Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, a Highly Selective ALK Inhibitor, in Healthy Subjects

Abstract

Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non-small cell lung cancer who have progressed, on or are intolerant to, crizotinib. This study assessed the effect of a high-fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open-label, 2-group study in healthy subjects. In group 1 (n = 18), subjects were randomly assigned to a 2-treatment (A, fasted conditions; B, following a high-fat meal), 2-sequence (AB or BA) crossover assessment, separated by a 10-day washout. In group 2 (n = 24), subjects were enrolled in a 2-period, fixed-sequence crossover assessment to evaluate the effect of esomeprazole. PK parameters were evaluated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Administration of alectinib following a high-fat meal substantially increased the combined exposure of alectinib and M4 to 331% (90%CI, 279%-393%) and 311% (90%CI, 273%-355%) for C and AUC , respectively, versus fasted conditions. Coadministration of esomeprazole had no clinically relevant effect on the combined exposure of alectinib and M4. Alectinib should be administered under fed conditions to maximize its bioavailability, whereas no restrictions are required with antisecretory agents.

Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects

“…The alectinib and M4 PK parameters were substantially increased, by approximately 3‐fold, under fed conditions relative to fasted conditions for the reference 50% SLS formulation and for the bioequivalent 25% SLS formulation consistent with predictions from the in vitro solubility data. These findings are also consistent with results from a dedicated alectinib food‐effect study, which demonstrated a similar substantial approximately 3‐fold food effect on the bioavailability of the reference 50% SLS formulation …”

“…The solubility of alectinib hydrochloride in fed‐state‐simulated intestinal fluid is substantially higher than that in fasted‐state‐simulated intestinal fluid, which is indicative of anticipated food effect, consistent with results from the completed food‐effect clinical PK study with the alectinib 50% SLS formulation . Thus, the NP29040 clinical study evaluated bioequivalence under both fasted conditions and following a high‐fat meal for evaluation under extreme meal conditions.…”

“…Under fed conditions, SLS may be expected to be less influential than in a fasted state because of the predominating effects of lipids and bile salts, which enhance solubilization. Indeed, results from the completed food‐effect study with the 50% SLS formulation showed that solubility enhancement of alectinib by coadministration with a high‐fat meal increased alectinib exposure by 3‐fold …”

“…SLS is included as a wetting agent and functional excipient intended to improve the oral bioavailability of alectinib . In addition, a completed food‐effect study has demonstrated that solubility enhancement by administration of a single 600‐mg dose of alectinib with a high‐fat, high‐calorie meal substantially increased alectinib exposure by approximately 3‐fold relative to fasted conditions . Therefore, in clinical studies in patients with ALK ‐positive NSCLC, alectinib has been administered under fed conditions to maximize its bioavailability.…”

Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

“…The clinical pharmacokinetics (PK) of alectinib have been characterized in healthy subjects and in patients with ALK + NSCLC . Following single oral administration to patients with ALK + NSCLC, alectinib was absorbed with a median time to maximum plasma concentration (T max ) reached by 4 hours and a single‐dose apparent half‐life (t 1/2 ) of approximately 20 hours .…”