PT  - JOURNAL ARTICLE
AU  - Minxia Michelle He
AU  - Sean Xiaochun Zhu
AU  - Joe R Cannon
AU  - Jesper Kammersgaard Christensen
AU  - Ruchia Duggal
AU  - Mithat Gunduz
AU  - Constanze Hilgendorf
AU  - Adam Hughes
AU  - Ivy Kekessie
AU  - Maximilian Kullmann
AU  - Dennis Leung
AU  - Carsten Terjung
AU  - Kai Wang
AU  - Frank Wesche
TI  - Metabolism and excretion of therapeutic peptides: current industry practices, perspectives, and recommendations
AID  - 10.1124/dmd.123.001437
DP  - 2023 Jan 01
TA  - Drug Metabolism and Disposition
PG  - DMD-AR-2023-001437
4099  - http://dmd.aspetjournals.org/content/early/2023/08/17/dmd.123.001437.short
4100  - http://dmd.aspetjournals.org/content/early/2023/08/17/dmd.123.001437.full
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.