Pharmacokinetic Profile of Myfortic in Combination With Tacrolimus in Fed Versus Fasting State

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT00585468
• Collaborator: (none)
• Enrollment: 21
• Location: 1
• Arms: 2
• Duration (Months): 43
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Literature regarding the effect of food on the pharmacokinetic (PK) profile of enteric-coated mycophenolate sodium combined with tacrolimus and corticosteroid withdrawal is lacking. The objective of this study is to identify pharmacokinetic variables of mycophenolate sodium (Myfortic®) in the fed and fasting state in stable renal transplant patients on tacrolimus in combination with a rapid steroid withdrawal protocol.

Condition or Disease	Intervention/Treatment	Phase
Kidney Transplantation	Drug: Myfortic	Phase 4

Detailed Description

Mycophenolate sodium (Myfortic®) is an antiproliferative immunosuppressant used in renal transplantation. Mycophenolate sodium is formulated as an enteric coated tablet that releases mycophenolic acid (MPA) which in turn inhibits inosine monophosphate dehydrogenase (IMPDH). Through inhibition of IMPDH, the de novo pathway of purine synthesis, which T and B lymphocytes rely on for proliferation, is blocked. The pharmacokinetic profile of mycophenolate sodium has mainly been studied in combination with cyclosporine and steroids. There is little information on the pharmacokinetics of mycophenolate sodium in combination with tacrolimus and currently no published information in steroid withdrawal. All current published data on the pharmacokinetics of MPA have been in patients receiving chronic corticosteroids as part of their immunosuppression regimen. As immunosuppression minimization, and especially corticosteroid withdrawal, become more popular it is important to understand how mycophenolate sodium and its metabolites behave in a two-drug maintenance immunosuppression regimen. The study will assess the pharmacokinetic profile of mycophenolate sodium in patients on tacrolimus dose adjusted based on levels, and a steroid withdrawal protocol.

Renal transplant patients will act as their own controls in a randomized crossover design with pharmacokinetic profiles occurring at two different time points. Immunosuppression will consist of induction therapy with maintenance immunosuppression consisting of tacrolimus plus mycophenolate sodium. Corticosteroids will be withdrawn per institutional protocol within the first week post transplant.

Approximately 3-4 weeks post transplant, patients that met enrollment criteria and have consented to participate in the study will be instructed to take 720 milligrams of mycophenolate sodium orally twice daily for one week either separated from food by two hours (fasting state) or with a meal (fed state). After one week, patients will be admitted for approximately 24 hours where they will continue to receive mycophenolate sodium with or without food. During this period, blood samples will be drawn at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours following the dose to evaluate levels of mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG). After 24 hours, patients will be discharged with instructions to take mycophenolate sodium in the opposite manner (fed or fasting state) than they had the week before. At the end of the second week the patients will return for a second PK evaluation with blood collection at the same time points following mycophenolate sodium dosing.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetic Profile of Myfortic (Enteric Coated Mycophenolate Sodium) in a Rapid Steroid Withdrawal Protocol in Combination With Tacrolimus in Stable Renal Transplant Recipients in the Fed and Fasting State
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Myfortic - Fed State Mycophenolate sodium taken with a meal.	Drug: Myfortic; Myfortic 720 mg orally twice daily; Other Names: mycophenolate sodium mycophenolic acid
Experimental: Myfortic - Fasting State Mycophenolate sodium taken separately from food by 2 hours.	Drug: Myfortic; Myfortic 720 mg orally twice daily; Other Names: mycophenolate sodium mycophenolic acid

Outcome Measures

Primary Outcome Measures

1. Maximum Observed Plasma Concentration (Cmax) of Mycophenolic Acid (MPA) [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose]

2. Minimum Observed Plasma Concentration (Cmin) of Mycophenolic Acid (MPA) [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose]

3. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mycophenolic Acid (MPA) [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose]

4. Area Under the Curve (AUC) From Time Zero to 12 Hours Post-Dose [AUC (0-12)] of Mycophenolic Acid (MPA) [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose]

   AUC (0-12) = Area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose, measured in microgram-hours per milliliter (mcg*h/mL)

5. Maximum Observed Plasma Concentration (Cmax) of Mycophenolic Acid Glucuronide (MPAG) [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose]

6. Minimum Observed Plasma Concentration (Cmin) of Mycophenolic Acid Glucuronide (MPAG) [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose]

7. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mycophenolic Acid Glucuronide (MPAG) [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose]

