Pharmacokinetics of Voriconazole in Obese Subjects

• Sponsor: Manjunath Prakash Pai (Other)
• Overall Status: Completed
• CT.gov ID: NCT01030653
• Collaborator: TKL Research, Inc. (Industry), Pfizer (Industry)
• Enrollment: 10
• Location: 1
• Arms: 2
• Duration (Months): 5.9
• Patients Per Site Per Month: 1.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Voriconazole low dose; Drug: Voriconazole high dose	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Health Services Research
• Official Title: Pharmacokinetics of Voriconazole in Obese Subjects
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
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)	Drug: Voriconazole low dose; Voriconazole 400 mg po x 2 doses (loading dose)then 200 mg po twice daily x 7 doses; Other Names: Vfend ; Drug: Voriconazole high dose; Voriconazole 400 mg po x 2 doses (loading dose)then 300 mg po twice daily x 7 doses; Other Names: Vfend
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)	Drug: Voriconazole low dose; Voriconazole 400 mg po x 2 doses (loading dose)then 200 mg po twice daily x 7 doses; Other Names: Vfend ; Drug: Voriconazole high dose; Voriconazole 400 mg po x 2 doses (loading dose)then 300 mg po twice daily x 7 doses; Other Names: Vfend

Outcome Measures

Primary Outcome Measures

1. Steady-State Cmax and Cmin of Two Voriconazole Dosing Regimens [Day 5]

   Cmax is the maximum concentration, and Cmin is the minimum concentration. These measurements are based on analysis of plasma. The units shown are milligrams of voriconazole per liter of plasma. The two dosing regimens are: a loading dose (400 mg x 2 doses, day 1) and maintenance doses (200 mg every 12 hours x 7 doses) in obese subjects. a loading dose (400 mg x 2 doses, day 1) and maintenance doses (300 mg every 12 hours x 7 doses) in obese subjects.

2. Geometric Mean Ratio of the AUC Between the High and Low Dose Voriconazole [14 days]

   AUC is the area under the concentration-time curve. The Geometric Mean Ratio and 90% confidence interval around this value permit an assessment of the bioequivalence of two dosing regimens in the same group. The geometric mean is computed based on the ratio of the AUC value from the high dose compared to the AUC value from the low dose for each individual. This ratio provides a more robust interpretation of the differences between the two dosing arms because each individual serves as their own control.

Secondary Outcome Measures

1. The Area Under the Curve Over the Dosing Interval for All Participants While on the High Dose and Low Dose Interventions. [12 hours]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	TKL Research Inc	Paramus	New Jersey	United States	07652

Sponsors and Collaborators

• Manjunath Prakash Pai
• TKL Research, Inc.
• Pfizer

Investigators

• Principal Investigator: Manjunath P Pai, PharmD, University of Michigan

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Manjunath Prakash Pai, Associate Professor, University of Michigan
• ClinicalTrials.gov Identifier: NCT01030653
• Other Study ID Numbers: 09010
• First Posted: Dec 11, 2009
• Last Update Posted: Feb 9, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by Manjunath Prakash Pai, Associate Professor, University of Michigan: Voriconazole; Pharmacokinetics; Obese; Healthy Volunteer
• Additional relevant MeSH terms: Voriconazole

Study Results

Participant Flow

Recruitment Details	Clinical research unit, subjects recruited over a 6 month period
Pre-assignment Detail	This was a healthy volunteer study that did not require any pre assignment study procedures. 10 participants were consented but 8 were sufficient to complete the study. The remaining two subjects were not assigned to any arm, comparable to a screen failure. No intervention other than consent and screening occurred for these two subjects.

