Concomitant Oral and Intravenous Pharmacokinetics of Dabrafenib, a BRAF Inhibitor, in Patients with BRAF V600 Mutation‐Positive Solid Tumors

Abstract

Dabrafenib is an orally bioavailable, potent, and selective inhibitor of human wild-type BRAF and CRAF kinases as well as mutant forms of BRAF kinase. The aim of this phase 1, single-center, open-label study in four patients with BRAF mutation-positive solid tumors was to determine the absolute bioavailability of a 150 mg oral dose of dabrafenib. A microtracer study approach, in which a 50 µg radiolabeled intravenous (IV) microdose of dabrafenib was given concomitantly with a 150 mg oral dose, was used to simultaneously recover IV and oral pharmacokinetic parameters. The least squares mean (90% CI) absolute bioavailability of dabrafenib (HPMC capsules) was 94.5% (81.3%, 109.7%). Median T(max) after oral administration was 2.0 hours and the geometric mean terminal half-life was 4.8 hours. The geometric mean clearance and volume of distribution after IV administration were 12.0 L/h and 45.5 L, respectively. Human clearance and volume of distribution at steady state were in agreement with predictions made using allometric scaling of pharmacokinetic parameters from four preclinical species. In conclusion, dabrafenib absolute bioavailability was high, whereas first-pass metabolism was low. Furthermore, the microtracer approach provided an innovative and efficient method for assessing the absolute bioavailability of dabrafenib in patients with advanced cancer.

To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

“…Table 2 lists the compoundspecific preclinical input we used to predict the local C max values as input for the decision tree (Eqs. [1][2][3][4]. No P app was available for propafenone to estimate the fraction absorbed.…”

“…Table 4 shows the C max values in intestinal lumen, enterocytes, liver, and plasma (total and unbound) as predicted from in vitro data and physicochemical properties (Eqs. [1][2][3][4][5][6][7][8]. The predicted C max in plasma is plotted against the observed C max for the therapeutic dose in the studies under consideration in Fig.…”

“…In microtracer studies, a low dose of radiolabeled compound is added to a high dose of the unlabeled compound or a potentially interacting drug, by the same or alternate routes of administration. This allows gaining additional pharmacokinetic information cost effectively from already planned clinical trials, such as absolute oral bioavailability [1][2][3] and drug-drug interactions (DDIs) [4]. These (micro)tracer studies have become increasingly common in clinical drug development [12].…”

“…In each panel, the bars show the predicted maximum concentrations in gastrointestinal lumen, enterocytes, liver, and plasma (unbound) (Eqs [1][2][3][4]. for a compound at the tested (therapeutic) dose.…”

Dabrafenib for the treatment of melanoma

“…At the recommended Phase II dose (RP2D) of 150 mg twice daily, the half-life was estimated at around 5.2 h ± 1.44. The mean C max was 806 ng/ml and the AUC (0 --12) was 2619 ng  h/ml after 15 days at a dose of 150 mg twice daily [ Pivotal trial(s) [6,7,15,16,25] Pharmaprojects -copyright to Citeline Drug Intelligence (an informa business). Readers are referred to Informa-Pipeline (http:// informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).…”