Pediatric Liver Transplantation
Conditions
Brief summary
The study is planned to be conducted in 2 parts. The first part (open label, multi-center, non-controlled) of the study will estimate a dose that would provide a mycophenolic acid (MPA) exposure in pediatric participant that is comparable to that achieved in adult liver transplant participants receiving the approved dose of mycophenolate mofetil (MMF, CellCept). The second part (open-label, multi-center, single-arm Phase IV study) of the study will provide the pharmacokinetics, efficacy and safety profile of the proposed dose in the immediate post-transplant period. This study will be conducted at two centers based in the United States of America. Twelve pediatric transplant participants receiving a first liver allograft from a cadaveric or living donor will be enrolled in this study. Stable pediatric liver transplant participants who are at least 6 months post-transplant and who were already receiving stable dose of MMF in combination with cyclosporine will be enrolled into the study. Participants should have received stable MMF dose according to center practice for at least seven days in order to get steady state pharmacokinetics (PK). Participants also should have received stable concomitant doses of cyclosporine (for at least 2 days) and corticosteroids per center practice. Participants will be aged between 9 months and 12 years, with at least 6 participants greater than or equal to (\>/=) 9 months and less than (\<) 36 months, of whom at least 2 will be \<24 months.
Interventions
DRUGCorticosteroids
Corticosteroids will be administered as per center practice. The choice of corticosteroid drug will also be based on center practice.
DRUGCyclosporine
Cyclosporine will be administered as per center practice.
DRUGmycophenolate mofetil
Part 1: Mycophenolate mofetil will be administered as per center practice. Part 2: Mycophenolate mofetil will be administered as per dose determined in Part 1.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 12 Years
Healthy volunteers
No
Inclusion criteria
* Male or female participant must be between 3 months and 12 years of age * Participant is a recipient of a first liver allograft from cadaveric or living donors * Participant is a single-organ recipient (liver only) * Female participants of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 50 milli International Units per milliliter (mIU/mL) within one week prior to PK sampling * Female participants of childbearing potential must use two reliable forms of contraception simultaneously unless abstinence is the chosen method * Effective contraception must be used before beginning of PK sampling * Participants must be able to receive oral medication * Participants must be at least 6 months post-transplant and had started on MMF in the early post-transplant period (within 2 weeks of transplant) * Participants must be receiving stable doses of MMF per center practice for at least 7 days prior to PK sampling * In addition, participants must be receiving stable doses of cyclosporine and corticosteroids, according to center practice * Participants' parent/guardian are capable of understanding the purposes and risks of the study and must sign an informed consent for the study
Exclusion criteria
* Pregnant or nursing adolescents * Participants who had undergone dialysis within two weeks before PK sampling * Participants with active systemic infections * Participants with absolute neutrophil counts (ANC) of less than 1300 per microliter (µL), or platelets counts less than 50 000/µL or hemoglobin at a concentration below a set lower limit (according to center practice, but not less than 8 grams per deciliter) at the time of study entry * Participants with active peptic ulcer disease * Participants with severe diarrhea (more than 5 watery stools per day) or other gastrointestinal disorders which might interfere with their ability to absorb oral medication * History of positive human immunodeficiency virus (HIV) test
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From 0 to 12 Hours of Mycophenolic Acid Normalized for Dose And for Body Surface Area | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants greater than (>) 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants less than (<) 24 months | The area under the plasma concentration-time curve from time zero to twelve hours (AUC \[0-12h\]) is area under the plasma concentration-time curve from time zero through 12 hours. AUC (0-12) hours was computed using the linear trapezoidal rule. For the calculations of AUC (0-12h), concentrations below the limit of quantification were assigned a value of zero if they occurred at the beginning of a profile. When such values appeared at the end of a profile they were assigned as missing data. AUC0-12h was normalized to 600 milligram per square meter (mg/m\^2) and 1.5 gram. AUC was reported in microgram hour per milliliter (mcg\*h/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Time Curve From 0-12 Hours for Mycophenolic Acid and Mycophenolic Acid Glucuronide Phenolic Glucuronide of Mycophenolic Acid | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants greater than (>) 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants less than (<) 24 months | The area under the plasma concentration-time curve from time zero to twelve hours (AUC \[0-12h\]) is area under the plasma concentration-time curve from time zero through 12 hours. AUC (0-12) hours was computed using the linear trapezoidal rule. For the calculations of AUC (0-12h), concentrations below the limit of quantification were assigned a value of zero if they occurred at the beginning of a profile. When such values appeared at the end of a profile they were assigned as missing data. AUC was reported in microgram hour per milliliter (mcg\*h/mL). |
| Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants > 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants < 24 months | The Plasma Concentration (Cmax) is defined as maximum observed analyte concentration. Cmax was obtained directly from the measured plasma concentration-time curves. |
| Time to Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants > 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants < 24 months | Tmax is the amount of time after dosing to when the maximum concentration of MPA and MPAG was achieved. |
| Number of Participants With Adverse Events and Serious Adverse Events | Up to Day 32 | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is a significant medical event. |
| Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants greater than (>) 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants less than (<) 24 months | Mycophenolic Acid Glucuronide (MPAG) is an active metabolite of Mycophenolic Acid (MPA). |
Countries
United States
Participant flow
Recruitment details
The study was conducted between 02 May 2003 and 20 January 2005. This study was conducted at 2 sites in United States (US). Overall, 9 participants entered the study.
