Towards better dose individualisation: metabolic phenotyping to predict cabazitaxel pharmacokinetics in men with prostate cancer

Abstract

Background: Cabazitaxel is approved for treatment of castration-resistant metastatic prostate cancer. The current dosing strategy of cabazitaxel is based on body surface area (BSA). Body surface area is known as a poor predictor for total systemic exposure to drugs, since it does not take into account variability in activity of metabolising enzymes, necessary for clearance of drugs. As exposure to cabazitaxel is related to treatment response, it is essential to develop a better individualised dosing strategy.

Methods: Ten patients with metastatic castration-resistant prostate cancer, who received cabazitaxel dosed on BSA as a part of routine palliative care, were enrolled in this study. Midazolam was administered as phenotyping probe for cytochrome P450 isoenzyme 3A (CYP3A). The relationship between midazolam and cabazitaxel clearance was investigated using non-linear mixed effects modelling.

Results: The clearance of Midazolam highly correlated with cabazitaxel clearance (R=0.74). Midazolam clearance significantly (P<0.004) explained the majority (∼60%) of the inter-individual variability in cabazitaxel clearance in the studied population.

Conclusions: Metabolic phenotyping of CYP3A using midazolam is a promising strategy to individualise cabazitaxel dosing. Before clinical application, a randomised study is warranted.

Figure 1

Pharmacokinetic models for midazolam and cabazitaxel.Schematic representation of the pharmacokinetic models for midazolam and cabazitaxel. CL_base=clearance of cabazitaxel in the base model, CL_CBZ=clearance of cabazitaxel, CL_mdz=clearance of midazolam, CL_mdz,i=clearance of midazolam individual, CL_mdz,pop=Clearance of midazolam population, Q=intercompartmental clearance, V₁=volume of distribution of the central compartment of cabazitaxel, V₂=Volume of distribution of the peripheral compartment of cabazitaxel, V₃=Volume of distribution of the central compartment of midazolam, θ_clearance=gradient of the correlation between the clearance of midazolam and cabazitaxel.

Figure 2

Relationship between individual estimates for clearance of midazolam and cabazitaxel.Empirical Bayes estimates for midazolam and cabazitaxel clearance (black dots) and their model-predicted relationship (dotted line) from the final model.

Figure 3

Prediction-corrected visual predictive check of cabazitaxel final model.The prediction-corrected simulated (shaded areas) and observed (circles and lines) cabazitaxel concentrations vs time (h), based on 1000 simulations are shown. The thick black line connects the observed median values per bin. The dotted grey lines connect the 5th and 95th percentiles of the observations. The light grey areas are the 95% confidence interval of the 5th and 95th percentiles. The dark grey area indicates the confidence interval of the median.