ABCB1 and ABCG2 Restrict Brain and Testis Accumulation and, Alongside CYP3A, Limit Oral Availability of the Novel TRK Inhibitor Selitrectinib

• Published in: Molecular cancer therapeutics Vol. 20; no. 6; pp. 1173 - 1182
• Main Authors: Li, Wenlong, Sparidans, Rolf W, Martins, Margarida L F, El-Lari, Mujtaba, Lebre, Maria C, van Tellingen, Olaf, Beijnen, Jos H, Schinkel, Alfred H
• Format: Journal Article
• Language: English
• Published: United States 01.06.2021
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; Aza Compounds - pharmacokinetics; Aza Compounds - pharmacology; Biological Availability; Brain - drug effects; Brain - metabolism; Cytochrome P-450 CYP3A - metabolism; Dogs; Enzyme Inhibitors - pharmacology; Humans; Madin Darby Canine Kidney Cells; Male; Mice; Neoplasm Proteins - metabolism; Testis - drug effects; Testis - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-20-0705

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. , 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 (twofold) and (5.8-fold) compared with wild-type mice, but not in single 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 mice. In 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.