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.

• Authors: Erich Brendel, Matthias Ludwig, Chetan Lathia, Caroline Robert, Stanislas Ropert, Jean-Charles Soria, Jean-Pierre Armand
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 68 Issue 1 Pg. 53-61 (Jul 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20821331 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzenesulfonates
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Pyridines
• Niacinamide
• imidazole-4-carboxamide
• Aminoimidazole Carboxamide
• Dacarbazine
• Sorafenib

Topics

• Aminoimidazole Carboxamide (analogs & derivatives, blood, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, therapeutic use)
• Benzenesulfonates (administration & dosage, blood, pharmacokinetics, therapeutic use)
• Dacarbazine (administration & dosage, blood, metabolism, pharmacokinetics)
• Disease Progression
• Female
• Humans
• Male
• Neoplasms (drug therapy, metabolism)
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Protein Kinase Inhibitors (administration & dosage, blood, pharmacokinetics, therapeutic use)
• Pyridines (administration & dosage, blood, pharmacokinetics, therapeutic use)
• Sorafenib