Mourad Hamimed1,2, Pierre Leblond3,4, Aurélie Dumont5, Florence Gattacceca6,7, Emmanuelle Tresch-Bruneel8, Alicia Probst9, Pascal Chastagner10, Anne Pagnier11, Emilie De Carli12, Natacha Entz-Werlé13, Jacques Grill14, Isabelle Aerts15, Didier Frappaz3, Anne-Isabelle Bertozzi-Salamon16, Caroline Solas17,18, Nicolas André19, Joseph Ciccolini6,7,18. 1. SMARTc Unit, Cancer Research Center of Marseille, Inserm U1068-CNRS UMR 7258, Aix-Marseille University U105, 27 Boulevard Jean Moulin, 13385, Marseille, France. mourad.hamimed@univ-amu.fr. 2. Inria-Inserm COMPO Team, Centre Inria Sophia Antipolis - Méditerranée, Inserm U1068-CNRS UMR 7258, Aix-Marseille University U105, Marseille, France. mourad.hamimed@univ-amu.fr. 3. Institute of Pediatric Hematology and Oncology IHOPe, Léon Bérard Cancer Center, Lyon, France. 4. Department of Pediatric Oncology, Oscar Lambret Cancer Center, Lille, France. 5. Unité d'Oncologie Moléculaire Humaine, Oscar Lambret Cancer Center, Lille, France. 6. SMARTc Unit, Cancer Research Center of Marseille, Inserm U1068-CNRS UMR 7258, Aix-Marseille University U105, 27 Boulevard Jean Moulin, 13385, Marseille, France. 7. Inria-Inserm COMPO Team, Centre Inria Sophia Antipolis - Méditerranée, Inserm U1068-CNRS UMR 7258, Aix-Marseille University U105, Marseille, France. 8. Department of Biostatistics, Oscar Lambret Cancer Center, Lille, France. 9. Département de la Recherche Clinique et Innovation, Oscar Lambret Cancer Center, Lille, France. 10. Service d'Hémato-Oncologie Pédiatrique, Nancy University Hospital, Nancy, France. 11. Service d'Hémato-Oncologie Pédiatrique, Grenoble University Hospital, Grenoble, France. 12. Service d'Hémato-Oncologie Pédiatrique, Angers University Hospital, Angers, France. 13. Pédiatrie Onco-Hématologie Université de Strasbourg, CHRU Hautepierre, UMR CNRS 7021, Strasbourg, France. 14. Département de Cancérologie de l'Enfant et de l'Adolescent et UMR CNRS 8203 Université Paris Saclay, Gustave Roussy, Villejuif, France. 15. SIREDO Centre (Care, Innovation and Research in Paediatric, Adolescent and Young Adult Oncology), Institut Curie-Oncology Center, Paris, France. 16. Service d'Hémato-Oncologie Pédiatrique, Toulouse University Hospital, Toulouse, France. 17. Unité des Virus Émergents (UVE), Aix-Marseille Univ-IRD 190-Inserm 1207, Marseille, France. 18. Clinical Pharmacokinetics and Toxicology Laboratory, La Timone University Hospital of Marseille, APHM, Marseille, France. 19. Department of Pediatric Oncology, La Timone University Hospital of Marseille, APHM, Marseille, France.
Abstract
PURPOSE: Better understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients. DESIGN/ METHODS: We collected blood samples from 36 patients (mean age 11.6 years) of the OVIMA multicentric phase II study in children with recurrent/progressive low-grade glioma. Patients received 60 mg/m2 of oral VNR on days 1, 8, and 15 during the first 28-day treatment cycle and 80 mg/m2, unless contraindicated, from cycle 2-12. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling within the Monolix® software. Fifty SNPs of pharmacokinetic-related genes were genotyped. The influence of demographic, biological, and pharmacogenetic covariates on pharmacokinetic parameters was investigated using a stepwise multivariate procedure. RESULTS: A three-compartment model, with a delayed double zero-order absorption and a first-order elimination, best described VNR pharmacokinetics in children. Typical population estimates for the apparent central volume of distribution (Vc/F) and elimination rate constant were 803 L and 0.60 h-1, respectively. Following covariate analysis, BSA, leukocytes count, and drug transport ABCB1-rs2032582 SNP showed a dramatic impact on Vc/F. Conversely, age and sex had no significant effect on VNR pharmacokinetics. CONCLUSION: Beyond canonical BSA and leukocytes, ABCB1-rs2032582 polymorphism showed a meaningful impact on VNR systemic exposure. Simulations showed that the identified covariates could have an impact on both efficacy and toxicity outcomes. Thus, a personalized dosing strategy, using those covariates, could help to optimize the efficacy/toxicity balance of VNR in children.
PURPOSE: Better understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients. DESIGN/ METHODS: We collected blood samples from 36 patients (mean age 11.6 years) of the OVIMA multicentric phase II study in children with recurrent/progressive low-grade glioma. Patients received 60 mg/m2 of oral VNR on days 1, 8, and 15 during the first 28-day treatment cycle and 80 mg/m2, unless contraindicated, from cycle 2-12. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling within the Monolix® software. Fifty SNPs of pharmacokinetic-related genes were genotyped. The influence of demographic, biological, and pharmacogenetic covariates on pharmacokinetic parameters was investigated using a stepwise multivariate procedure. RESULTS: A three-compartment model, with a delayed double zero-order absorption and a first-order elimination, best described VNR pharmacokinetics in children. Typical population estimates for the apparent central volume of distribution (Vc/F) and elimination rate constant were 803 L and 0.60 h-1, respectively. Following covariate analysis, BSA, leukocytes count, and drug transport ABCB1-rs2032582 SNP showed a dramatic impact on Vc/F. Conversely, age and sex had no significant effect on VNR pharmacokinetics. CONCLUSION: Beyond canonical BSA and leukocytes, ABCB1-rs2032582 polymorphism showed a meaningful impact on VNR systemic exposure. Simulations showed that the identified covariates could have an impact on both efficacy and toxicity outcomes. Thus, a personalized dosing strategy, using those covariates, could help to optimize the efficacy/toxicity balance of VNR in children.
Authors: Michael J Waring; John Arrowsmith; Andrew R Leach; Paul D Leeson; Sam Mandrell; Robert M Owen; Garry Pairaudeau; William D Pennie; Stephen D Pickett; Jibo Wang; Owen Wallace; Alex Weir Journal: Nat Rev Drug Discov Date: 2015-06-19 Impact factor: 84.694
Authors: Zahari Vinarov; Mohammad Abdallah; José A G Agundez; Karel Allegaert; Abdul W Basit; Marlies Braeckmans; Jens Ceulemans; Maura Corsetti; Brendan T Griffin; Michael Grimm; Daniel Keszthelyi; Mirko Koziolek; Christine M Madla; Christophe Matthys; Laura E McCoubrey; Amitava Mitra; Christos Reppas; Jef Stappaerts; Nele Steenackers; Natalie L Trevaskis; Tim Vanuytsel; Maria Vertzoni; Werner Weitschies; Clive Wilson; Patrick Augustijns Journal: Eur J Pharm Sci Date: 2021-03-20 Impact factor: 4.384
Authors: Anne F Schott; James M Rae; Kent A Griffith; Daniel F Hayes; Vered Sterns; Laurence H Baker Journal: Cancer Chemother Pharmacol Date: 2005-11-08 Impact factor: 3.333