RESUMO
Selitrectinib (BAY2731954; LOXO-195) is a promising oral tropomyosin receptor kinase (TRK) inhibitor currently in phase I/II clinical trials for the treatment of histology-agnostic cancers positive for TRK fusions. With therapeutic resistance eventually developing with first-generation TRK inhibitors, selitrectinib was designed to overcome resistance mediated by acquired kinase domain mutations. Using genetically modified mouse models and pharmacological inhibitors, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing CYP3A enzyme complex in selitrectinib pharmacokinetics. In vitro, selitrectinib was markedly transported by mouse Abcg2 and human ABCB1, and modestly by human ABCG2. Following oral administration at 10 mg/kg, selitrectinib brain-to-plasma ratios were increased in Abcb1a/1b-/- (twofold) and Abcb1a/1b;Abcg2-/- (5.8-fold) compared with wild-type mice, but not in single Abcg2-/- mice. Testis distribution showed similar results. mAbcb1a/1b and mAbcg2 each restricted the plasma exposure of selitrectinib: With both systems absent oral availability increased by 1.7-fold. Oral administration of the ABCB1/ABCG2 inhibitor elacridar boosted plasma exposure and brain accumulation in wild-type mice to the same levels as seen in Abcb1a/1b;Abcg2-/- mice. In Cyp3a-/- mice, plasma exposure of selitrectinib over 4 hours was increased by 1.4-fold and subsequently reduced by 2.3-fold upon transgenic overexpression of human CYP3A4 in liver and intestine. The relative tissue distribution of selitrectinib remained unaltered. Thus, selitrectinib brain accumulation and oral availability are substantially restricted by ABCB1 and ABCG2, and this can be reversed by pharmacological inhibition. Moreover, oral availability of selitrectinib is limited by CYP3A activity. These insights may be useful to optimize the clinical application of selitrectinib.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Compostos Aza/farmacocinética , Encéfalo/metabolismo , Citocromo P-450 CYP3A/metabolismo , Testículo/metabolismo , Animais , Compostos Aza/farmacologia , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Cães , Inibidores Enzimáticos/farmacologia , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Proteínas de Neoplasias/metabolismo , Testículo/efeitos dos fármacosRESUMO
Fisogatinib (BLU-554) is a highly selective and potent oral fibroblast growth factor receptor 4 (FGFR4) inhibitor currently in Phase I clinical trials for treatment of hepatocellular carcinoma (HCC). Using (male) genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in fisogatinib pharmacokinetics. In vitro, fisogatinib was modestly transported by hABCB1. Upon oral administration of 10 mg/kg fisogatinib, its brain accumulation was substantially increased in Abcb1a/1b-/- (6.3-fold) and Abcb1a/1b;Abcg2-/- mice (7.2-fold) compared to wild-type mice, but not in single Abcg2-/- mice. The oral plasma pharmacokinetics and liver distribution of fisogatinib were not significantly affected by the absence of Oatp1a/1b drug uptake transporters. We further found that plasma exposure of fisogatinib in Cyp3a-/- mice increased by 1.4-fold, and was subsequently 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. However, the relative tissue distribution of fisogatinib remained unaltered. In summary, in mice, fisogatinib brain accumulation is substantially limited by ABCB1 P-glycoprotein in the blood-brain barrier, and oral availability of fisogatinib is markedly restricted by CYP3A activity. The obtained insights may be useful for optimizing the clinical efficacy and safety of fisogatinib.