Pharmacokinetic and ADME challenges of GLP-1 based Multireceptor therapeutics: mechanisms, models and development strategies.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a paradigm shifting class of therapeutics for type 2 diabetes, obesity and associated cardiometabolic conditions. This review integrates a pharmacokinetic and ADME (absorption, distribution, metabolism, and excretion)-focused analysis of the challenges that have guided the design and delivery of GLP-1-based drugs, particularly multi-receptor analogues. we review the impact of receptor targeting, delayed gastric emptying, and transporter interactions on drug absorption, and the structural approaches, such as lipidation, PEGylation, and Fc-fusion, that prolong half-life and improve plasma stability. Formulation strategies targeting enhanced permeability and resistance against enzymatic degradation are discussed, including oral delivery systems, depot technologies and nano carrier systems. It covers biodistribution, plasma protein binding, and depot formation as determinants of tissue targeting and drug accumulation, and their significance for efficacy and long-term safety. Drug–drug interaction liability driven by prolonged half-lives and protein-binding characteristics is discussed within the context of regulatory requirements with respect to DMPK profiling, safety evaluation, and clinical trial conduct. Emerging new dual-agonists and combination therapy (eg Tirzepatide) are evaluated for their distinctive metabolic effects and regulatory implications. Finally, we provide context for the accelerated clinical and commercial ascent of GLP-1 analogues, including their continually widening therapeutic use, including in CNS and addiction research, and the regulatory templates that enable rapid development. Collectively, these findings emphasize the importance of integrated DMPK strategies to help define the next generations of GLP-1-based therapeutics across a spectrum of disease states.