Population pharmacokinetic-pharmacodynamic modelling and simulation of neutropenia induced by TP300, a novel topoisomerase I inhibitor.

ABSTRACT

OBJECTIVES: TP300 is a novel topoisomerase I inhibitor with neutropenia as a significant toxicity. We developed and evaluated a pharmacokinetic-pharmacodynamic (PK-PD) model, using data from Phase I and II trials to predict neutrophil decrease in patients treated with TP300. METHODS: Plasma drug concentrations of TP300, its active form TP3076 and active metabolite TP3011 and absolute neutrophil counts (ANCs) from a Phase I trial were analysed as a training dataset. A two-plus-two-compartment model was applied to the pharmacokinetics of TP3076 and TP3011. A semi-mechanistic model was used to describe the PK-PD relationship between the plasma concentration of TP3076 and TP3011, and changes in ANC. KEY FINDINGS: The model fitted well to plasma concentrations of TP3076 and TP3011. Model appropriateness was confirmed in a Phase II trial validation dataset. Body weight and liver biochemistry values were identified as covariates. A semi-mechanistic PK-PD model was applied and the longitudinal decrease in ANC was simulated. Neutrophil counts reached their nadir approximately 2 weeks after administration of TP300, and the proportion of subjects affected increased with dose. CONCLUSIONS: This PK-PD model to predict neutropenia following treatment with TP300 fitted well the decrease in ANC with total concentration of TP3076 and TP3011.