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Impact of pharmacogenetics on variability in exposure to oral vinorelbine among pediatric patients: a model‐based population pharmacokinetic analysis

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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.

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Data availability statement

The data that support the findings of this study are available on request from the corresponding author with the permission of the Principal Investigator (PL).

Code availability

The model source code that we developed is provided as an electronic supplementary file (ESM3).

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Acknowledgements

We gratefully acknowledge Professor Athanassios ILIADIS for his continuous technical support, invaluable advice, and the fruitful discussions during the model development. We would like to thank Pierre Fabre’s Oncology unit for supplying Vinorelbine (NAVELBINE®). The authors would like to thank managers and contributors of the ONCO-PK association for financial support of scientific communication of our works.

Funding

This study was funded by French Ministry of Health (PHRC grants).

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Contributions

PL, NA, AD, ET, JC, CS, and MH were responsible for the conception and design of the work. All authors provided resources. MH conducted the data analysis. MH wrote the original draft, which was commented by JC, NA, PL, AD, and FG. All authors gave final approval of the version to be published.

Corresponding author

Correspondence to Mourad Hamimed.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

This study was approved by local independent ethics committee (Committee for the Protection of Persons North West IV, Lille, France; on February 11th, 2014). This study was conducted in accordance with the ethical principles of the 7th revision of the Declaration of Helsinki (enacted in Korea, 2008), with the rules of Good Clinical Practice defined by the International Conference on Harmonization (ICH-E6, 17/7/96).

Consent to participate

Written informed consent was provided by children’s parents/legal guardian and/or patients themselves before any study procedure was undertaken.

Principal investigator statement

The authors confirm that the principal investigators for this paper are Prof. Pierre LEBLOND and Prof. Nicolas ANDRÉ, and that they had direct clinical responsibility for the participants enrolled in this study.

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Hamimed, M., Leblond, P., Dumont, A. et al. Impact of pharmacogenetics on variability in exposure to oral vinorelbine among pediatric patients: a model‐based population pharmacokinetic analysis. Cancer Chemother Pharmacol 90, 29–44 (2022). https://doi.org/10.1007/s00280-022-04446-y

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