Mourad Hamimed1,2, Florence Gattacceca1,2, Nicolas André1,3, Emmanuelle Tresch-Bruneel4, Alicia Probst5, Pascal Chastagner6, Anne Pagnier7, Emilie De Carli8, Natacha Entz-Werlé9, Jacques Grill10, Isabelle Aerts11, Didier Frappaz12, Anne-Isabelle Bertozzi-Salamon13, Caroline Solas14,15, Pierre Leblond12,16. 1. SMARTc Unit, Cancer Research Center of Marseille, Inserm U1068 - CNRS UMR 7258 - Aix-Marseille University U105, Marseille, France. 2. Inria - Inserm COMPO team, Centre Inria Sophia Antipolis - Méditerranée, Inserm U1068 - CNRS UMR 7258 - Aix-Marseille University U105, Marseille, France. 3. Department of Pediatric Oncology, La Timone University Hospital of Marseille, APHM, Marseille, France. 4. Department of Biostatistics, Oscar Lambret Cancer Center, Lille, France. 5. Département de la Recherche Clinique et Innovation, Oscar Lambret Cancer Center, Lille, France. 6. Service d'hémato-oncologie pédiatrique, Nancy University Hospital, Nancy, France. 7. Service d'hémato-oncologie pédiatrique, Grenoble University Hospital, Grenoble, France. 8. Service d'hémato-oncologie pédiatrique, Angers University Hospital, Angers, France. 9. Pédiatrie Onco-Hématologie Université de Strasbourg, CHRU Hautepierre, - UMR CNRS 7021, Strasbourg, France. 10. Département de Cancérologie de l'Enfant et de l'Adolescent et UMR CNRS 8203, Université Paris Saclay, Gustave Roussy, Villejuif, France. 11. SIREDO Centre (Care, innovation and research in paediatric, adolescent and young adult oncology), Institut Curie-Oncology Center, Paris, France. 12. Institute of Pediatric Hematology and Oncology IHOPe, Léon Bérard Cancer Center, Lyon, France. 13. Service d'hémato-oncologie pédiatrique, Toulouse University Hospital, Toulouse, France. 14. Unité des Virus Émergents (UVE), Aix-Marseille Univ-IRD 190-Inserm 1207, Marseille, France. 15. Clinical Pharmacokinetics and Toxicology Laboratory, La Timone University Hospital of Marseille, APHM, Marseille, France. 16. Department of Pediatric Oncology, Oscar Lambret Cancer Center, Lille, France.
Abstract
AIMS: There is a crucial need for pharmacokinetic (PK) data on oral vinorelbine (VNR) in the paediatric 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 multicentre, 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 tumours, 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 = .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 paediatric patients.
AIMS: There is a crucial need for pharmacokinetic (PK) data on oral vinorelbine (VNR) in the paediatric 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 multicentre, 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 tumours, 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 = .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 paediatric patients.