Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites.
The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 inhibitor, trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction (DDI) risk assessment, which is currently an important part of drug development, regulatory submission, and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy-, and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, and OAT3. The DDI Guidance risk assessment decision criteria for inhibition of BCRP, OATP1B1 and OAT3 were slightly exceeded and therefore a minor DDI effect resulting from inhibition of these transporters remained possible. Biliary secretion is the major excretion pathway of dabrafenib-related material (71.1% of orally administered radiolabeled dose recovered in feces), whereas urinary excretion was observed as well (22.7% of the dose). In vitro uptake into human hepatocytes of the dabrafenib metabolites, but not of dabrafenib parent compound, was mediated, at least in part, by hepatic uptake transporters. The transporters responsible for uptake of the pharmacologically active hydroxy- and desmethyl dabrafenib could not be identified, whereas carboxy-dabrafenib was a substrate of several OATPs. Dabrafenib, hydroxy-, and desmethyl-dabrafenib were substrates of P-gp and BCRP, whereas carboxy-dabrafenib was not. Although a small increase in exposure to carboxy-dabrafenib upon inhibition of OATPs and an increase in exposure to desmethyl-dabrafenib upon inhibition of P-gp or BCRP cannot be excluded, the clinical significance of such increases is likely to be low.
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania harmaellens@gmail.com.
Harma
H
Ellens
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
Marta
M
Johnson
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
Sarah K
SK
Lawrence
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
Cory
C
Watson
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
Liangfu
L
Chen
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
Lauren E
LE
Richards-Peterson
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D004285:Dogs; D004347:Drug Interactions / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000378:metabolism* / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D010091:Oximes / Q000378:metabolism* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*
D007093:Imidazoles; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D010091:Oximes; D047428:Protein Kinase Inhibitors; C561627:dabrafenib