ABCB1 and ABCG2, but not CYP3A4 limit oral availability and brain accumulation of the RET inhibitor pralsetinib

• Published in: Pharmacological research Vol. 172; p. 105850
• Main Authors: Wang, Yaogeng, Sparidans, Rolf W., Potters, Sander, Lebre, Maria C., Beijnen, Jos H., Schinkel, Alfred H.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-10-2021
• Subjects: Administration, Oral; Animals; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; BCRP/ABCG2; Biological Availability; Brain - metabolism; Brain accumulation; Cytochrome P-450 CYP3A - genetics; Cytochrome P450-3A; Female; Male; Mice; Mice, Knockout; Oral availability; Organic Anion Transporters - antagonists & inhibitors; Organic Anion Transporters - genetics; Organic Anion Transporters - metabolism; P-glycoprotein/ABCB1; Pralsetinib; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - pharmacokinetics; Proto-Oncogene Proteins c-ret - antagonists & inhibitors; Pyrazoles - blood; Pyrazoles - pharmacokinetics; Pyridines - blood; Pyridines - pharmacokinetics; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Testis - metabolism; h as prefix; RET; Pralsetinib; ABC; ABCB1; BBB; P-glycoprotein/ABCB1; Oral availability; MKIs; LC-MS/MS; CYP; MDCK; Brain accumulation; BCRP; Zosuquidar (PubChem CID: 3036703); Elacridar (PubChem CID: 119373); P-gp; SLCO; OATP; BCRP/ABCG2; BTB; m as prefix; TKI; Vandetanib (PubChem CID: 3081361); Cytochrome P450-3A; Pralsetinib (PubChem CID: 129073603); Cabozantinib (PubChem CID: 25102847); Selpercatinib (PubChem CID: 134436906); Cyp3aXAV; ABCG2
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2021.105850

Pralsetinib is an FDA-approved oral small-molecule inhibitor for treatment of rearranged during transfection (RET) proto-oncogene fusion-positive non-small cell lung cancer. We investigated how the efflux transporters ABCB1 and ABCG2, the SLCO1A/1B uptake transporters and the drug-metabolizing enzyme CYP3A influence pralsetinib pharmacokinetics.
In vitro, transepithelial pralsetinib transport was assessed. In vivo, pralsetinib (10 mg/kg) was administered orally to relevant genetically modified mouse models. Pralsetinib concentrations in cell medium, plasma samples and organ homogenates were measured using liquid chromatography-tandem mass spectrometry.
Pralsetinib was efficiently transported by human (h)ABCB1 and mouse (m)Abcg2, but not hACBG2. In vivo, mAbcb1a/1b markedly and mAbcg2 slightly limited pralsetinib brain penetration (6.3-and 1.8-fold, respectively). Testis distribution showed similar results. Abcb1a/1b;Abcg2-/- mice showed 1.5-fold higher plasma exposure, 23-fold increased brain penetration, and 4-fold reduced recovery of pralsetinib in the small intestinal content. mSlco1a/1b deficiency did not affect pralsetinib oral availability or tissue exposure. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted pralsetinib plasma exposure (1.3-fold) and brain penetration (19.6-fold) in wild-type mice. Additionally, pralsetinib was a modest substrate of mCYP3A, but not of hCYP3A4, which did not noticeably restrict the oral availability or tissue distribution of pralsetinib.
SLCO1A/1B and CYP3A4 are unlikely to affect the pharmacokinetics of pralsetinib, but ABCG2 and especially ABCB1 markedly limit its brain and testis penetration, as well as oral availability. These effects are mostly reversed by oral coadministration of the ABCB1/ABCG2 inhibitor elacridar. These insights may be useful in the further clinical development of pralsetinib.
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