8. Area Under the Curve From Time Zero to 12 Hours Post-Dose [AUC (0-12)] of Mycophenolic Acid Glucuronide (MPAG) [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose]

   AUC (0-12) = Area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose, measured in microgram-hours per milliliter (mcg*h/mL)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Renal transplant recipients greater than 18 years of age, who have given written consent

Exclusion Criteria:

• Taking medications that may alter the metabolism of tacrolimus or mycophenolate sodium

• Experienced an acute rejection episode prior to the pharmacokinetic profile collection

• Serum creatinine >2 mg/dL

• Neutropenia (Absolute Neutrophil Count < 1.3x10^3/mL)

• Received a previous transplant other than a kidney

• Receiving chronic steroids at time of transplant

• Known hypersensitivity to tacrolimus, mycophenolate mofetil, mycophenolate sodium, mycophenolic acid or any of its excipients

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ of Utah-Solid Organ Transplant	Salt Lake City	Utah	United States	84119

Sponsors and Collaborators

• University of Utah

Investigators

• Principal Investigator: Fuad Shihab, MD, University of Utah

Study Documents (Full-Text)

None provided.

More Information

Publications

• Arns W, Breuer S, Choudhury S, Taccard G, Lee J, Binder V, Roettele J, Schmouder R. Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin Transplant. 2005 Apr;19(2):199-206.
• Kaplan B, Meier-Kriesche HU, Minnick P, Bastien MC, Sechaud R, Yeh CM, Balez S, Picard F, Schmouder R. Randomized calcineurin inhibitor cross over study to measure the pharmacokinetics of co-administered enteric-coated mycophenolate sodium. Clin Transplant. 2005 Aug;19(4):551-8.
• van Gelder T, Klupp J, Barten MJ, Christians U, Morris RE. Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid. Ther Drug Monit. 2001 Apr;23(2):119-28.
• Zucker K, Rosen A, Tsaroucha A, de Faria L, Roth D, Ciancio G, Esquenazi V, Burke G, Tzakis A, Miller J. Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings. Transpl Immunol. 1997 Sep;5(3):225-32.

• Responsible Party: University of Utah
• ClinicalTrials.gov Identifier: NCT00585468
• Other Study ID Numbers: 15121; Award# CERL080AUS33
• First Posted: Jan 3, 2008
• Last Update Posted: May 6, 2016
• Last Verified: Apr 1, 2016

• Additional relevant MeSH terms: Mycophenolic Acid

Study Results

Participant Flow

Arm/Group Title	Fed State First, Then Fasting State	Fasting State First, Then Fed State
Arm/Group Description	720 milligrams (mg) mycophenolate sodium orally twice daily with a meal for one week in the first intervention period, followed by one week of 720 mg mycophenolate sodium orally twice daily separated by food by 2 hours in the second intervention period.	720 mg mycophenolate sodium orally twice daily separated from food by 2 hours for one week in the first intervention period, followed by one week of 720 mg mycophenolate sodium orally twice daily with a meal in the second intervention period.
Period Title: First Intervention
STARTED	10	11
COMPLETED	9	10
NOT COMPLETED	1	1
Period Title: First Intervention
STARTED	9	10
COMPLETED	9	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to the Fed State first and to the Fasted State first
Overall Participants	21
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	21 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.6 (9.8)
Sex: Female, Male (Count of Participants)
Female	6 28.6%
Male	15 71.4%
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Mycophenolic Acid (MPA)
Time Frame	0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Myfortic - Fed State	Myfortic - Fasting State
Arm/Group Description	Mycophenolate sodium taken with a meal	Mycophenolate sodium taken separately from food by 2 hours
Measure Participants	19	19
Mean (Standard Deviation) [micrograms per milliliter]	12.8 (6.7)	18.7 (7.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myfortic - Fed State, Myfortic - Fasting State
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0163
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Minimum Observed Plasma Concentration (Cmin) of Mycophenolic Acid (MPA)
Time Frame	0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Myfortic - Fed State	Myfortic - Fasting State
Arm/Group Description	Mycophenolate sodium taken with a meal. Myfortic: Myfortic 720 mg orally twice daily	Mycophenolate sodium taken separately from food by 2 hours. Myfortic: Myfortic 720 mg orally twice daily
Measure Participants	19	19
Mean (Standard Deviation) [micrograms per milliliter]	2.2 (0.6)	1.7 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myfortic - Fed State, Myfortic - Fasting State
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mycophenolic Acid (MPA)
Time Frame	0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Myfortic - Fed State	Myfortic - Fasting State
Arm/Group Description	Mycophenolate sodium taken with a meal. Myfortic: Myfortic 720 mg orally twice daily	Mycophenolate sodium taken separately from food by 2 hours. Myfortic: Myfortic 720 mg orally twice daily
Measure Participants	19	19
Median (Full Range) [hours]	5	3

4. Primary Outcome

Title	Area Under the Curve (AUC) From Time Zero to 12 Hours Post-Dose [AUC (0-12)] of Mycophenolic Acid (MPA)
Description	AUC (0-12) = Area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose, measured in microgram-hours per milliliter (mcg*h/mL)
Time Frame	0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Myfortic - Fed State	Myfortic - Fasting State
Arm/Group Description	Mycophenolate sodium taken with a meal. Myfortic: Myfortic 720 mg orally twice daily	Mycophenolate sodium taken separately from food by 2 hours. Myfortic: Myfortic 720 mg orally twice daily
Measure Participants	19	19
Mean (Standard Deviation) [mcg*h/mL]	56.5 (15.2)	63.9 (15.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myfortic - Fed State, Myfortic - Fasting State
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.146
	Comments
	Method	t-test, 2 sided
	Comments

5. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Mycophenolic Acid Glucuronide (MPAG)
Time Frame	0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Myfortic - Fed State	Myfortic - Fasting State
Arm/Group Description	Mycophenolate sodium taken with a meal. Myfortic: Myfortic 720 mg orally twice daily	Mycophenolate sodium taken separately from food by 2 hours. Myfortic: Myfortic 720 mg orally twice daily
Measure Participants	19	19
Mean (Standard Deviation) [micrograms per milliliter]	104.9 (35.7)	113.0 (36.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myfortic - Fed State, Myfortic - Fasting State
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4937
	Comments
	Method	t-test, 2 sided
	Comments

6. Primary Outcome

Title	Minimum Observed Plasma Concentration (Cmin) of Mycophenolic Acid Glucuronide (MPAG)
Time Frame	0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Myfortic - Fed State	Myfortic - Fasting State
Arm/Group Description	Mycophenolate sodium taken with a meal. Myfortic: Myfortic 720 mg orally twice daily	Mycophenolate sodium taken separately from food by 2 hours. Myfortic: Myfortic 720 mg orally twice daily
Measure Participants	19	19
Mean (Standard Deviation) [micrograms per milliliter]	59.4 (24.9)	57.0 (23.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myfortic - Fed State, Myfortic - Fasting State
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9669
	Comments
	Method	t-test, 2 sided
	Comments

7. Primary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mycophenolic Acid Glucuronide (MPAG)
Time Frame	0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Myfortic - Fed State	Myfortic - Fasting State
Arm/Group Description	Mycophenolate sodium taken with a meal. Myfortic: Myfortic 720 mg orally twice daily	Mycophenolate sodium taken separately from food by 2 hours. Myfortic: Myfortic 720 mg orally twice daily
Measure Participants	19	19
Median (Full Range) [hours]	3	3

8. Primary Outcome

Title	Area Under the Curve From Time Zero to 12 Hours Post-Dose [AUC (0-12)] of Mycophenolic Acid Glucuronide (MPAG)
Description	AUC (0-12) = Area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose, measured in microgram-hours per milliliter (mcg*h/mL)
Time Frame	0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Myfortic - Fed State	Myfortic - Fasting State
Arm/Group Description	Mycophenolate sodium taken with a meal. Myfortic: Myfortic 720 mg orally twice daily	Mycophenolate sodium taken separately from food by 2 hours. Myfortic: Myfortic 720 mg orally twice daily
Measure Participants	19	19
Mean (Standard Deviation) [mcg*h/mL]	967.5 (364.0)	962.2 (289.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Myfortic - Fed State, Myfortic - Fasting State
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9607
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Adverse Event Reporting Description	Adverse events were not collected in this study
Arm/Group Title	Myfortic - Fed State		Myfortic - Fasting State
Arm/Group Description	Mycophenolate sodium taken with a meal		Mycophenolate sodium taken separately from food by 2 hours
All Cause Mortality
	Myfortic - Fed State		Myfortic - Fasting State
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Myfortic - Fed State		Myfortic - Fasting State
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Myfortic - Fed State		Myfortic - Fasting State
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.