Reducing the Burden of Interaction Studies in Cancer Patients Using a Stable Isotopically Labeled Microtracer: A Proof-of-Concept Study with Alectinib.

Abstract

Traditional drug-food interaction studies of oral anticancer agents have a high patient burden. A patient-friendly alternative approach to studying food effects could be the use of stable isotopically labeled microtracers. A prospective, single-center, open-label, crossover, food effect study with the microtracer ²H₆-alectinib was conducted in patients with ALK-positive, non-small cell lung cancer treated with 600 mg alectinib bidaily. On occasion 1 (fed state), patients received 100 μg ²H₆-alectinib in addition to their usual dose of alectinib and a standardized Dutch breakfast (320-392 kcal and 7.5-7.8 g fat). On occasion 2 (fasted state), patients received ²H₆-alectinib and alectinib after overnight fasting. Pharmacokinetic (PK) samples were collected up to 8 hours after intake of ²H₆-alectinib. The effect of food on relative bioavailability (F) and mean transit time of ²H₆-alectinib was assessed by population PK modeling. Differences in area under the plasma concentration-time curve (AUC) and maximum concentration (C_max) between fed and fasted states were estimated by simulations. MTT in the fed state was 3.14 hours (relative standard error (RSE): 16.0%). MTT and F in the fasted state were 28% (RSE: 20.5%) and 35% (RSE: 12.4%) lower, respectively, compared to the fed state. The geometric mean ratio (fed vs. fasted) of AUC and C_max was 1.52 (90% confidence interval (CI): 1.25-1.89) and 1.42 (90% CI: 1.16-1.76), respectively. These results showed that the intake of a Dutch breakfast leads to a higher total exposure of alectinib. More importantly, the feasibility of a microtracer food effect study to reduce patient burden was demonstrated.