RT Journal Article
SR Electronic
T1 Metabolism and excretion of therapeutic peptides: current industry practices, perspectives, and recommendations
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2023-001437
DO 10.1124/dmd.123.001437
A1 Minxia Michelle He
A1 Sean Xiaochun Zhu
A1 Joe R Cannon
A1 Jesper Kammersgaard Christensen
A1 Ruchia Duggal
A1 Mithat Gunduz
A1 Constanze Hilgendorf
A1 Adam Hughes
A1 Ivy Kekessie
A1 Maximilian Kullmann
A1 Dennis Leung
A1 Carsten Terjung
A1 Kai Wang
A1 Frank Wesche
YR 2023
UL http://dmd.aspetjournals.org/content/early/2023/08/17/dmd.123.001437.abstract
AB Therapeutic peptides (TPeps) have expanded from the initial endogenous peptides to complex modified peptides through medicinal chemistry efforts for almost a century. Different from small molecules and large proteins, the diverse submodalities of TPeps have distinct structures and carry different absorption, distribution, metabolism, and excretion (ADME) properties. There is no distinct regulatory guidance for the industry on conducting ADME studies (what, how, and when) for TPeps. Therefore, the Peptide ADME Working Group sponsored by the Translational and ADME Sciences Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) was formed with the goal to develop a white paper focusing on metabolism and excretion studies to support discovery and development of TPeps. In this paper, the key learnings from an IQ industry survey and FDA/EMA submission documents of TPeps approved between 2011 and 2022 are outlined in detail. In addition, a comprehensive assessment of in vitro and in vivo metabolism and excretion studies, mitigation strategies for TPep metabolism, analytical tools to conduct studies, regulatory status, and MIST considerations are provided. Finally, an industry recommendation on conducting metabolism and excretion studies is proposed for regulatory filing of TPeps. Significance Statement This white paper presents current industry practices for metabolism and excretion studies of therapeutic peptides based on an industry survey, regulatory submission documents, and expert opinions from the participants in the IQ peptide ADME working group. The group also provides recommendations on the MIST consideration and metabolism and excretion studies for regulatory filing of therapeutic peptides.