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Article

Sirolimus Pharmacokinetics Variability Points to the Relevance of Therapeutic Drug Monitoring in Pediatric Oncology

1
Laboratoire de Biochimie et Biologie Moléculaire, Hôpitaux Universitaires de Strasbourg, 67200 Strasbourg, France
2
Laboratoire de Pharmacologie et Toxicologie Neurocardiovasculaire, Unité de Recherche 7296, Faculté de Médecine de Maïeutique et des Métiers de la Santé, Centre de Recherche en Biomédecine de Strasbourg (CRBS), 67085 Strasbourg, France
3
Unité d’Onco-Hématologie Pédiatrique, Hôpitaux Universitaires de Strasbourg, 67200 Strasbourg, France
4
Service de la Pharmacie, Hôpitaux Universitaires de Strasbourg, 67200 Strasbourg, France
5
Unité Mixte de Recherche (UMR) 7021, Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bioimagerie et Pathologies, Signalisation Tumorale et Cibles Thérapeutiques, Faculté de Pharmacie, Université de Strasbourg, 67401 Illkirch, France
*
Authors to whom correspondence should be addressed.
Academic Editor: José B. Fariña
Received: 1 March 2021 / Revised: 21 March 2021 / Accepted: 25 March 2021 / Published: 30 March 2021
(This article belongs to the Special Issue Development and Adaptation of New and Better Pediatric Drugs)
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. View Full-Text
Keywords: sirolimus; pharmacokinetics; therapeutic drug monitoring; pediatric oncology; Monolix® software; pharmacokinetic population modeling sirolimus; pharmacokinetics; therapeutic drug monitoring; pediatric oncology; Monolix® software; pharmacokinetic population modeling
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MDPI and ACS Style

Sabo, A.-N.; Jannier, S.; Becker, G.; Lessinger, J.-M.; Entz-Werlé, N.; Kemmel, V. Sirolimus Pharmacokinetics Variability Points to the Relevance of Therapeutic Drug Monitoring in Pediatric Oncology. Pharmaceutics 2021, 13, 470. https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040470

AMA Style

Sabo A-N, Jannier S, Becker G, Lessinger J-M, Entz-Werlé N, Kemmel V. Sirolimus Pharmacokinetics Variability Points to the Relevance of Therapeutic Drug Monitoring in Pediatric Oncology. Pharmaceutics. 2021; 13(4):470. https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040470

Chicago/Turabian Style

Sabo, Amelia-Naomi, Sarah Jannier, Guillaume Becker, Jean-Marc Lessinger, Natacha Entz-Werlé, and Véronique Kemmel. 2021. "Sirolimus Pharmacokinetics Variability Points to the Relevance of Therapeutic Drug Monitoring in Pediatric Oncology" Pharmaceutics 13, no. 4: 470. https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040470

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