Pharmacokinetic interaction between mitotane and etoposide in adrenal carcinoma: a pilot study

{Background: The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug-drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients. Methods: Five consecutive ACC patients treated with platinum etoposide (120-150 mg/m(2) day 1-2-3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle. Results: Patients received two to six chemotherapy cycles, in association with mitotane (N=4) or after mitotane discontinuation (N=1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h