Population pharmacokinetics modelling for clinical dose adjustment of carboplatin in dogs

Béguin, Jérémy; Mahfoudhi, Sarra; Uzel, Marie; Rostang, Antoine; Ibish, Catherine; Ferran, Aude; Pelligand, Ludovic; Hulin, Anne; Kohlhauer, Matthias

Abstract

Carboplatin is a human chemotherapeutic agent which is frequently used in dogs for the management of solid tumors. In human patient, its dosage is adjusted carefully, based on the creatinine clearance computation. In dogs however, the pharmacokinetics of carboplatin is poorly known and the dose 300mg/m2 is based mostly on empirical data. Here, we aimed at characterizing the pharmacokinetics of carboplatin and determined the influence of several covariates, including creatinine plasma concentration and neutering status, in dogs, and used this model to predict myelotoxicity. Sixteen client owned dogs were included after carboplatin administration (300mg/m2). For each animals, three to four plasma samples were collected and free plasma concentration of carboplatin was determined by HPLC/MS and analysed using Monolix® software with Non-linear mixed effect modelling. A mono-compartmental model best described the plasma concentration of carboplatin with log plasma creatinine concentration and sterilization status as covariates. After adjustment with the covariates, median population clearance was 3.62[3.15 – 4.12] L/h/kg and volume of distribution was 3.93 [3.84 – 4.14] L/kg. The application of this model in 14 additional dogs demonstrates that individual drug exposure (model-predicted Area Under the Curve) predicted thrombocyte blood reduction (pearson coefficient r2= 0.73) better than dose, after 14 days following administration of carboplatin. Based on our results, dose adjustments of carboplatin on the plasma creatinine concentration and on the sterilization status should be recommended in dogs in order to adjust dosage for minimizing thrombocyte toxicity.

Citation

Béguin, J., Mahfoudhi, S., Uzel, M., Rostang, A., Ibish, C., Ferran, A., Pelligand, L., Hulin, A., & Kohlhauer, M. (in press). Population pharmacokinetics modelling for clinical dose adjustment of carboplatin in dogs. BMC Veterinary Research, https://doi.org/10.1186/s12917-024-04404-1

• Journal Article Type: Article
• Acceptance Date: Nov 25, 2024
• Online Publication Date: Dec 23, 2025
• Deposit Date: Oct 12, 2024
• Publicly Available Date: Jan 23, 2025
• Electronic ISSN: 1746-6148
• Publisher: BioMed Central
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1186/s12917-024-04404-1