Abstract

A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multi-kinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and free brain-to-plasma ratios (Kp or Kp,uu) were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp (Mdr1a/b(–/–)Bcrp1(–/–)) compared to the wild-type mice. The triple knockout mice had a greater than an additive increase in the brain exposure of ponatinib when compared to single knockout mice (Bcrp1(–/–) or Mdr1a/b(-/-)), suggesting functional compensation of transporter-mediated drug efflux. Based on the BBB model characterizing the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were approximately 15-fold higher in the wild-type mice compared to Mdr1a/b(–/–)Bcrp1(–/–) mice, resulting in a significant increase in the mean transit time (MTT; the average time spent by ponatinib in the brain in a single passage) in the absence of efflux transporters (P-gp and Bcrp). This study characterized transporter-mediated drug efflux from the brain; a process that reduces the duration and extent of ponatinib exposure in the brain, and has critical implications on the use of targeted drug delivery for brain tumors.