An Adaptive Dosing Tool For Etoposide Using Neutrophil Counts Based on a Semi-Physiological Model
Wallin, Johan E, Friberg Lena E., Karlsson Mats O.
Division of Pharmacokinetics and Drug Therapy, Uppsala University, Sweden;
Background: Neutropenia is one of the major challenges in the dosing of anticancer drugs. A previously published semi-physiological model for myelosuppression  has successfully been applied for several cytotoxic drugs, one of them being etoposide, a topoisomerase II-inhibitor. Initial dose level is usually based on body surface area, and if patient experience low blood cell counts next dose is either postponed or reduced. To individualize the treatment the observed neutrophil counts from the first cycle could be used for dose adjustment in the next cycle, in order to avoid neutropenia, a prolonged treatment interval and/or a suboptimal tumor effect.
Aim: To develop a dosing tool based on a pharmacokinetic-pharmacodynamic (PKPD) model for myelosuppression, where the user can obtain an adaptive dose for the next treatment cycle from a user-defined nadir and information from neutrophil counts from the first cycle.
Methods: To provide a familiar environment for clinicians, MS Excel was chosen as platform. The add-in PopTools (CSIRO, Australia) for Excel was applied to handle the differential equations. Estimates of typical parameters and IIV for etoposide were taken from Toffoli et al  for the PK model and Friberg et al  for the PD model. Individual parameters were obtained from a Bayesian process using information on dose, concentration and/or neutrophil measurements from the first course. These parameters were used to compute the dose which would result in the user-provided nadir in the next course. Individual parameter estimates were compared with those obtained using the POSTHOC option in NONMEM and was used to evaluate the model’s predictive capacity by comparing the observed myelosuppression in the second course of treatment based on information from the first course of treatment.
Results: Three different spreadsheets are now provided by the authors for intravenous dosing of etoposide, using PK-, PD- or PK+PD-information for dose individualization. Computation time is approximately 3-6 minutes for individual parameter estimation and somewhat shorter for the desired nadir. Individual parameter estimates were similar to those obtained by NONMEM.
Conclusions: The tool adequately implements the model, but the user-friendliness and clinical value needs to be assessed in a clinical setting. It is generic and can be adapted for individualization of other drugs. There are also possibilities to include covariate models for the various parameters.
 Friberg LE et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs J Clin Oncol 20:4713–4721, 2002
 Toffoli G et al. Population pharmacokinetics and pharmacodynamics of oral etoposide, Br J Clin Pharm, 52:511-519, 2001