Transplantation, Immunosuppression, Drug Interaction
Conditions
Keywords
immunosuppressive medication, mycophenolic acid, interaction, proton pump inhibitor, pantoprazole, renal transplant patients, pharmacokinetics, pharmacodynamics, bioavailability
Brief summary
The objective of this pharmacokinetic study is to examine a possible drug-drug interaction of Pantoprazole on the bioavailability mycophenolic acid.
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).
Interventions
DRUGPantoprazole
Daily dose: 40mg. Application together with CellCept® or Myfortic® .
DRUGMycophenolate mofetil
Daily dose: 1000mg, 1500mg, 2000mg. Application alone or with Pantozol® .
Daily dose: 720mg, 1080mg, 1440mg. Application alone or together with Pantozol®.
Sponsors
Novartis Pharmaceuticals
Klemens Budde
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Germany
Participant flow
Recruitment details
Recruitment lastet between January 2012 - March 2013.
Participants by arm
| Arm | Count |
|---|---|
| Sequence A 1. st period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d.
2. nd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d.
3. 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.
4. 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. | 5 |
| Sequence B 1. st period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d.
2. 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.
3. 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.
4. th period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d. | 5 |
| Sequence C 1. 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.
2. 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.
3. rd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d.
4. th period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d. | 5 |
| Sequence D 1. 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.
2. nd period: Mycophenolate mofetil (MMF) tablet (500, 750 or 1000mg) b.i.d. every 12 hours for 10-14d.
3. rd period: Mycophenolate sodium (EC-MPS) tablet (720, 1080, 1440) b.i.d. every 12 hours for 10-14d.
4. 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. | 5 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 | Withdrawal by Subject | 0 | 1 | 0 | 0 |
| Period 2 | Withdrawal by Subject | 1 | 0 | 0 | 0 |
| Period 4 | Protocol Violation | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Sequence D | Sequence C | Sequence B | Sequence A |
|---|---|---|---|---|---|
| Age at study enrollment | 51 years STANDARD_DEVIATION 16 | 51 years STANDARD_DEVIATION 19 | 44 years STANDARD_DEVIATION 15 | 46 years STANDARD_DEVIATION 16 | 63 years STANDARD_DEVIATION 11 |
| Age, Continuous | 44 y STANDARD_DEVIATION 16 | 43 y STANDARD_DEVIATION 14 | 33 y STANDARD_DEVIATION 17 | 42 y STANDARD_DEVIATION 14 | 59 y STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 12 Participants | 1 Participants | 5 Participants | 3 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 19 | 3 / 18 | 2 / 18 | 2 / 18 |
| serious Total, serious adverse events | 1 / 19 | 1 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
Dose-normalized AUC of Mycophenolic Acid
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mycophenolate Mofetil (MMF) | Dose-normalized AUC of Mycophenolic Acid | 41 mg*h/L | Standard Deviation 18 |
| MMF+PAN | Dose-normalized AUC of Mycophenolic Acid | 38 mg*h/L | Standard Deviation 18 |
| EC-MPS | Dose-normalized AUC of Mycophenolic Acid | 43 mg*h/L | Standard Deviation 19 |
| EC-MPS + PAN | Dose-normalized AUC of Mycophenolic Acid | 46 mg*h/L | Standard Deviation 18 |