1. Sirolimus Pharmacokinetics Variability Points to the Relevance of Therapeutic Drug Monitoring in Pediatric Oncology
- Author
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Jean-Marc Lessinger, Véronique Kemmel, Sarah Jannier, Guillaume Becker, Natacha Entz-Werle, and Amelia-Naomi Sabo
- Subjects
Oncology ,medicine.medical_specialty ,Monolix® software ,therapeutic drug monitoring ,pharmacokinetic population modeling ,Population ,lcsh:RS1-441 ,Pharmaceutical Science ,030226 pharmacology & pharmacy ,Article ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,cardiovascular diseases ,education ,Body surface area ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,pediatric oncology ,equipment and supplies ,Transplantation ,Irinotecan ,surgical procedures, operative ,sirolimus ,Therapeutic drug monitoring ,030220 oncology & carcinogenesis ,Sirolimus ,cardiovascular system ,business ,pharmacokinetics ,Blood sampling ,medicine.drug - Abstract
Sirolimus is widely used in transplantation, where its therapeutic drug monitoring (TDM) is well established. Evidence of a crucial role for sirolimus in the PI3K/AkT/mTor pathway has stimulated interest in its involvement in neoplasia, either as monotherapy or in combination with other antineoplastic agents. However, in cancer, there is no consensus on sirolimus TDM. In the RAPIRI phase I trial, the combination sirolimus + irinotecan was evaluated as a new treatment for refractory pediatric cancers. Blood sampling at first sirolimus intake (D1) and at steady state (D8), followed by LC/MS2 analysis, was used to develop a population pharmacokinetic model (Monolix® software). A mono-compartmental model with first-order absorption and elimination best fit the data. The only covariate retained for the final model was “body surface area” (D1 and D8). The model also demonstrated that 1.5 mg/m2 would be the recommended sirolimus dose for further studies and that steady-state TDM is necessary to adjust the dosing regimen in atypical profiles (36.4% of the population). No correlation was found between sirolimus trough concentrations and efficacy and/or observed toxicities. The study reveals the relevance of sirolimus TDM in pediatric oncology as it is needed in organ transplantation.
- Published
- 2021