Oral coadministration of elacridar and ritonavir enhances brain accumulation and oral availability of the novel ALK/ROS1 inhibitor lorlatinib.

Abstract

Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a-/- mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a-/- mice, without altering the relative tissue distribution of lorlatinib. Moreover, simultaneous pharmacological inhibition of P-glycoprotein and CYP3A4 with oral elacridar and ritonavir in CYP3A4-humanized mice profoundly increased lorlatinib brain concentrations, but not its oral availability or other relative tissue distribution. Oral lorlatinib pharmacokinetics was not significantly affected by absence of the multispecific Oatp1a/1b drug uptake transporters. The absolute oral bioavailability of lorlatinib over 8 h in wild-type, Cyp3a-/-, and CYP3A4-humanized mice was 81.6%, 72.9%, and 58.5%, respectively. Lorlatinib thus has good oral bioavailability, which is markedly restricted by human CYP3A4 but not by mouse Cyp3a. Pharmacological inhibition of CYP3A4 reversed these effects, and simultaneous P-gp inhibition with elacridar boosted absolute brain levels of lorlatinib by 16-fold without obvious toxicity. These insights may help to optimize the clinical application of lorlatinib.

• Authors: Wenlong Li, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Jos H Beijnen, Alfred H Schinkel
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 136 Pg. 120-130 (Mar 2019) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 30660696 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Acridines
• Aminopyridines
• Cytochrome P-450 CYP3A Inhibitors
• Lactams
• Lactams, Macrocyclic
• Proto-Oncogene Proteins
• Pyrazoles
• Tetrahydroisoquinolines
• Alk protein, mouse
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases
• Ros1 protein, mouse
• Elacridar
• Ritonavir
• lorlatinib

Topics

• Acridines (administration & dosage, metabolism)
• Administration, Intravenous
• Administration, Oral
• Aminopyridines
• Anaplastic Lymphoma Kinase (antagonists & inhibitors, metabolism)
• Animals
• Biological Availability
• Brain (drug effects, metabolism)
• Cytochrome P-450 CYP3A Inhibitors (administration & dosage, metabolism)
• Drug Interactions (physiology)
• Drug Synergism
• Lactams
• Lactams, Macrocyclic (administration & dosage, metabolism)
• Mice
• Mice, Knockout
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Pyrazoles
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Ritonavir (administration & dosage, metabolism)
• Tetrahydroisoquinolines (administration & dosage, metabolism)