EurJ Cancer Clin Ond, Vol. 23, No. 1I, pp. 16274632, 1987 Printed in Great Britain 0277-5379/87$3.00+0.00 0 1987 Rrgamon Journals Ltd. Clinical Pharmacology of High-dose Etoposide Associated with Cisplatin. Pharmacokinetic and Metabolic Studies ALAIN GOUYETTE,*f$ ANNE DENIEL,* JO% ?-LUIS PICO,§ JEAN-PIERRE DROZ,$ DANIEL BAUME,§ MAURICE OSTRONOFF,§ NATHALIE LE BAIL@ and MARCEL HAYAT *Service de Pharmacologic Clinique (UA 147 CNRS, 11140 INSERM) and $0 p t e ar ement de Medecine, Institut Gustave-Roussy, Villejui~ France Abstract-Twelve patients were treated with high-dose etoposide given alone or in combination with cisplatin during a clinical trial. We had previously observed, in some subjects who received a combination of high-dose etoposide (350 mglm2/day X 5 days) and cisplatin (40 mg/m2/ day X 5 days), delayed hematological recovery after autologous bone marrow transplantation. Therefore we investigated the pharmacokinetics of etoposide and did notJind any drug interaction with cisplatin. In four of these patients we also monitored etoposide salivary excretion and found saliva to plasma ratios in the range 0.003-0.25. The secretion of etoposide into saliva may be of concern if we consider that perioxidases in salivary glands are able to oxidize the drug leading to free radicals. In vitro experiments showed that sulfhrdryl compounds are able to inhibit the formation of the etoposide radical. Furthermore, we were able to detect the presence of a new biotransformation product of etoposide in plasma samples of some patients. Fast atom bombard- ment liquid chromatography-mass spectrometry allowed us to identafy this metabolite as the etoposide aglycone. The presence of this derivative in plasma 48 h after the last injection prompted us to delay autologous bone marrow transplantation to 72 h after the end of treatment, since the aglycone is cytotoxic and able to induce DNA strand breaks mediated by topoisomerase II. INTRODUCTION CISPLATIN(CDDP) given with etoposide (VP16, 1, Fig. 1) has shown synergistic therapeutic activity in both animal models [l] and clinical trials [2]. A more recent phase II study demonstrated the effi- cacy of the association of VP16 and CDDP with or without bleomycin in patients with testicular non- seminomas [3]. Although the prognosis of non- seminomatous germ cell tumors (NSGCT) thus clearly improved, refractory or relapsed patients still have poor survival rates. Therefore the use of high-dose chemotherapy (HDC) followed by autologous bone marrow trans- plantation (ABMT) was evaluated in a group of poor prognosis young patients with NSGCT [4]. At conventional dosages (100-290 mg/m2), myelosuppression is the dose-limiting toxicity of Accepted 11 M ay 1987. tTo whom correspondence and requests for reprints should be addressed at: Pavilion de Recherche, Institut Gustave-Roussy, 39, rue Camille-Desmoulins, 94805 Villejuif Cedex, France. $Supported by INSERM, CNRS and Institut Gustave-Roussy (grant No. 84/D13). H Fig. 1. Chemical structures of the epipodophyllotoxin derivatives: 1, ctoposide or VP16; 2, teniposide or VM26;3, aglycone. VP16. However, the doses of myelotoxic antineo- plastic drugs can be escalated to more effective levels if followed by ABMT in order to prevent severe marrow suppression [5]. It has also been reported [6] that renal clearance 1627