(M0930-05-28) In Vitro ADME, Mouse Pharmacokinetics, and Bioanalysis of LD14b: A Novel Aβ 17β-HSD10 Modulator for the Treatment of Alzheimer’s disease

Monday, November 10, 2025

9:30 AM - 10:30 AM CT

Presenting Author(s)

SD

Sohel Daria, MS

Graduate Research Assistant
University of Nebraska Medical Center
Omaha, Nebraska, United States

Main Author(s)

SD

Sohel Daria, MS

Graduate Research Assistant
University of Nebraska Medical Center
Omaha, Nebraska, United States

Co-Author(s)

DK

Devendra Kumar, Ph.D.

Post-doc
University of Nebraska Medical Center
Omaha, Nebraska, United States
NG

Nagsen Gautam, Ph.D.

Senior Scientist III
Arrowhead Pharmaceutical Inc.
Madison, Wisconsin, United States
JA

Jawaher Abdullah Alamoudi

Associate Professor
Princess Nourah bint Abdulrahman University
Riyad, Ar Riyad, Saudi Arabia
LD

Louise F. Dow

Graduate Research Assistant
University of Nebraska Medical Center
Omaha, Nebraska, United States
PT

Paul C. Trippier, Ph.D. (he/him/his)

Professor
University of Nebraska Medical Center
Omaha, Nebraska, United States
YA

Yazen Alnouti, Ph.D.

Professor
University of Nebraska Medical Center
Omaha, Nebraska, United States

Purpose: LD14b is an amyloid-β (Aβ) 17β-hydroxysteroid dehydrogenase type 10 (Aβ-17β-HSD10) protein-protein interaction modulator that shows promising in vitro and ex vivo activity to rescue Aβ-induced mitochondrial dysfunction, Aβ-induced toxicity, and Aβ-mediated inhibition of estradiol synthesis.

Methods: Experimental

Design: The current study investigated in vitro human S9 fractions metabolic stability, apparent permeability across Caco-2 cells monolayer, human and mouse plasma protein binding, in vivo pharmacokinetics, and tissue distribution in Balb/cJ mice.

Results: A fast, sensitive, reliable, and reproducible LC-MS/MS method was developed and validated over the dynamic range of 1-1000 ng/mL for the quantification of LD14b in different biological matrices (plasma, liver, kidney, brain, lungs, heart). LD14b was metabolically stable in human liver S9 fractions with 70% remaining after 90 minutes of incubation. It had intermediate apparent permeability of 3.55 × 10^-06 cm/s and 6.16 × 10^-06 cm/s for apical-to-basolateral (A-to-B) and basolateral-to-apical (B-to-A), respectively across the Caco-2 monolayer, and was medium/highly bound to human plasma proteins (84.1%), mouse plasma proteins (85.7%). LD14b had a 52% oral bioavailability in Balb/cJ mice and was well-distributed to the peripheral tissues (liver, kidney, lungs, and heart) including the brain. Orally, maximum plasma concentration (1780±131.6 ng/mL) was achieved in 0.45 h with a half-life of 3.8 h, a clearance 3.65 L/h/kg. About 5-7 folds higher brain concentration of LD14b was found compared to plasma concentration.

Conclusion: In conclusion, these results support the further development of LD14b as a potential therapeutic modality for Alzheimer’s disease via oral administration.

References: Daria, S., Kumar, D., Gautam, N., Alamoudi, J. A., Dow, L. F., Trippier, P. C., & Alnouti, Y. (2024). In vitro ADME, mouse pharmacokinetics of LD14b, and bioanalysis of a novel aβ 17β-HSD10 modulator for the treatment of Alzheimer’s disease. Xenobiotica, 54(9), 711–722. https://doi.org/10.1080/00498254.2024.2402033

Acknowledgements: The work was funded by grant number 3523313 from the Texas Alzheimer’s Research and Care Consortium Investigator Grant Program (TARCC-IGP) to P.C.T., grant number 01100674 from the Otis Glebe Medical Research Foundation to P.C.T. and the Vada Kinman Oldfield Award for Research in Alzheimer’s Disease (P.C.T.). L.F.D. thanks the Kinman-Oldfield Family Foundation for a Nancy and Ronald Reagan Alzheimer’s Scholarship. We would also like to acknowledge the Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2024R340), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia for the support.

Figure 1: DMPK profile of LD14b