Kidney Transplantation
Conditions
Brief summary
This open-label, 2-arm study will compare the pharmacokinetics of CellCept and mycophenolate sodium in kidney transplanted patients on a calcineurininhibitor-free mycophenolic acid-based therapy. On the study day patients will take their prescribed medication (either CellCept or mycophenolate sodium). Blood samples will be drawn directly before and at intervals up to 12 hours after intake of the study medication. Anticipated time on study treatment is 12 hours and target sample size is 24.
Interventions
DRUGMMF
1 g per day b.i.d. p.o. for at least 1 month
DRUGEC-MPS
720 mg b.i.d. p.o. for at least 1 month
DRUGPrednisone
5 mg per day p.o.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* adult patients, \>/=18 years of age * kidney transplantation \>/=6 months ago * on mycophenolic acid-based, calcineurininhibitor-free therapy for \>/=3 months, \>/=1 month on stable dose * co-therapy with 5mg prednisone for \>/=1 month
Exclusion criteria
* active gastrointestinal ulcus * severe diarrhea od gastrointestinal disease * severe impairment of renal function * current malignancy * Lesch-Nyhan- or Kelley-Seegmiller-Syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours | — |
| Pre-dose Trough Concentration (C0) | Day 1 predose | The mean mycophenolic acid (MPA) concentration in plasma was determined (in milligrams per liter \[mg/L\]) from blood samples collected predose (immediately before receiving study treatment). |
| Dose-Normalized C0 | Day 1 predose | Dose normalized C0 was determined (in mg/L) from blood samples collected predose. Both MMF and EC-MPS doses were normalized to a standard dose of 1 g MMF or 720 mg EC-MPS, respectively. The dose normalization was calculated as follows: For the MMF group: Dose normalized C0 equals (=) C0 divided by (/) (actual dose taken/1000) For the EC-MPS group: Dose normalized C0 = C0 / (actual dose taken/720) |
| Minimum Plasma Concentration (Cmin) | Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours | The mean minimum MPA concentration in plasma was determined (in mg/L) from blood samples collected predose and postdose on Day 1. |
| Dose-Normalized Cmin | Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours | Dose-normalized Cmin was determined (in mg/L) from blood samples collected predose and postdose. Both MMF and EC-MPS doses were normalized to a standard dose of 1 g MMF or 720 mg EC-MPS, respectively. The dose normalization was calculated as follows: For the MMF group: Dose normalized Cmin = Cmin/ (actual dose taken/1000) For the EC-MPS group: Dose normalized Cmin = Cmin / (actual dose taken/720) |
| Maximum Plasma Concentration (Cmax) | Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours | The mean maximum MPA concentration in plasma was determined (in mg/L) in blood samples collected predose and postdose on Day 1. |
| Dose-Normalized Cmax (mg/L) | Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours | Dose-normalized Cmax in plasma was determined (in mg/L) from blood samples collected predose and postdose on Day 1. Both MMF and EC-MPS doses were normalized to a standard dose of 1 g MMF or 720 mg EC-MPS, respectively. The dose normalization was calculated as follows: For the MMF group: Dose normalized Cmax = Cmax / (actual dose taken/1000) For the EC-MPS group: Dose normalized Cmax = Cmax / (actual dose taken/720) |
| MPA Area Under the Curve From 0 to 12 Hours (AUC0-12) | Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours | The mean MPA AUC0-12 in plasma was determined (in mg multiplied by hours, per Liter \[mg\*h/L\]) from blood samples collected predose and postdose on Day 1. |
| Dose-Normalized MPA AUC0-12 | Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours | Dose-normalized MPA AUC0-12 in plasma was determined (mg\*h/L) from blood samples collected predose and postdose on Day 1. Both MMF and EC-MPS doses were normalized to a standard dose of 1 g MMF or 720 mg EC-MPS, respectively. The dose normalization was calculated as follows: For the MMF group: Dose normalized MPA AUC = MPA AUC / (actual dose taken/1000) For the EC-MPS group: Dose normalized MPA AUC = MPA AUC / (actual dose taken/720) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Regression Coefficients For Participants Receiving MMF | Day 1 at 30 minutes and 1 and 2 hours postdose | The estimated regression coefficients for participants who received MMF presented in milligrams per liter (mg/L). |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MMF/Prednisone Participants were administered MMF tablets or capsules, PO, at a dose prescribed by their physician and prednisone up to 5 mg PO on Day 1. | 12 |
