Pharmacokinetic results of a phase I trial of sorafenib in combination with dacarbazine in patients with advanced solid tumors

Abstract

Purpose: Sorafenib, a multikinase inhibitor of Raf and several growth factor receptors, is under investigation in combination with dacarbazine, a commonly used chemotherapeutic agent for the treatment of many cancers. The current phase I study investigates the effects of sorafenib on the pharmacokinetic (PK) profile of dacarbazine and its metabolite 5-amino-imidazole-4-carboxamide (AIC). (AIC is formed in amounts equimolar to the active alkylating moiety, methane diazohydroxide, which is undetectable by known validated assays.)

Methods: Patients with advanced solid tumors received intravenous dacarbazine 1,000 mg/m(2) on day 1 of a 21-day cycle to evaluate the PK of dacarbazine alone. Sorafenib 400 mg was administered twice daily continuously starting at day 2 of cycle 1. The PK of dacarbazine in the presence of sorafenib was assessed on day 1 of cycle 2. Sorafenib PK was also assessed at steady state.

Results: PK data were available for 15 of 23 patients. With concomitant administration of sorafenib, the mean AUC and C (max) values of dacarbazine were reduced by 23 and 16%, respectively. Mean AUC and C (max) values of AIC were increased by 41 and 45%, respectively, with individual increases of up to 106 and 136%, respectively. The apparent terminal half-lives of the two compounds were not significantly influenced by sorafenib. Based on coefficients of variation, the AUC and C (max) values for sorafenib and its three metabolites were highly variable with dacarbazine coadministration.

Conclusions: Concomitant administration of sorafenib and dacarbazine as described above may result in decreased dacarbazine exposure but increased AIC exposure.

Fig. 1

a Plasma concentrations (geometric means/geometric standard deviation) of dacarbazine after a 1-h intravenous infusion of 1,000 mg/m² dacarbazine without (cycle 1) or with (cycle 2) concomitant multiple oral doses of 400 mg bid sorafenib (n = 15) b Plasma concentrations (geometric means/geometric standard deviation) of AIC after a 1-h intravenous infusion of 1,000 mg/m² dacarbazine without (cycle 1) or with (cycle 2) concomitant multiple oral doses of 400 mg bid sorafenib (n = 15) c Plasma concentrations (geometric means/geometric standard deviation) of sorafenib after multiple oral doses of 400 mg bid sorafenib and following a concomitant 1-h intravenous infusion of 1,000 mg/m² dacarbazine on day 1 of cycle 2 (n = 15)