michigan
Verification Date December 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP