Influence of Pantoprazole on the Bioavailability of MMF and EC-MPS

• Sponsor: Klemens Budde (Other)
• Overall Status: Completed
• CT.gov ID: NCT01801280
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 20
• Location: 1
• Arms: 4
• Duration (Months): 26
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The objective of this pharmacokinetic study is to examine a possible drug-drug interaction of Pantoprazole on the bioavailability mycophenolic acid.

Condition or Disease	Intervention/Treatment	Phase
Transplantation; Immunosuppression; Drug Interaction	Drug: Mycophenolate sodium; Drug: Pantoprazole; Drug: Mycophenolate mofetil	Phase 4

Detailed Description

It is a randomized open-label 4-sequence 4-period pharmacokinetic cross-over study. The objective of the pharmacokinetic study is to examine a drug-drug interaction of pantoprazole on the bioavailability mycophenolic acid administered as either mycophenolate mofetil (Cellcept(R) or mycophenolate Sodium; EC-MPS (Myfortic (R) in stable renal allograft recipients under maintenance immunosuppressive therapy (cyclosporine +/- low dose glucocorticoids).

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetic Cross-over Study to Evaluate the Influence of Pantoprazole on MPA Bioavailability Administered as Mycophenolate Mofetil and Enteric Coated Mycophenolate Sodium in Maintenance Renal Transplant Patients
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Mycophenolate mofetil (C) Mycophenolate mofetil (C) b.i.d. every 12 hours for 2 weeks.	Drug: Mycophenolate mofetil; Daily dose: 1000mg, 1500mg, 2000mg. Application alone or with Pantozol® .; Other Names: Cellcept®
Other: Mycophenolate mofetil+Pantoprazole (C+P) Mycophenolate mofetil b.i.d and Pantoprazole o.m. for 2 weeks.	Drug: Pantoprazole; Daily dose: 40mg. Application together with CellCept® or Myfortic® .; Other Names: Pantozol® ; Drug: Mycophenolate mofetil; Daily dose: 1000mg, 1500mg, 2000mg. Application alone or with Pantozol® .; Other Names: Cellcept®
Other: Mycophenolate sodium (M) Mycophenolate sodium (M) b.i.d. every 12 hours for 2 weeks.	Drug: Mycophenolate sodium; Daily dose: 720mg, 1080mg, 1440mg. Application alone or together with Pantozol®.; Other Names: Myfortic®
Other: Mycophenolate sodium+Pantoprazole (M+P) Mycophenolate mofetil b.i.d and Pantoprazole 40mg o.m. for 2 weeks.	Drug: Mycophenolate sodium; Daily dose: 720mg, 1080mg, 1440mg. Application alone or together with Pantozol®.; Other Names: Myfortic® ; Drug: Pantoprazole; Daily dose: 40mg. Application together with CellCept® or Myfortic® .; Other Names: Pantozol®

Outcome Measures

Primary Outcome Measures

1. Dose-normalized AUC of Mycophenolic Acid [Study duration for each patient: 2 months. After 10-14 days of drug intake blood samples for PK/PD analysis will be collected. On the next day new treatment starts. There are 4 study visits at the study center. Duration will be approximately 12hours]

   Bioavailability (12h AUC) of mycophenolic acid in renal transplant patients after administration of MMF+/-PAN and EC-MPS+/-PAN For evaluation of pharmacokinetic and pharmacodynamic parameters blood will be collected before, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h after drug intake.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• patients >18 years old

• patients who are on stable immunosuppressive therapy for at least one month with ciclosporin, EC-MPS or MMF +/- corticosteroids

• renal transplantation, at least 6 months prior study inclusion

• suitable and willing to switch treatment according to the study plan

• women of childbearing potential must have a negative serum pregnancy test before study start and effective contraception must be used (method with PEARL index <1%)

Exclusion Criteria:

• patients with renal function <30ml/min (estimated by Cockcroft Gault formula)

