PHARMACOKINETICS AND PHARMACODYNAMICS OF PROLONGED ORAL ETOPOSIDE IN WOMEN WITH METASTATIC BREAST-CANCER

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUG) (0-24 h) 1.95 +/- 0.87 mg/ml per min (mean +/- SD), apparent oral clearance 60.9 +/- 21.7 ml/ min per 1.73 m(2), peak plasma concentration 5.6 +/- 2.5 mu g/ml, time to peak concentration 73 +/- 35 min and half-life 220 +/- 83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E(max) equation. A good fit was found between day 1 AUC and neutrophil toxicity (R(2) = 0.77). All patients who had a day 1 AUC > 2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m(2)). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R(2) = 98.9%). The equation AUC(pr) = -0.376 + 0.631 x C-4h + 0.336 x C-6h was validated on the test set with a relative mean predictive error of -0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.