Clinical Pharmacokinetics and Pharmacodynamics of Dabrafenib

AbstractDabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastaticBRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring theBRAFV600E mutation. The recommended dose of dabrafenib is 150  mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/F) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP)  3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75– 300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically signifi cant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the...
Source: Clinical Pharmacokinetics - Category: Drugs & Pharmacology Source Type: research