Abstract
Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAFV600E) which is commonly found in metastatic melanoma. Clinical trials with dabrafenib are showing encouraging results, however the CNS distribution of dabrafenib remains unknown. Thus the objective of the current study was to evaluate the brain distribution of dabrafenib in mouse and to see whether active efflux by P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) restrict its delivery across blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II (MDCKII) cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in basolateral to apical direction with corrected efflux ratios of greater than 2 for both P-gp and Bcrp1 transfected cell lines. In vivo, the Kp (AUCbrain / AUCplasma) of dabrafenib after an iv dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b-/-Bcrp1-/- mice to 0.42. Dabrafenib plasma exposure was ~2-fold greater in Mdr1 a/b-/-Bcrp1-/- mice as compared to wild-type with an oral dose (25 mg/kg), however the brain distribution was increased by ~10-fold with a resulting Kp of 0.25. Further, compared to vemurafenib, dabrafenib has greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model and the data presented herein may have clinical implications in the prevention and treatment of melanoma brain metastases.
- Received October 29, 2012.
- Revision received December 14, 2012.
- Accepted December 14, 2012.
- The American Society for Pharmacology and Experimental Therapeutics