MODELING INTERPATIENT PHARMACODYNAMIC VARIABILITY OF ETOPOSIDE

This report describes approaches to modeling interpatient pharmacodynamic variability of etoposide effect as measured by white blood cell count nadir. Such models may be utilized in adaptive control dosing to individualize the dose administered to a patient with the aim of lessening the risk of severe myelosuppression. We have successfully employed adaptive control dosing of etoposide administered by 72-hour continuous infusion based on our prior pharmacodynamic model for white blood cell count nadir. Data from our most recent series of 41 patients were used to investigate new linear and nonlinear pharmacodynamic models. We then cross-validated our best models on data from an independent series of 27 similarly treated patients. We identified an unbiased model that exhibited high precision in both data sets (root mean square errors of 1.11 X 10(3) and 1.20 x 10(3) cells/mu-L, respectively). The optimal model was a nonlinear Hill model defined by 24-hour etoposide concentration, pretreatment white blood cell count, and pretreatment serum albumin level. The level of albumin was found to be both a component of kinetic (protein binding) and dynamic (patient health) variability. Patients with lower pretreatment albumin levels are at higher risk of severe myelosuppression during etoposide therapy.