A. Salminen1, D. Dies1, D. Austin1, J.A. Willoughby, Sr1, H. Walker2, J. McKim1
1LifeNet Health LifeSciences, Virginia Beach, VA 2Bayer Healthcare LLC, Whippany, NJ
Background and Purpose:
Pharmacokinetics plays a pivotal role in preclinical drug development, yet traditional in vivo studies are often limited by cost, complexity, and translational relevance. Microphysiological systems (MPS), which integrate reconstructed human organ models under dynamic flow conditions, offer a promising alternative for simulating absorption, distribution, metabolism, and excretion (ADME) in vitro. This study explores the utility of a three-organ MPS platform to evaluate the pharmacokinetics of an active pharmaceutical ingredient (API) delivered via a self-nano-emulsifying drug delivery system (SNEDDS), a formulation strategy designed to enhance oral bioavailability and protect APIs from degradation and first-pass metabolism.
Methods:
A human-based MPS platform comprising EpiIntestinal™ (intestine), TruVivo™ (liver), and HK-2 (kidney) cultures connected through a series of semi-permeable membranes and a micro syringe pump (McKim et al., 2024) was employed to assess the pharmacokinetics of an API formulated in a SNEDDS. Preliminary cytotoxicity (MTT for intestine; ATP, Urea, LDH for liver; ATP, KIM-1, β-NAG for Kidney) and intestinal absorption studies were conducted using three SNEDDS variants (A, B, and C) at a final concentration of 0.4% v/v. Based on absorption performance and safety profiles, SNEDDS C was selected for full pharmacokinetic evaluation in the MPS. The API (200 μg/mL) was loaded in SNEDDS C in buffer and applied to the apical surface of the intestinal tissue, and media samples were collected from all organ compartments over 72 hours. API concentrations were quantified via liquid chromatography tandem mass spectrometry (LC-MS/MS).
Results:
Minimal to no cytotoxicity was observed in response to 24-hour exposure to the SNEDDS, whether delivered alone or loaded with the API (100, 10, and 1 μg/mL for the intestine mimicking oral exposure; 20, 2, and 0.2 ng/mL for liver and kidney mimicking predicted in vivo Cmax). When compared to the API delivered in buffer, two of the three SNEDDS facilitated slightly increased intestinal absorption of the higher doses of the API (100 and 10 μg/mL) over the 24-hour exposure period, with permeability coefficient equal to 1.50 ± 0.03 x10-6 cm/s, 1.68 ± 0.05 x10-6 cm/s and 1.69 ± 0.04 x10-6 cm/s for API alone, API in SNEDDS B, and API in SNEDDS C, respectively. In the MPS platform, the candidate SNEDDS, SNEDDS C, permitted sustained absorption of the API through the intestinal culture, which was subsequently distributed throughout the liver and kidney compartments.
Conclusions:
This study demonstrates the value of MPS platforms for evaluating formulation-dependent pharmacokinetics in a human-relevant, interconnected organ system. While SNEDDS C modestly improved intestinal absorption, it did not significantly alter downstream pharmacokinetics, supporting its role as a protective oral delivery vehicle. Importantly, the findings underscore the MPS platform’s potential as a translational tool for formulation screening, mechanistic ADME analysis, and physiologically based pharmacokinetic (PBPK) modeling, bridging the gap between in vitro and in vivo pharmacokinetics.