ETOPOSIDE COMBINED WITH INTERFERON ALFA-2B - NOVEL EXPLOITATION OF ESTABLISHED ETOPOSIDE PHARMACOKINETICS AND PHARMACODYNAMICS

Purpose: To construct an efficient pilot study design to determine whe ther interferon alfa-2b modifies the pharmacokinetics and pharmacodyna mics of continuous-infusion etoposide. Patients and methods: A two-sta ge randomized 2 x 2 factorial design was used to evaluate interferon a lfa-2b at two doses (2 or 10 MU/m(2)/day SQ for 3 days) and two schedu les (interferon alfa-2b administered before or concurrent with 72-hour continuous-infusion etoposide), Etoposide was administered at 75, 100 , or 125 mg/m(2)/day, Ln lieu of comparing the experimental arms to an etoposide-alone control arm to determine effect of interferon alfa-2b dose and schedule, a novel analytic approach was used. The effect of interferon alfa-2b on etoposide-induced leukopenia was assessed indire ctly by comparison of the observed white blood cell (WBC) nadir to the nadir predicted from an established pharmacodynamic model for single agent etoposide, Results: Based on 29 patients, dose-normalized 24-hou r total and estimated free etoposide concentrations did not differ wit h interferon alfa-2b dose or schedule, Patients treated with interfero n alfa-2b before etoposide had, on average a WBC nadir 545 +/- 225 cel ls/mu l lower than that predicted by a pharmacodynamic model for etopo side alone. An optimal nonlinear model for leukopenia was defined by i nterferon alfa-2b schedule in addition to 24-hour etoposide concentrat ion. Conclusion: A novel study design and statistical analysis provide d an efficient preliminary evaluation of the combination of interferon alfa-2b with etoposide in a modest number of patients. Exploitation o f a previously validated pharmacodynamic model allowed evaluation of i nterferon alfa-2b effect and eliminated the need for an etoposide-alon e control arm. The pharmacokinetics of continuous-infusion etoposide a t doses from 75 to 125 mg/m(2)/day appear to be unchanged by interfero n alfa-2b at the doses and schedules tested and the combination appear s to be feasible. We hypothesize that leukopenia may be enhanced when interferon alfa-2b is administered before etoposide, especially at a h igher dose of interferon alfa-2b.