Dose Selection, Pharmacokinetics, and Pharmacodynamics of BRAF-inhibitor Dabrafenib (GSK2118436)
Menée sur 184 patients atteints d'une tumeur solide de stade métastatique, cette étude évalue la toxicité et divers paramètres pharmacocinétiques ou pharmacodynamiques du dabrafenib, un inhibiteur de BRAF, puis détermine une dose recommandée pour un essai de phase II
Purpose: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 18F-labelled fluorodeoxyglucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship. Methods: Dabrafenib was administered orally once, twice (BID), or three times (TID) daily. Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase 2 dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data. Results: 184 patients were enrolled and treated with doses ranging from 12mg once daily to 300mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation-positive melanoma. A favorable activity and tolerability profile was demonstrated at 150mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in melanoma patients. Conclusion: The RP2D of dabrafenib was determined to be 150mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined.