Chemotherapeutic dosing implicated by pharmacodynamic modeling of in vitro cytotoxic data: a case study of paclitaxel.

Conventional maximum tolerated doses (MTD) in chemotherapy are recently challenged by an alternative dosing method with low doses and high dosing frequency (LDHF). Still, it remains unclear which chemotherapies would potentially benefit from LDHF. The pharmacokinetic (PK) differences between MTD and LDHF are drug exposure magnitude (concentration) and exposure duration (time), two fundamental PK elements that are associated with the pharmacodynamics (PD) of chemotherapies. Here we hypothesized that quantitatively analyzing the contribution of each PK element to the overall cytotoxic effects would provide insights to the selection of the preferred chemotherapeutic dosing. Based on in vitro cytotoxic data, we developed a cellular PD model, which assumed that tumor cells were generally comprised of two subpopulations that were susceptible to either concentration- or time-dependent cytotoxicity. The developed PD model exhibited high flexibility to describe diverse patterns of cell survival curves. Integrated with a PK model, the cellular PD model was further extended to predict and compare the anti-tumor effect of paclitaxel in two dosing regimens: multiple MTD bolus and continuous constant infusion (an extreme LDHF). Our simulations of paclitaxel in treatment of three types of cancers were consistent with clinical observations that LDHF yielded higher patient efficacy than MTD. Our further analysis suggested that the ratio between drug steady-state concentrations and its cytotoxic sensitivity (C ss /KC 50 ) was a critical factor that largely determines favored dosing regimen. LDHF would produce higher efficacy when the ratio C ss /KC 50 is greater than 1. Otherwise MTD was favored. The developed PD model presented an approach simply based on in vitro cytotoxic data to predict the potentially favored chemotherapeutic dosing between MTD and LDHF.