Drug transporters such as PgP and BCRP limit the exposure of several drugs to the brain. This study investigated the effect of the PgP/BCRP inhibitor elacridar at the blood brain barrier of mice and cancer patients using the PET tracer [11C]erlotinib.
Elacridar (10, 25, 50 mg/kg) and cold erlotinib (20 mg/kg) were administered orally to wild type (WT) mice (n = 4 per group). Erlotinib was measured in blood and the brain ex vivo using LC-MS/MS. In addition, brain uptake was assessed using [11C]erlotinib (SA > 18.5 GBq/µmol, 10 MBq) time-activity curves (TAC) and ex vivo scintillation counting in WT (n = 2) and PgP/BCRP knockout (KO) mice (n = 2). Six patients underwent [11C]erlotinib PET before and after an oral dose of 1000 mg elacridar. Uptake of [11C]erlotinib (SA > 18.5 GBq/µmol, 370 MBq) in the brain was quantified by pharmacokinetic modeling using volume of distribution (VT) as the outcome parameter. VT is defined as activity in the brain/activity in plasma and was estimated using the two tissue reversible metabolite corrected plasma input curve. [15O]H2O (800 MBq) scans were used to measure cerebral blood flow (CBF). Elacridar plasma concentrations were measured at the start and end of each scan.
Brain uptake of [11C]erlotinib was higher in PgP/BCRP KO mice than in WT mice, both as TAC and ex vivo as % of injected dose/gram tissue (2.6-fold, p = 0.01). In WT mice, elacridar concentrations of ≥200 ng/mL resulted in increased brain concentration of erlotinib, achieving levels similar to KO mice, without affecting erlotinib plasma concentration. In patients, VT of [11C]erlotinib did not increase after intake of elacridar (0.236 ± 0.11 versus 0.205 ± 0.07, mean ±SD, p = 0.43). [15O]H2O PET showed no significant changes in CBF. Elacridar exposure in patients was 340 ± 192 ng/mL (mean ±SD).
When PgP/BCRP was disabled in mice, brain uptake of erlotinib increased both at a tracer and pharmacological dose. In patients, brain uptake of [11C]erlotinib was not higher after administration of elacridar. The discrepancy between the preclinical and clinical results may be due to interspecies differences in abundance, activity and specificity of drug transporters in the mouse and human brain.
Clinical trial identification
Netherlands Trial Registry number: NTR4780 EUdraCT clinical trial database: 2014-000281-21
Legal entity responsible for the study
Netherlands Cancer Institute
Netherlands Cancer Institute
O. van Tellingen: Received research funding from Alion Pharmaceuticals (paid to institute). Is co-inventor of patent US20140235631A1. A.A. Lammertsma: Received research funding from Avid (paid to institute), recieved travel expenses and accommodation for a meeting co-sponsored by Philips. J.H. Beijnen: Owns stock in Modra Pharmaceuticals Holding, owns a patent on oral taxane formulations. N. Steeghs: Received research funding from Pfizer, GlaxoSmithKline, Novartis, Bayer, Boehringer Ingelheim and Roche. All other authors have declared no conflicts of interest.