The impact of P‐glycoprotein and breast cancer resistance protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors

• Published in: International journal of cancer Vol. 142; no. 2; pp. 381 - 391
• Main Authors: de Gooijer, Mark C., Zhang, Ping, Weijer, Ruud, Buil, Levi C.M., Beijnen, Jos H., van Tellingen, Olaf
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.01.2018
• Subjects: ABC transporters; Animals; ATP Binding Cassette Transporter, Subfamily B - physiology; ATP Binding Cassette Transporter, Subfamily G, Member 2 - physiology; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; Brain cancer; Breast cancer; Cancer; Clinical trials; Drug delivery; Extracellular signal-regulated kinase; Glioblastoma; glioma; Inhibition; Inhibitors; MAP kinase; MAP Kinase Kinase 1 - antagonists & inhibitors; Medical research; MEK inhibitor; MEK inhibitors; Mice; Mice, Knockout; P-Glycoprotein; Pharmacodynamics; Pharmacokinetics; Plasma levels; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Proteins; Tissue Distribution; Tumors; pharmacokinetics; glioma; ABC transporters; MEK inhibitor; blood-brain-barrier
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31052

Mitogen/extracellular signal‐regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood‐brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP‐dependent efflux transport proteins, of which P‐gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain. We investigated their impact on the pharmacokinetics and target engagement of a panel of clinically applied MEK inhibitors, in order to select the most promising candidate for brain cancers in the context of clinical pharmacokinetics and inhibitor characteristics. To this end, we used in vitro drug transport assays and conducted pharmacokinetic and pharmacodynamic studies in wildtype and ABC‐transporter knockout mice. PD0325901 displayed more promising characteristics than trametinib (GSK1120212), binimetinib (MEK162), selumetinib (AZD6244), and pimasertib (AS703026): PD0325901 was the weakest substrate of P‐gp and BCRP in vitro, its brain penetration was only marginally higher in Abcb1a/b;Abcg2−/− mice, and efficient target inhibition in the brain could be achieved at clinically relevant plasma levels. Notably, target inhibition could also be demonstrated for selumetinib, but only at plasma levels far above levels in patients receiving the maximum tolerated dose. In summary, our study recommends further development of PD0325901 for the treatment of intracranial neoplasms. What's new? Almost all brain cancers—adult and pediatric, primary and secondary—harbor an overactivated MAPK pathway. Clinical studies are still few, but the key role and downstream location of MEK render MEK inhibitors of potential interest for the treatment of intracranial neoplasms. However, the blood‐brain barrier is a major impediment to the brain penetration and intracranial efficacy of drugs. To support successful clinical implementation of MEK inhibitors, the authors investigated the brain penetration of five clinically applied MEK inhibitors in mice, and selected PD0325901 as the candidate with the most promising pharmacokinetic and pharmacodynamics properties for the treatment of intracranial tumors.