| EC-MPS/Prednisone Participants were administered EC-MPS tablets, PO, at a dose prescribed by their physician and prednisone up to 5 mg PO on Day 1. | 11 |
| Total | 23 |
Baseline characteristics
| Characteristic | MMF/Prednisone | EC-MPS/Prednisone | Total |
|---|---|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 11.06 | 58.0 years STANDARD_DEVIATION 8.04 | 59.8 years STANDARD_DEVIATION 9.68 |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 11 |
| serious Total, serious adverse events | 0 / 12 | 0 / 11 |
Outcome results
Primary
Dose-Normalized C0
Dose normalized C0 was determined (in mg/L) from blood samples collected predose. Both MMF and EC-MPS doses were normalized to a standard dose of 1 g MMF or 720 mg EC-MPS, respectively. The dose normalization was calculated as follows: For the MMF group: Dose normalized C0 equals (=) C0 divided by (/) (actual dose taken/1000) For the EC-MPS group: Dose normalized C0 = C0 / (actual dose taken/720)
Time frame: Day 1 predose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF/Prednisone | Dose-Normalized C0 | 2.962 mg/L | Standard Deviation 1.4439 |
| EC-MPS/Prednisone | Dose-Normalized C0 | 4.658 mg/L | Standard Deviation 3.1121 |
p-value: 0.2548Wilcoxon (Mann-Whitney)
Primary
Dose-Normalized Cmax (mg/L)
Dose-normalized Cmax in plasma was determined (in mg/L) from blood samples collected predose and postdose on Day 1. Both MMF and EC-MPS doses were normalized to a standard dose of 1 g MMF or 720 mg EC-MPS, respectively. The dose normalization was calculated as follows: For the MMF group: Dose normalized Cmax = Cmax / (actual dose taken/1000) For the EC-MPS group: Dose normalized Cmax = Cmax / (actual dose taken/720)
Time frame: Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF/Prednisone | Dose-Normalized Cmax (mg/L) | 18.402 mg/L | Standard Deviation 5.4349 |
| EC-MPS/Prednisone | Dose-Normalized Cmax (mg/L) | 29.996 mg/L | Standard Deviation 11.3229 |
p-value: 0.0106Wilcoxon (Mann-Whitney)
Primary
Dose-Normalized Cmin
Dose-normalized Cmin was determined (in mg/L) from blood samples collected predose and postdose. Both MMF and EC-MPS doses were normalized to a standard dose of 1 g MMF or 720 mg EC-MPS, respectively. The dose normalization was calculated as follows: For the MMF group: Dose normalized Cmin = Cmin/ (actual dose taken/1000) For the EC-MPS group: Dose normalized Cmin = Cmin / (actual dose taken/720)
Time frame: Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF/Prednisone | Dose-Normalized Cmin | 1.702 mg/L | Standard Deviation 0.8018 |
| EC-MPS/Prednisone | Dose-Normalized Cmin | 2.613 mg/L | Standard Deviation 1.0291 |
p-value: 0.0455Wilcoxon (Mann-Whitney)
Primary
Dose-Normalized MPA AUC0-12
Dose-normalized MPA AUC0-12 in plasma was determined (mg\*h/L) from blood samples collected predose and postdose on Day 1. Both MMF and EC-MPS doses were normalized to a standard dose of 1 g MMF or 720 mg EC-MPS, respectively. The dose normalization was calculated as follows: For the MMF group: Dose normalized MPA AUC = MPA AUC / (actual dose taken/1000) For the EC-MPS group: Dose normalized MPA AUC = MPA AUC / (actual dose taken/720)
Time frame: Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF/Prednisone | Dose-Normalized MPA AUC0-12 | 61.53862 mg*h/L | Standard Deviation 21.003959 |
| EC-MPS/Prednisone | Dose-Normalized MPA AUC0-12 | 94.65765 mg*h/L | Standard Deviation 29.307839 |
p-value: 0.0074Wilcoxon (Mann-Whitney)
Primary
Maximum Plasma Concentration (Cmax)
The mean maximum MPA concentration in plasma was determined (in mg/L) in blood samples collected predose and postdose on Day 1.
Time frame: Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF/Prednisone | Maximum Plasma Concentration (Cmax) | 15.385 mg/L | Standard Deviation 5.232 |
| EC-MPS/Prednisone | Maximum Plasma Concentration (Cmax) | 17.827 mg/L | Standard Deviation 4.2898 |
p-value: 0.23Wilcoxon (Mann-Whitney)
Primary
Minimum Plasma Concentration (Cmin)
The mean minimum MPA concentration in plasma was determined (in mg/L) from blood samples collected predose and postdose on Day 1.
