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.

Autor: Ye N; AstraZeneca, Cambridge, MA, USA., Monk SA; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Daga P; AstraZeneca, Cambridge, MA, USA., Bender DM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA., Rosen LB; AstraZeneca, Cambridge, MA, USA., Mullen J; AstraZeneca, Cambridge, MA, USA., Minkwitz MC; AstraZeneca, Cambridge, MA, USA., Kugler AR; AstraZeneca, Cambridge, MA, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2018 Mar; Vol. 7 (3), pp. 233-243. Date of Electronic Publication: 2018 Jan 10.
DOI: 10.1002/cpdd.422
Abstrakt: 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 AUC 0-∞ (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.
(© 2018, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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