Clinical Bioavailability of the Novel BACE1 Inhibitor Lanabecestat (AZD3293): Assessment of Tablet Formulations Versus an Oral Solution and the Impact of Gastric pH on Pharmacokinetics. Issue 3 (10th January 2018)

• Record Type: Journal Article
• Authors: Ye, Naidong; Monk, Scott A.; Daga, Pankaj; Bender, David M.; Rosen, Laura B.; Mullen, Jamie; Minkwitz, Margaret C.; Kugler, Alan R.
• Is Part Of: Clinical pharmacology in drug development. Volume 7:Issue 3(2018)
• Page Start: 233
• Page End: 243
• Publication Date: 2018-01-10
• Subjects: Alzheimer's -- AZD3293 -- BACE1 -- bioavailability -- pharmacokinetics; Drugs -- Testing -- Periodicals; Drug development -- Periodicals; Clinical pharmacology -- Periodicals; 615.580724
• DOI: 10.1002/cpdd.422
• Languages: English
• ISSNs: 2160-7648

Abstract

Abstract: The relative bioavailability of lanabecestat administered as 2 tablet formulations versus an oral solution was investigated. This phase 1 single‐center, open‐label, randomized, 3‐period crossover study involved healthy male and nonfertile female subjects aged 18–55 years (NCT02039180). Subjects received a single 50‐mg lanabecestat dose as solution, tablet A, or tablet B on day 1 of each crossover period; 14 of 16 subjects completed the study. Relative bioavailability based on plasma lanabecestat AUC0–∞ (area under the plasma drug concentration–time curve from zero to infinity) geometric mean ratio versus oral solution (primary variable) was: tablet A, 1.052 (90% confidence interval [CI], 1.001–1.106); tablet B, 1.040 (0.989–1.093). These 90%CIs for geometric mean ratios are within accepted standard bioequivalence boundaries for all other pharmacokinetic (PK) parameters for both lanabecestat and metabolite (AZ13569724). All 3 formulations had similar plasma lanabecestat concentration–time profiles. Six adverse events were reported by 6 subjects (37.5%, all mild). GastroPlus modeling predicted a negligible impact of gastric pH changes on systemic PK (up to pH 7.4). Both tablet formulations fall within standard accepted bioequivalence criteria versus the oral solution. A single 50‐mg lanabecestat dose was well tolerated as a solution or tablet formulation in this population.