CLINICAL AND PHARMACOLOGICAL ANALYSIS OF HYPERFRACTIONATED DAILY ORAL ETOPOSIDE

Purpose: The antitumor effect of etoposide is increased by maintaining a low blood level, whereas high peak levels may cause myelotoxicity. We investigated whether a constant low blood level could be obtained by the administration of oral etoposide three times daily. Patients and Methods: Nineteen patients with non-small-cell lung cancer were treated with oral etoposide (25 mg three times daily for 21 days) as monotherapy or in combination with cisplatin 80 mg/m(2). A pharmacokinetic model that predicted the mean blood concentration (C-mean) was developed in the 10 patients on etoposide monotherapy and validated in the nine patients on combination chemotherapy. Pharmacodynamic relationships were evaluated in each group. Results: Etoposide dose per body-surface area ranged from 45 to 63 mg/m(2)/d (median, 53), but did not correlate with plasma level. C-mean was 1.1 +/- 0.3 mu g/mL. Peak concentrations ranged from 0.6 to 2.5 mu g/mL. The intrapatient coefficient of variation for plasma etoposide concentrations was 22% +/- 10%, C-mean was accurately estimated as follows: C-mean = 0.098 + 0.413 x C-0 + x C-2 (r = .97, P = .0001), where C-0 and C-2 represent concentrations before and 2 hours after administration, This model was unbiased (mean predictive error [MPE], 0.0 mu g/mL) and precise (root mean square error [RMSE], 0.1 mu g/mL). Leukopenia was the major toxicity. The surviving fraction of leukocytes (SF; nadir count/pretreatment count) was correlated to C-mean as follows: SF = 0.87 - 0.34 x C-mean (r = .67, P = .03) in the monotherapy group and SF = 0.64 - 0.33 x C-mean (R = .77, P = .03) in the combination chemotherapy group. Two and four patients treated with monotherapy and combination chemotherapy showed responses, respectively. All responders had a C-mean greater than or equal to 1.0 mu g/mL. Conclusion: Hyperfractionated oral etoposide achieveda stable plasma level that could be predicted by measurement at only two times. (C) 1995 by American Society of Clinical Oncology.