Time frame: Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF/Prednisone | Minimum Plasma Concentration (Cmin) | 1.385 mg/L | Standard Deviation 0.6061 |
| EC-MPS/Prednisone | Minimum Plasma Concentration (Cmin) | 1.620 mg/L | Standard Deviation 0.6632 |
p-value: 0.4417Wilcoxon (Mann-Whitney)
Primary
MPA Area Under the Curve From 0 to 12 Hours (AUC0-12)
The mean MPA AUC0-12 in plasma was determined (in mg multiplied by hours, per Liter \[mg\*h/L\]) from blood samples collected predose and postdose on Day 1.
Time frame: Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF/Prednisone | MPA Area Under the Curve From 0 to 12 Hours (AUC0-12) | 50.36348 mg*h/L | Standard Deviation 15.42323 |
| EC-MPS/Prednisone | MPA Area Under the Curve From 0 to 12 Hours (AUC0-12) | 57.06682 mg*h/L | Standard Deviation 10.965285 |
p-value: 0.3401Wilcoxon (Mann-Whitney)
Primary
Percentage of Participants By Time to Maximum Plasma Concentration (Tmax)
Time frame: Day 1 predose and postdose at 30 and 60 minutes and 2, 3, 4, 5, 6, 8 10 and 12 hours
Population: PK population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=1.0667 hrs | 8.3 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.0167 hrs | 0.0 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=0.6000 hrs | 16.7 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.0833 hrs | 0.0 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=1.0833 hrs | 16.7 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.1000 hrs | 0.0 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=0.7667 hrs | 8.3 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.1167 hrs | 0.0 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=1.1167 hrs | 8.3 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.1667 hrs | 0.0 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=0.7333 hrs | 16.7 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=3.1167 hrs | 0.0 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=1.2167 hrs | 8.3 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=3.1833 hrs | 0.0 percentage of participants |
| MMF/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax equals (=) 0.5333 hours (hrs) | 16.7 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=3.1833 hrs | 9.1 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax equals (=) 0.5333 hours (hrs) | 0.0 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=0.6000 hrs | 0.0 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=0.7333 hrs | 0.0 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=0.7667 hrs | 0.0 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=1.0667 hrs | 9.1 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=1.0833 hrs | 0.0 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=1.1167 hrs | 0.0 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=1.2167 hrs | 0.0 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.0167 hrs | 9.1 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.0833 hrs | 18.2 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.1000 hrs | 9.1 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.1167 hrs | 27.3 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=2.1667 hrs | 9.1 percentage of participants |
| EC-MPS/Prednisone | Percentage of Participants By Time to Maximum Plasma Concentration (Tmax) | Tmax=3.1167 hrs | 9.1 percentage of participants |
p-value: 0.0002Wilcoxon (Mann-Whitney)
Primary
Pre-dose Trough Concentration (C0)
The mean mycophenolic acid (MPA) concentration in plasma was determined (in milligrams per liter \[mg/L\]) from blood samples collected predose (immediately before receiving study treatment).
Time frame: Day 1 predose
Population: Pharmacokinetic (PK) population: all participants who took study drug and for whom all defined blood samples at the planned sampling time points were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF/Prednisone | Pre-dose Trough Concentration (C0) | 2.387 mg/L | Standard Deviation 1.1327 |
| EC-MPS/Prednisone | Pre-dose Trough Concentration (C0) | 2.944 mg/L | Standard Deviation 2.2103 |
p-value: 0.8055Wilcoxon (Mann-Whitney)
Secondary
Regression Coefficients For Participants Receiving MMF
The estimated regression coefficients for participants who received MMF presented in milligrams per liter (mg/L).
Time frame: Day 1 at 30 minutes and 1 and 2 hours postdose
Population: PK population. Only participants in the MMF/Prednisone group were assessed for this outcome measure, n=12.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF/Prednisone | Regression Coefficients For Participants Receiving MMF | Concentration at 30 minutes (C0.5) | 0.74031 mg/L |
| MMF/Prednisone | Regression Coefficients For Participants Receiving MMF | Intercept | 2.17192 mg/L |
| MMF/Prednisone | Regression Coefficients For Participants Receiving MMF | Concentration at 1 hour (C1) | 1.89323 mg/L |
| MMF/Prednisone | Regression Coefficients For Participants Receiving MMF | Concentration at 2 hours (C2) | 2.85923 mg/L |