Clinically Negligible Pharmacokinetic and Pharmacodynamic Interactions Between Lanabecestat and Dabigatran Etexilate, a Prototypical P‐gp Substrate. (18th December 2019)

• Record Type: Journal Article
• Authors: Monk, Scott A.; Kugler, Alan R.; Andersen, Scott W.; Ayan‐Oshodi, Mosun A.; James, Douglas E.; Mullen, Jamie; Zimmer, Jennifer A.; Willis, Brian A.
• Is Part Of: Journal of clinical pharmacology. Volume 60:Number 5(2020)
• Page Start: 586
• Page End: 594
• Publication Date: 2019-12-18
• Subjects: clinical pharmacology -- clinical research -- drug‐drug interactions -- pharmacodynamics -- pharmacokinetics -- drug metabolism; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.1558
• Languages: English
• ISSNs: 0091-2700

Abstract

Abstract: Lanabecestat, a novel β‐site amyloid precursor protein–cleaving enzyme 1 inhibitor evaluated for Alzheimer treatment, inhibits P‐glycoprotein (P‐gp) activity in vitro. After oral 50‐mg lanabecestat administration, gastric fluid lanabecestat concentrations exceed half‐maximal inhibitory concentration (IC50 ), suggesting P‐gp inhibition at the intestinal wall. Plasma drug concentrations following 50 mg lanabecestat administered once daily are <10% of IC50, suggesting minimal systemic P‐gp interaction. Dabigatran etexilate (DE) is the prodrug of dabigatran, a thrombin inhibitor and P‐gp substrate, making dabigatran exposure an intestinal P‐gp activity indicator. This study (NCT02568397) was conducted in 60 healthy subjects receiving a single dose of 150 mg DE alone or during a lanabecestat treatment regimen. On day 16, lanabecestat and DE were coadministered; on day 20, DE was dosed 4 hours after lanabecestat. Safety was assessed using clinical labs, electrocardiogram, vital signs, Columbia Suicide Severity Rating Scale scores, adverse events, and eye and skin examinations. Pharmacokinetic/pharmacodynamic samples were collected up to 36 hours postdose. Geometric mean plasma dabigatran area under the curve from time 0 to infinity (AUC0‐∞ ) and the maximum plasma drug concentration (Cmax ) increased by 15% and 17%, respectively, when coadministered with lanabecestat. When DE was dosed 4 hours after lanabecestat, there was no effect on plasma dabigatran AUC0‐∞, Cmax, or thrombin time. DE had no effect on lanabecestat's AUC0‐∞ and Cmax at steady state (day 16) versus lanabecestat alone (day 15). No clinically relevant safety concerns were observed. Lanabecestat has no clinically meaningful effect on dabigatran exposure or on P‐gp activity at the intestinal wall.