Pre-assignment details
Thirty five participants were screened; 9 entered the study following a screening period of up to 14 days. Stable pediatric liver transplant participants who were at least 6 months post-transplant and who were receiving stable dose of Mycophenolate Mofetil (MMF) in combination with cyclosporine were enrolled into the study.
Participants by arm
| Arm | Count |
|---|---|
| Drug MMF Participants receiving drug MMF twice daily along with stable concomitant doses of cyclosporine (for at least 2 full days) and corticosteroids as per center practice for at least 7 days prior to Pharmacokinetic (PK) sampling were observed up to Day 16 | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative | 1 |
Baseline characteristics
| Characteristic | Drug MMF |
|---|---|
| Age, Continuous | 1.3 years STANDARD_DEVIATION 1.5 |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From 0 to 12 Hours of Mycophenolic Acid Normalized for Dose And for Body Surface Area
The area under the plasma concentration-time curve from time zero to twelve hours (AUC \[0-12h\]) is area under the plasma concentration-time curve from time zero through 12 hours. AUC (0-12) hours was computed using the linear trapezoidal rule. For the calculations of AUC (0-12h), concentrations below the limit of quantification were assigned a value of zero if they occurred at the beginning of a profile. When such values appeared at the end of a profile they were assigned as missing data. AUC0-12h was normalized to 600 milligram per square meter (mg/m\^2) and 1.5 gram. AUC was reported in microgram hour per milliliter (mcg\*h/mL).
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants greater than (>) 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants less than (<) 24 months
Population: The pharmacokinetic (PK) population included all randomized and replaced participants adherent to the PK section of the protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drug MMF | Area Under the Plasma Concentration-Time Curve From 0 to 12 Hours of Mycophenolic Acid Normalized for Dose And for Body Surface Area | Normalized to 600mg/m^2 | 65.6 mcg*h/mL | Standard Deviation 56.2 |
| Drug MMF | Area Under the Plasma Concentration-Time Curve From 0 to 12 Hours of Mycophenolic Acid Normalized for Dose And for Body Surface Area | Normalized to 1.5g | 363 mcg*h/mL | Standard Deviation 360 |
Secondary
Area Under the Plasma Concentration Time Curve From 0-12 Hours for Mycophenolic Acid and Mycophenolic Acid Glucuronide Phenolic Glucuronide of Mycophenolic Acid
The area under the plasma concentration-time curve from time zero to twelve hours (AUC \[0-12h\]) is area under the plasma concentration-time curve from time zero through 12 hours. AUC (0-12) hours was computed using the linear trapezoidal rule. For the calculations of AUC (0-12h), concentrations below the limit of quantification were assigned a value of zero if they occurred at the beginning of a profile. When such values appeared at the end of a profile they were assigned as missing data. AUC was reported in microgram hour per milliliter (mcg\*h/mL).
