Influence of Food With Different Fat Concentrations on Alectinib Exposure: A Randomized Crossover Pharmacokinetic Trial

Abstract

Background: Alectinib is the keystone treatment in advanced anaplastic lymphoma kinase–positive (ALK+) non–small cell lung cancer (NSCLC). An exposure–response threshold of 435 ng/mL has recently been established, albeit 37% of patients do not reach this threshold. Alectinib is orally administered, and absorption is largely influenced by food. Hence, further investigation into this relationship is needed to optimize its bioavailability. Patients and Methods: In this randomized 3-period crossover clinical study in ALK+ NSCLC, alectinib exposure was compared among patients with different diets. Every 7 days, the first alectinib dose was taken with either a continental breakfast, 250-g of low-fat yogurt, or a self-chosen lunch, and the second dose was taken with a self-chosen dinner. Sampling for alectinib exposure (Ctrough) was performed at day 8, just prior to alectinib intake, and the relative difference in Ctrough was compared. Results: In 20 evaluable patients, the mean Ctrough was 14% (95% CI, −23% to −5%; P=.009) and 20% (95% CI, −25% to −14%; P<.001) lower when taken with low-fat yogurt compared with a continental breakfast and a self-chosen lunch, respectively. Administration with a self-chosen lunch did not change exposure compared with a continental breakfast (+7%; 95% CI, −2% to +17%; P=.243). In the low-fat yogurt period, 35% of patients did not reach the threshold versus 5% with the other meals (P<.01). Conclusions: Patients and physicians should be warned for a detrimental food–drug interaction when alectinib is taken with low-fat yogurt, because it results in a clinically relevant lower alectinib exposure. Intake with a self-chosen lunch did not change drug exposure and could be a safe and patient-friendly alternative.

Evaluation of Solubility, Dissolution Rate, and Oral Bioavailability of β-Cyclodextrin and Hydroxypropyl β-Cyclodextrin as Inclusion Complexes of the Tyrosine Kinase Inhibitor, Alectinib

“…ALB belongs to Class IV BCS (low solubility and high permeability) and is administered with food [ 16 ]. ALB has a low oral bioavailability rate of around 37% [ 18 ], and food positively affects its bioavailability, as explained by Lanser et al [ 19 ]. The oral bioavailability of the drug molecule is based on various parameters, including drug permeability, aqueous solubility, pre-systemic metabolism, first-pass metabolism, the dissolution rate, and efflux mechanisms dependent on vulnerability.…”