title: Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects.
abstract: The anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK-positive non-small-cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with the reduced wetting agent sodium lauryl sulfate (SLS) content. This randomized, 4-period, 4-sequence, crossover study compared alectinib (600 mg) as 25%, 12.5%, and 3% SLS hard capsule formulations with the reference 50% SLS clinical formulation in healthy subjects under fasted conditions (n = 49), and following a high-fat meal (n = 48). Geometric mean ratios and 90% confidence intervals (CIs) for Cmax, AUC0-last, and AUC0-∞of alectinib, its major active metabolite, M4, and alectinib plus M4 were determined for the test formulations versus the reference formulation. Bioequivalence was concluded if the 90%CIs were within the 80% to 125% boundaries. The 25% SLS formulation demonstrated bioequivalence to the reference 50% SLS formulation for Cmax, AUC0-last, and AUC0-∞of alectinib, M4, and alectinib plus M4 under both fasted and fed conditions. Further reductions in SLS content (12.5% and 3% SLS) did not meet the bioequivalence criteria. Cross-group comparisons showed an approximately 3-fold positive food effect. Reducing SLS to 25% resulted in a formulation that is bioequivalent to the current 50% SLS formulation used in alectinib pivotal trials.
authors.affiliation: Roche Innovation Center, New York, NY, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
authors.affiliation: F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Ludger
authors.initials: L
authors.lastname: Banken
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Timpe
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Lindenberg
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Guerini
authors.affiliation: d3 Medicine, Parsippany, NJ, USA.
authors.forename: Georgina
authors.initials: G
authors.lastname: Dall
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Katrijn
authors.initials: K
authors.lastname: Bogman
authors.affiliation: F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Carolina
authors.initials: C
authors.lastname: Sturm
authors.affiliation: F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Ali
authors.initials: A
authors.lastname: Zeaiter
authors.affiliation: Roche Innovation Center, Basel, Switzerland.
authors.forename: Meret
authors.initials: M
authors.lastname: Martin-Facklam
authors.affiliation: Roche Products Ltd, Welwyn, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Phipps
mesh_terms: D000328:Adult; D002214:Capsules; D002227:Carbazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D059305:Diet, High-Fat; D005215:Fasting; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology*; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D002214:Capsules; D002227:Carbazoles; D010880:Piperidines; D013501:Surface-Active Agents; D012967:Sodium Dodecyl Sulfate; C582670:alectinib
keywords: ALK inhibitor; SLS; alectinib; formulation; pharmacokinetics