DDT-IST-000034 Liver acinus microphysiological systems (LAMPS) for determining drug candidate dosing in clinical trials of liver disease.

About This Grant

Project Summary Liver disease can significantly affect the bioavailability of drugs due to altered hepatic metabolism and transporter activity. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the United States and affects nearly 30% of the global population. Significant alterations in drug metabolizing enzymes have been observed in MASLD patients with both increased and decreased activity being reported which affect the clearance of drugs potentially resulting in adverse drug reactions or apparent inefficacy. Current approaches used to estimate dosing in clinical trials that are based on healthy liver function are inadequate for drugs in development for patients with liver disease. Thus, there is an unmet need in understanding how to effectively translate safety and pharmacokinetic (PK) data from healthy volunteers to a patient population with liver disease. Our human liver acinus Microphysiological systems (LAMPS) platform has been optimized to maximally recapitulate liver structure and function to address the complexity of studying absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox), in both healthy and diseased liver states. One of the objectives of our Translational Center for microphysiological systems (TraCe) is to qualify the LAMPS platform as a drug development tool (DDT) to establish the hepatic clearance of drug candidates in patients with MASLD and assist in the determination of drug candidate dosing in clinical trials when patients with MASLD are included. Our letter of intent for this context of use was determined to be reviewable by the Innovative Science and Technology Approaches for New Drugs program. In this proposal we are addressing two gaps that need to be filled for advancing to the next step towards qualification: 1) expand the number and range of reference drugs to validate the DDT for determining changes in hepatic clearance and the need for dose adjustment in patients with hepatic impairment; and 2) establish the concordance between the LAMPS disease phenotypes and clinical stages of hepatic disease to better define which patient population will benefit from the predicted dose adjustments.