dabrafenib

Ligand id: 6494

Name: dabrafenib

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Structure and Physico-chemical Properties

2D Structure
Calculated Physico-chemical Properties
Hydrogen bond acceptors 7
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 147.48
Molecular weight 519.1
XLogP 4.79
No. Lipinski's rules broken 0

Molecular properties generated using the CDK

No information available.
Summary of Clinical Use
Dabrafenib is a kinase inhibitor approved for the treatment of patients with unresectable or metastatic melanoma with BRAF mutations as detected by an FDA-approved test and should not be used to treat patients with wildytpe BRAF tumors.
Marketed formulations contain dabrafenib mesylate (PubChem CID 44516822).
Mechanism Of Action and Pharmacodynamic Effects
Dabrafenib potently inhibits (IC50 in low nanomolar concentrations) constitutively active BRAF kinase with mutations V600E (VAR_018629)., V600K, and V600D in vitro. The mechanism of tumor inhibition is thought to be via dabrafenib-induced inhibition of phosphorylated ERK resulting in a decrease in cell proliferation. Downstream mediators of the MAPK pathway are also inhibited. Dabrafenib also inhibits wild-type BRAF and CRAF kinases at low IC50 concentrations and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations.
Pharmacokinetics
Absorption/Distribution
Peak plasma concentration is reached 2 hours after oral administration. It is recommended to dose in the fasted state. Mean absolute bioavailability of oral dabrafenib is 95%. Dabrafenib is 99.7% bound to human plasma proteins.
Biotransformation/Metabolism
Dabrafenib is excreted in urine and bile as carboxy-dabrafenib (by the sequential actions of CYP2C8 and CYP3A4). Desmethyl-dabrafenib is a decarboxylation metabolite that may be reabsorbed from the gut. The parent drug and the hydroxy- metabolite have similar terminal half-lives (10 hours), but the carboxy- and desmethyl- metabolites have extended half-lives (21-22 hours). Both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib.
Elimination
Excretion of dabrafenib is primarily via feces (71%) with urinary excretion accounting for 23% ( recovered as metabolites only).
Population pharmacokinetics
There are no clinically relevant differences in exposure to dabrafenib associated with age, gender or weight. The pharmacokinetics of dabrafenib have not been studied in pediatric patients.
Organ function impairment
Mild or moderate renal impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with severe renal impairment. Mild hepatic impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with moderate to severe hepatic impairment.
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