Population pharmacokinetics modelling for clinical dose adjustment of carboplatin in dogs

Background: 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 300 mg/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.

Results: Sixteen client owned dogs were included after carboplatin administration (300 mg/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, p = 0.002) better than dose after 14 days following administration of carboplatin.

Conclusion: Based on our results, plasma creatinine concentration and the sterilization status are relevant explanatory covariates for the pharmacokinetics variability of carboplatin in client owned dogs. Dose adjustment based on these parameters could represent a promising strategy for minimizing thrombocyte toxicity.