Prednisolone pharmacokinetics after oral prednisone administration in paediatric patients with kidney transplant
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Published on: November 8, 2015
Camille de Truchis1, Naïm Bouazza2,3,4, Frantz Foissac2,3,4
1Service de Néphrologie Pédiatrique, CRMR MARHEA, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Insights
This study developed a population pharmacokinetics model for prednisolone in pediatric kidney transplant patients. Bodyweight and cyclosporine significantly impacted drug levels, suggesting personalized dosing is crucial for optimizing treatment and minimizing side effects.
Area of Science:
- Pharmacology
- Nephrology
- Pediatric Transplantation
Background:
- Glucocorticoids, specifically prednisone, are essential immunosuppressants in pediatric kidney transplantation.
- Understanding the pharmacokinetics of prednisolone, the active metabolite, is crucial for optimizing treatment outcomes in this population.
Purpose of the Study:
- To develop a population pharmacokinetic (PPK) model for free prednisolone in pediatric kidney transplant recipients.
- To identify factors (covariates) contributing to interindividual variability (IIV) in prednisolone pharmacokinetics.
- To explore relationships between drug exposure and adverse events, such as hypertension and new-onset diabetes.
Main Methods:
- A PPK analysis was conducted using data from 39 pediatric kidney transplant recipients (aged 3.4-17.2 years).
- Ninety-seven samples were analyzed to characterize prednisolone concentrations over time.
- The Monolix software was employed for the PPK modeling.
Main Results:
- A one-compartment model effectively described prednisolone concentrations, revealing significant IIV.
- Bodyweight and concomitant use of cyclosporine were identified as key covariates influencing prednisolone pharmacokinetics.
- Cyclosporine significantly reduced clearance (CLU) by 67%, while higher prednisolone exposure was linked to hypertension and post-transplant diabetes.
Conclusions:
- This is the first PPK analysis of prednisolone in pediatric kidney transplant recipients.
- Bodyweight and cyclosporine significantly explain some of the IIV in PK parameters.
- Findings support the need for dose adjustments based on identified variability factors to enhance efficacy and reduce toxicity, highlighting the potential utility of therapeutic drug monitoring.
Aims:
Glucocorticoids are 1 of the primary treatments in paediatric kidney transplantation. The aims of this study were: (i) to build a population pharmacokinetics (PPK) model of free prednisolone, which is the active form of prednisone, in paediatric kidney transplant recipients; (ii) to identify covariates accounting for interindividual variability (IIV) of pharmacokinetics (PK) parameters; and (iii) to investigate drug exposure-safety relationships.
Methods:
Ninety-seven samples were obtained from 39 paediatric kidney transplant recipients (aged 3.4-17.2 years) in order to investigate prednisone PPK. We selected children receiving oral prednisone as part of their immunosuppressive regimen. A PPK analysis was performed using Monolix.
Results:
A 1-compartment model best described prednisolone concentrations. Large IIV was observed as prednisolone was undetectable at H12 in some patients but could still be detected at H24 in others. Both bodyweight and ciclosporin cotreatment influenced the PK. The clearance (CLU ) and volume of distribution of free prednisolone allometrically scaled to 70 kg were 27.6 L/h and 101 L. Ciclosporin cotreatment decreased CLU by 67%. High blood pressure and new onset diabetes after transplantation were associated with daily free prednisolone exposure.
Conclusion:
This study is the first analysis of prednisolone PPK in kidney-transplanted children. Some of the IIV in the PK parameters was explained by bodyweight and ciclosporin cotreatment. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy and limit side effects. The use of therapeutic drug monitoring in kidney-transplanted children may be useful, especially with respect to safety issues.
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