Arm/Group Title	Voriconazole High Dose First Then Low Dose	Voriconazole Low Dose First Then High Dose
Arm/Group Description	Active: Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Two Fixed Maintenance Doses ( 300 mg Every 12 Hours x 7 Doses) followed by a 7-day washout period then a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses ( 200 mg Every 12 Hours x 7 Doses)	Active: Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Two Fixed Maintenance Doses ( 200 mg Every 12 Hours x 7 Doses) followed by a 7-day washout period then a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses ( 300 mg Every 12 Hours x 7 Doses)
Period Title: Loading Dose & First Maintenance Regimen
STARTED	4	4
COMPLETED	4	4
NOT COMPLETED	0	0
Period Title: Loading Dose & First Maintenance Regimen
STARTED	4	4
COMPLETED	4	4
NOT COMPLETED	0	0
Period Title: Loading Dose & First Maintenance Regimen
STARTED	4	4
COMPLETED	4	4
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Voriconazole High Dose First Then Low Dose	Voriconazole Low Dose First Then High Dose	Total
Arm/Group Description	Both voriconazole arms are shown as a single group because the same individuals received both arms of the intervention in a cross-over design.	Total of all reporting groups
Overall Participants	4	4	8
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 100%	4 100%	8 100%
>=65 years	0 0%	0 0%	0 0%
Gender (Count of Participants)
Female	3 75%	3 75%	6 75%
Male	1 25%	1 25%	2 25%
Region of Enrollment (participants) [Number]
United States	4 100%	4 100%	8 100%

Outcome Measures

1. Primary Outcome

Title	Steady-State Cmax and Cmin of Two Voriconazole Dosing Regimens
Description	Cmax is the maximum concentration, and Cmin is the minimum concentration. These measurements are based on analysis of plasma. The units shown are milligrams of voriconazole per liter of plasma. The two dosing regimens are: a loading dose (400 mg x 2 doses, day 1) and maintenance doses (200 mg every 12 hours x 7 doses) in obese subjects. a loading dose (400 mg x 2 doses, day 1) and maintenance doses (300 mg every 12 hours x 7 doses) in obese subjects.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

The same subjects were analyzed in a cross-over design at two dose levels

Arm/Group Title	Voriconazole Lower Dose	Voriconazole Higher Dose
Arm/Group Description	Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (200 mg or Every 12 Hours x 7 Doses)	Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (300 mg or Every 12 Hours x 7 Doses)
Measure Participants	8	8
Cmax	2.36	4.16
Cmin	0.81	1.76

2. Primary Outcome

Title	Geometric Mean Ratio of the AUC Between the High and Low Dose Voriconazole
Description	AUC is the area under the concentration-time curve. The Geometric Mean Ratio and 90% confidence interval around this value permit an assessment of the bioequivalence of two dosing regimens in the same group. The geometric mean is computed based on the ratio of the AUC value from the high dose compared to the AUC value from the low dose for each individual. This ratio provides a more robust interpretation of the differences between the two dosing arms because each individual serves as their own control.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

This is a comparison of the same group analyzed through a cross-over design of two voriconazole dosing regimens

Arm/Group Title	Voriconazole High : Low Dose
Arm/Group Description	Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (200 mg or Every 12 Hours x 7 Doses) Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (300 mg or Every 12 Hours x 7 Doses)
Measure Participants	8
Number (90% Confidence Interval) [Ratio]	2

3. Secondary Outcome

Title	The Area Under the Curve Over the Dosing Interval for All Participants While on the High Dose and Low Dose Interventions.
Time Frame	12 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Voriconazole Lower Dose	Voriconazole Higher Dose
Arm/Group Description	Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (200 mg or Every 12 Hours x 7 Doses)	Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (300 mg or Every 12 Hours x 7 Doses)
Measure Participants	8	8
Geometric Mean (95% Confidence Interval) [hour*milligram/Liter]	14.6	29.2

Adverse Events

Time Frame	14 days
Arm/Group Title	Voriconazole High Dose		Voriconazole Low Dose
Arm/Group Description	Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (300 mg or Every 12 Hours x 7 Doses)		Voriconazole Administered by Mouth as a Loading Dose (400 mg x 2 Doses, Day 1) and as Maintenance Doses (200 mg or Every 12 Hours x 7 Doses)
All Cause Mortality
	Voriconazole High Dose		Voriconazole Low Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Voriconazole High Dose		Voriconazole Low Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Voriconazole High Dose		Voriconazole Low Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)

Limitations/Caveats

The study sample size was small.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.