Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar

Crizotinib is an oral tyrosine kinase inhibitor approved for treating patients with non-small cell lung cancer (NSCLC) containing an anaplastic lymphoma kinase (ALK) rearrangement. We used knockout mice to study the roles of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) in plasma pharmacokinetics and brain accumulation of oral crizotinib, and the feasibility of improving crizotinib kinetics using coadministration of the dual ABCB1/ABCG2 inhibitor elacridar. In vitro, crizotinib was a good transport substrate of human ABCB1, but not of human ABCG2 or murine Abcg2. With low-dose oral crizotinib (5 mg/kg), Abcb1a/1b(-/-) and Abcb1a/1b;Abcg2(-/-) mice had an approximately twofold higher plasma AUC than wild-type mice, and a markedly (approximate to 40-fold) higher brain accumulation at 24 hr. Also at 4 hr, crizotinib brain concentrations were approximate to 25-fold, and brain-to-plasma ratios approximate to 14-fold higher in Abcb1a/1b(-/-) and Abcb1a/1b;Abcg2(-/-) mice than in wild-type mice. High-dose oral crizotinib (50 mg/kg) resulted in comparable plasma pharmacokinetics between wild-type and Abcb1a/1b(-/-) mice, suggesting saturation of intestinal Abcb1. Nonetheless, brain accumulation at 24 hr was still approximate to 70-fold higher in Abcb1a/1b(-/-) than in wild-type mice. Importantly, oral elacridar coadministration increased the plasma and brain concentrations and brain-to-plasma ratios of crizotinib in wild-type mice, equaling the levels in Abcb1a/1b;Abcg2(-/-) mice. Our results indicate that crizotinib oral availability and brain accumulation were primarily restricted by Abcb1 at a non-saturating dose, and that coadministration of elacridar with crizotinib could substantially increase crizotinib oral availability and delivery to the brain. This principle might be used to enhance therapeutic efficacy of crizotinib against brain metastases in NSCLC patients. What's new? Crizotinib is an oral tyrosine kinase inhibitor approved for treating non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase rearrangements. While NSCLC patients are likely to develop brain metastases, brain accumulation of crizotinib is limited. This study investigates the consequences of crizotinib transport by murine Abcb1 and Abcg2 and ways to counter them. Crizotinib oral availability and brain accumulation were restricted by Abcb1 at a non-saturating dose, and co-administration of the dual ABCB1/ABCG2 inhibitor elacridar drastically increased oral availability and brain delivery. This principle might be used to enhance therapeutic efficacy of crizotinib against brain metastases in NSCLC patients.