PHASE-I STUDY AND CLINICAL PHARMACOLOGICAL EVALUATION OF DAILY ORAL ETOPOSIDE COMBINED WITH CARBOPLATIN IN PATIENTS WITH LUNG-CANCER

Twenty-eight patients with inoperable or relapsed lung cancer were giv en a combination of oral etoposide, administered once a day at doses r anging from 40 to 60 mg/m(2)/day (d) for 21 consecutive days, and carb oplatin, administered intravenously over 1 h at doses ranging from 300 to 400 mg/m(2) on day 1 to determine the appropriate doses of this co mbination. In addition, pharmacokinetic and pharmacodynamic analyses w ere performed. All the patients had a performance status of 0 to 1. Se rum etoposide and free platinum (Pt) concentrations were measured usin g high-performance liquid chromatography and atomic absorption, respec tively. Myelosuppression, nausea and vomiting were the dose-limiting t oxicities of this schedule. The maximum tolerated dose (MTD) was 50 mg /m(2)/d oral etoposide for 21 days and 400 mg/m(2) i.v. carboplatin on day 1. For heavily pretreated patients, the MTD was 40 mg/m(2)/d oral etoposide for 21 days and 350 mg/m(2) i.v. carboplatin on day 1. No c umulative increase in the area under the concentration-time curve (AUG ) for oral etoposide over time was observed. There were significant co rrelations between the free Pt serum level (6, 8, 12, 24 h post dose) and etoposide AUC level (days 1, 10 and 21) for graded hematological t oxicity, and the percentage decreases and nadir counts of hemoglobin, leukocytes, neutrophils and platelets. Several pharmacodynamic models were developed to predict the hematological toxicity. In order to faci litate pharmacodynamic evaluations in future studies, a limited sampli ng model for oral etoposide was also developed and validated.