• patients who are not on stable treatment with enzyme inductors or enzyme inhibitors for <1 month before study entry

• patients who take medication which is known for interfering with MPA absorption for <1 month before study entry

• known anamnestic hypersensitivity to one of the investigational products or drugs with similar chemical structure and to other components of the investigational products, respectively

• patients on treatment with clopidogrel

• acute rejection < 1 month before study inclusion

• patients who are HIV positive, hepatitis C virus (HCV) positive, HBsAg positive

• patients with gastrointestinal disorders which could affect resorption

• pregnancy and/or lactation

• drug or alcohol abuse in patient's history

• patients with history of psychological illness or condition, which might interfere with the ability to understand the requirements, consequences, possible outcome of the study and patients who are not willing to give valid informed consent

• patients with insufficient co-operation with the clinical investigator (e.g. suspicion of non-compliance)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Charité Hospital Campus Mitte	Berlin		Germany	10117

Sponsors and Collaborators

• Klemens Budde
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Klemens Budde, Prof Dr, Charite University, Berlin, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Klemens Budde, Professor Dr Klemens Budde, Charite University, Berlin, Germany
• ClinicalTrials.gov Identifier: NCT01801280
• Other Study ID Numbers: CERL 080A DE 20 T; 2010-021275-92
• First Posted: Feb 28, 2013
• Last Update Posted: Feb 21, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Klemens Budde, Professor Dr Klemens Budde, Charite University, Berlin, Germany: immunosuppressive medication; mycophenolic acid; interaction; proton pump inhibitor; pantoprazole; renal transplant patients; pharmacokinetics; pharmacodynamics; bioavailability
• Additional relevant MeSH terms: Mycophenolic Acid; Pantoprazole

Study Results

Participant Flow

Recruitment Details	Recruitment lastet between January 2012 - March 2013.

Arm/Group Title	Sequence A	Sequence B	Sequence C	Sequence D
Arm/Group Description	st period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. nd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. rd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. th period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d.	st period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. nd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. rd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. th period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d.	st period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. nd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. rd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. th period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d.	st period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. nd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. rd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. th period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d.
Period Title: Period 1
STARTED	5	5	5	5
COMPLETED	5	4	5	5
NOT COMPLETED	0	1	0	0
Period Title: Period 1
STARTED	5	4	5	5
COMPLETED	4	4	5	5
NOT COMPLETED	1	0	0	0
Period Title: Period 1
STARTED	4	4	5	5
COMPLETED	4	4	5	5
NOT COMPLETED	0	0	0	0
Period Title: Period 1
STARTED	4	4	5	5
COMPLETED	4	4	4	5
NOT COMPLETED	0	0	1	0

Baseline Characteristics

Arm/Group Title	Sequence A	Sequence B	Sequence C	Sequence D	Total
Arm/Group Description	st period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. nd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. rd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. th period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d.	st period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. nd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. rd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. th period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d.	st period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. nd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. rd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. th period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d.	st period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d. nd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. rd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. th period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. Pantoprazole 40mg tablet (PAN) each for 10-14d.	Total of all reporting groups
Overall Participants	5	5	5	5	20
Age (y) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [y]	59 (12)	42 (14)	33 (17)	43 (14)	44 (16)
Sex: Female, Male (Count of Participants)
Female	2 40%	2 40%	0 0%	4 80%	8 40%
Male	3 60%	3 60%	5 100%	1 20%	12 60%
Age at study enrollment (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63 (11)	46 (16)	44 (15)	51 (19)	51 (16)