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants greater than (>) 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants less than (<) 24 months
Population: The PK population included all randomized and replaced participants adherent to the PK section of the protocol
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drug MMF | Area Under the Plasma Concentration Time Curve From 0-12 Hours for Mycophenolic Acid and Mycophenolic Acid Glucuronide Phenolic Glucuronide of Mycophenolic Acid | MPA Raw | 29 mcg*h/mL | Standard Deviation 20.3 |
| Drug MMF | Area Under the Plasma Concentration Time Curve From 0-12 Hours for Mycophenolic Acid and Mycophenolic Acid Glucuronide Phenolic Glucuronide of Mycophenolic Acid | MPAG Raw | 487 mcg*h/mL | Standard Deviation 185 |
| Drug MMF | Area Under the Plasma Concentration Time Curve From 0-12 Hours for Mycophenolic Acid and Mycophenolic Acid Glucuronide Phenolic Glucuronide of Mycophenolic Acid | MPAG (MPA Equivalents) | 289 mcg*h/mL | Standard Deviation 109 |
Secondary
Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide
The Plasma Concentration (Cmax) is defined as maximum observed analyte concentration. Cmax was obtained directly from the measured plasma concentration-time curves.
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants > 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants < 24 months
Population: The PK population was used for the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drug MMF | Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide | MPA Raw | 7.98 mcg/mL | Standard Deviation 3.69 |
| Drug MMF | Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide | MPAG Raw | 54.6 mcg/mL | Standard Deviation 26.8 |
| Drug MMF | Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide | MPAG (MPA Equivalents) | 32.4 mcg/mL | Standard Deviation 15.9 |
Secondary
Number of Participants With Adverse Events and Serious Adverse Events
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is a significant medical event.
Time frame: Up to Day 32
Population: The safety population included all participants who were enrolled in the trial
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Drug MMF | Number of Participants With Adverse Events and Serious Adverse Events | Participants with AE | 1 participants |
| Drug MMF | Number of Participants With Adverse Events and Serious Adverse Events | Participants with SAE | 0 participants |
Secondary
Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point
Mycophenolic Acid Glucuronide (MPAG) is an active metabolite of Mycophenolic Acid (MPA).
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants greater than (>) 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants less than (<) 24 months
Population: The PK population included all randomized and replaced participants adherent to the PK section of the protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPA at 0.0 | 0.786 mcg/mL | Standard Deviation 0.681 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPA at 0.50 | 9.03 mcg/mL | Standard Deviation 4.34 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPA at 0.75 | 5.67 mcg/mL | Standard Deviation 3.14 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPA at 1.00 | 5.84 mcg/mL | Standard Deviation 3.13 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPA at 1.50 | 6.16 mcg/mL | Standard Deviation 5.08 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPA at 2.00 | 6.23 mcg/mL | Standard Deviation 4.54 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPA at 4.00 | 1.89 mcg/mL | Standard Deviation 1.9 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPA at 8.00 | 1.38 mcg/mL | Standard Deviation 1.72 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPA at 12.00 | 0.676 mcg/mL | Standard Deviation 0.795 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPAG at 0.00 | 26.2 mcg/mL | Standard Deviation 20.4 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPAG at 0.50 | 26.5 mcg/mL | Standard Deviation 1.13 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPAG at 0.75 | 45.8 mcg/mL | Standard Deviation 28.2 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPAG at 1.00 | 37.2 mcg/mL | Standard Deviation 4.81 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPAG at 1.50 | 43.2 mcg/mL | Standard Deviation 12.9 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPAG at 2.00 | 51.0 mcg/mL | Standard Deviation 27.9 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPAG at 4.00 | 46.3 mcg/mL | Standard Deviation 21.3 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPAG at 8.00 | 19.2 mcg/mL | Standard Deviation 13.4 |
| Drug MMF | Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point | Raw MPAG at 12.00 | 14.6 mcg/mL | Standard Deviation 7.35 |
Secondary
Time to Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide
Tmax is the amount of time after dosing to when the maximum concentration of MPA and MPAG was achieved.
Time frame: Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants > 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants < 24 months
Population: The PK population was used for the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Drug MMF | Time to Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide | MPA Raw | 1.35 hour |
| Drug MMF | Time to Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide | MPAG Raw | 1.99 hour |