Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites

Abstract

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.

Coproporphyrin I Can Serve as an Endogenous Biomarker for OATP1B1 Inhibition: Assessment Using a Glecaprevir/Pibrentasvir Clinical Study

“…which was derived from the simple generalized equation for the analysis of simultaneous inhibition by multiple inhibitors 23 . The same approach is also described elsewhere 24,25 . Because the OATP1B1 IC 50 value of PIB was determined in the presence of physiological concentration of albumin (4% bovine serum albumin), the total C max of PIB was compared with its IC 50 value ([C max ]/[OATP1B1 IC 50 ]), and the estimated total plasma exposure of PIB in the hepatic inlet was compared with IC 50 in the calculation of PIB OATP1B1 R value and the net OATP1B1 R value (total IC 50 method) 26 …”

Role of OATP1B1 and OATP1B3 in Drug-Drug Interactions Mediated by Tyrosine Kinase Inhibitors

“…In vitro, in vivo, and clinical data were extracted. The details of the articles were inserted into tables (shown in Supplementary Materials Tables S1–S9 ) [ 43 , 44 , 45 , 46 , 47 ] For alectinib, avapritinib, baracitinib, binimetinib, brigatinib, cobimetinib, dacomitinib, encorafenib, erdafitnib, fedratinib, gilteritinib, ibrutinib, laroctrectinib, lorlatinib, midostaurin, pexidartinib, ponatinib, trametinib, and zanbrutinib no published reports were found. In data collected for 17 TKIs, the results of the published data were largely inconsistent in that some of the published results for a given TKI identified the TKI as an inhibitor of OATP1B1 or OATP1B3, while other sources identified it expressly as a non-inhibitor.…”

MM-PBSA and the Importance of the Dielectric Constant for Kinase Drug Design

“…Interestingly, measured half-lives for CDB and DDB were longer than for DB and HDB [36]. The study of Ellens et al [37] reports that, based on in vitro antiproliferative IC50 measures, HDB and DDB should be potent inhibitors of BRAF-V600E, slightly less active than DB whereas the activity of CDB is largely reduced. Comparison of the affinity measures with the affinity ranking using MM-PBSA suggests that high values of the dielectric constant ( > 8) are appropriate to obtain the equivalent ranking of DB -HDB/DDB -CDB, from best to worst (compare Figure 3).…”