Outcome Measures

1. Primary Outcome

Title	Dose-normalized AUC of Mycophenolic Acid
Description	Bioavailability (12h AUC) of mycophenolic acid in renal transplant patients after administration of MMF+/-PAN and EC-MPS+/-PAN For evaluation of pharmacokinetic and pharmacodynamic parameters blood will be collected before, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h after drug intake.
Time Frame	Study duration for each patient: 2 months. After 10-14 days of drug intake blood samples for PK/PD analysis will be collected. On the next day new treatment starts. There are 4 study visits at the study center. Duration will be approximately 12hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mycophenolate Mofetil (MMF)	MMF+PAN	EC-MPS	EC-MPS + PAN
Arm/Group Description	Mycophenolate mofetil (MMF) tablet twice a day every 12 hours for two weeks. Mycophenolate mofetil daily dose: 1000mg, 1500mg, 2000mg.	Mycophenolate mofetil (MMF) tablet twice a day every 12 hours for two weeks. Mycophenolate mofetil daily dose: 1000mg, 1500mg, 2000mg. Pantoprazole daily dose: 40mg once in the morning together with Mycophenolate mofetil. Pantoprazole tablet (PAN) once a day in the morning for two weeks.	Mycophenolate sodium (EC-MPS) tablet twice a day every 12 hours for two weeks. Mycophenolate sodium daily dose: 720mg, 1080mg, 1440mg.	Mycophenolate sodium (EC-MPS) tablet twice a day every 12 hours for two weeks. Mycophenolate sodium daily dose: 720mg, 1080mg, 1440mg. Pantoprazole daily dose: 40mg once in the morning together with Mycophenolate sodium. Pantoprazole tablet (PAN) once a day in the morning for two weeks.
Measure Participants	17	17	17	17
Mean (Standard Deviation) [mg*h/L]	41 (18)	38 (18)	43 (19)	46 (18)

Adverse Events

Time Frame	Adverse event data were collected at every study visit. No follow up data.
Arm/Group Title	Mycophenolate Mofetil (MMF)		MMF + PAN		EC-MPS		EC-MPS + PAN
Arm/Group Description	Mycophenolate mofetil (MMF) tablet twice a day every 12 hours for two weeks. Mycophenolate mofetil daily dose: 1000mg, 1500mg, 2000mg.		Mycophenolate mofetil (MMF) tablet twice a day every 12 hours for two weeks. Mycophenolate mofetil daily dose: 1000mg, 1500mg, 2000mg. Pantoprazole daily dose: 40mg once in the morning together with Mycophenolate mofetil. Pantoprazole tablet (PAN) once a day in the morning for two weeks.		Mycophenolate sodium (EC-MPS) tablet twice a day every 12 hours for two weeks. Mycophenolate sodium daily dose: 720mg, 1080mg, 1440mg.		Mycophenolate sodium (EC-MPS) tablet twice a day every 12 hours for two weeks. Mycophenolate sodium daily dose: 720mg, 1080mg, 1440mg. Pantoprazole daily dose: 40mg once in the morning together with Mycophenolate sodium. Pantoprazole tablet (PAN) once a day in the morning for two weeks.
All Cause Mortality
	Mycophenolate Mofetil (MMF)		MMF + PAN		EC-MPS		EC-MPS + PAN
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Mycophenolate Mofetil (MMF)		MMF + PAN		EC-MPS		EC-MPS + PAN
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		1/18 (5.6%)		0/18 (0%)		0/18 (0%)
Gastrointestinal disorders
Noro virus infection	1/19 (5.3%)	1	0/18 (0%)	0	0/18 (0%)	0	0/18 (0%)	0
Renal and urinary disorders
Urinary tract infection	0/19 (0%)	0	1/18 (5.6%)	1	0/18 (0%)	0	0/18 (0%)	0
Other (Not Including Serious) Adverse Events
	Mycophenolate Mofetil (MMF)		MMF + PAN		EC-MPS		EC-MPS + PAN
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/19 (21.1%)		3/18 (16.7%)		2/18 (11.1%)		2/18 (11.1%)
Immune system disorders
Common cold	4/19 (21.1%)	4	3/18 (16.7%)	3	2/18 (11.1%)	2	2/18 (11.1%)	2

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.