Flora Musuamba and Oscar Della Pasqua
School of Pharmacy, University College London
Background: Tacrolimus is considered to be the mainstone of immunosuppressive therapy after solid organ transplantation. However, if its efficacy is now well established, the nephrotoxicity associated with its long-term use is currently the biggest challenge in the short term and long term outcome of pediatric and adult transplantation. Tacrolimus optimal dosing is therefore still challenging: tacrolimus dose is most frequently tailored either based on patient characteristics or based on monitored concentrations.
Objectives: The objective of this study is to characterise the relationships between the dose, the concentrations and the clinical effects but also target exposure levels for tacrolimus in pediatrics.
Methods: A physiologically based pharmacokinetic (PBPK) model was first developed for tacrolimus and was used to fit adult and pediatric patient data in different types of solid organ transplantations. Subsequently a pharmacokinetic-pharmacodynamic (PK/PD) model was developed to characterise the relationship between tacrolimus exposure, pharmacodynamic biomarkers (lymphocytes, leucocytes, interleukines, cytokines, etc) and clinical outcome (graft rejection and nephrotoxicity).
Results: The developed PBPK model displayed good fitting performances for pediatric and adult data and was used to predict tacrolimus exposure levels for subsequent PK/PD model development. Indirect exposure-response models were developed for the PD biomarkers whereas a time to event model was used to predict the clinical outcome based on the predicted biomarker levels.
Conclusion: The developed models constitute a first step toward a better characterisation of the target exposure for tacrolimus in pediatric patients. The developed model should be externally and prospectively validated before its implementation in clinical practice.
Reference: PAGE 23 () Abstr 3269 [www.page-meeting.org/?abstract=3269]
Poster: Drug/Disease modeling - Paediatrics