1. Pharmacokinetics of oral vinorelbine in French children with recurrent or progressive primary low‐grade glioma
- Author
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Alicia Probst, Emilie De Carli, Isabelle Aerts, Pascal Chastagner, Natacha Entz-Werle, Caroline Solas, Anne-Isabelle Bertozzi-Salamon, Nicolas André, Anne Pagnier, Emmanuelle Tresch-Bruneel, Pierre Leblond, Jacques Grill, Didier Frappaz, Mourad Hamimed, Florence Gattacceca, Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Centre Léon Bérard [Lyon], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Unité des Virus émergents [Marseille] (UVE - Faculté de Médecine), Université de la Méditerranée - Aix-Marseille 2-Faculté de Médecine [Marseille], Université de la Méditerranée - Aix-Marseille 2, and Hôpital de la Timone [CHU - APHM] (TIMONE)
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medicine.medical_specialty ,Adolescent ,Phases of clinical research ,Vinorelbine ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Bayesian multivariate linear regression ,Glioma ,Internal medicine ,Humans ,Medicine ,Pharmacology (medical) ,Child ,Infusions, Intravenous ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Pharmacology ,Body surface area ,Volume of distribution ,0303 health sciences ,business.industry ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,medicine.disease ,3. Good health ,030220 oncology & carcinogenesis ,Low-Grade Glioma ,Neoplasm Recurrence, Local ,business ,Half-Life ,medicine.drug - Abstract
AIM There is a crucial need for pharmacokinetic (PK) data of oral vinorelbine (VNR) in pediatric population. The aim of this work was to assess the PK profile of orally administered VNR in children with recurrent/progressive primary low-grade glioma (LGG). METHODS A multicentric, open-label, single-arm intervention phase II study was conducted. Patients, aged between 6 and 18 years, with histologically confirmed recurrent or progressive primary LGG or non-documented typical optic pathway tumors, were included. PK parameters were estimated by non-compartmental analysis using Phoenix WinNonlin® software (version 8.0, Certara, Inc.). The Influence of demographic and biological covariates on VNR PK parameters was investigated using a multivariate linear regression analysis. RESULTS PK analysis included 36 patients with a median age (range) of 11 (6-17) years. Estimates of apparent oral clearance (CL/F), apparent volume of distribution (V/F), half-life (t1/2 ) and their between-subject variability (CV%) at 60 mg.m-2 dose level, were 472 L.h-1 (51.8%), 7002 L (57.9%) and 10 h (21.0%), respectively. Negligible accumulation of VNR between C1 and C2 was observed. CL/F and V/F were found to increase with body surface area (BSA) (p = 0.004). Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. CONCLUSION Higher doses may be necessary for children with LGG. BSA showed a significant impact on VNR systemic exposure. We believe that our findings will serve as a basis for further studies to better characterize the concentration-response relationships of VNR among pediatric patients.
- Published
- 2021
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