Decoding DMPK Profiles of 37 FDA-Approved Peptides: Insights and Radiolabeling Considerations

Peptides are typically composed of 10 to 40 amino acids, with a molecular weight generally less than 10 kDa. Due to their molecular weight falling between small molecules and biological macromolecules, peptides exhibit characteristics such as high selectivity, high activity, low concentration, and low toxicity. In recent years, with the approval of several blockbuster drugs like Dulaglutide, Semaglutide, and Tirzepatide, peptide drugs have become one of the hottest areas in global pharmaceutical research and development. This blog summarizes the DMPK study profiles of 37 peptide drugs approved by the FDA from 2011 to 2023, along with considerations for radiolabeled ADME studies.

Utilization of radioisotopes in 37 marketed peptide drugs

Among the 37 peptide drugs on the market, 10 did not use radiolabeling technique, and 21 of the 27 drugs that were 14C radiolabeled, or 3H radiolabeled in early stage and 14C labeled in late stage, suggesting that 14C is a suitable radioisotope for peptide drugs. 14C labeling has advantages over other radioisotopes: using 3H may result in the loss of 3H from the molecule due to hydrogen-tritium exchange; using 125I may alter the structure and composition of the molecule and its ADME properties, especially for small molecular peptides.

Figure 1. 37 marketed peptide drugs and their radiolabeled isotopes

Classification of peptides and DMPK profiles of FDA-approved peptide drugs

Peptide drugs can be classified into three types based on structural differences:

• Linear peptides composed solely of natural amino acids (TPepA);

• Linear peptides containing unnatural amino acids and/or organic compounds with lipophilic side chains (TPepB);

• Cyclic peptides (TPepC).

All 37 peptide drugs underwent in vitro metabolism studies in multiple biological matrices, with liver-related matrices being the most commonly used for studying TPepB and TPepC peptide drugs.

Among these drugs, 73% (mainly TPepB and TPepC) conducted DMPK studies in animals and/or humans through radiolabeling technology. Nine drugs (Boceprevir, Telaprevir, Ombitasvir, Paritaprevir, Grazoprevir, Voxilaprevir, Difelikefalin, Odevixibat, and Trofinetide) have structures similar to small molecules and contain unnatural amino acids (TPepB), all of which performed human radiolabeled mass balance studies.

Industry recommendations for in vivo DMPK studies of peptide drugs

Currently, there are no specific regulatory guidelines for DMPK studies of peptide drugs. Based on the industry development and regulatory agency requirements, the white paper^[1] provides a decision tree for whether radiolabeled ADME experiments are needed for peptide drugs.

For peptides containing only natural amino acids (TPepA), in vitro metabolite identification and in vivo metabolism/excretion studies are not required, following ICH-S6(R1) for regulatory filing. For TPepB and TPepC peptide drugs, the following considerations should be taken into account:

• If the unnatural amino acids or organic moieties in the peptide drug have been used in approved drugs and shown to be safe in humans, radiolabeled in vivo PK studies may not be necessary, but metabolic studies are still recommended to evaluate potential active metabolites.

• If the peptide drug contains novel unnatural amino acids, it is generally recommended to conduct radiolabeled in vivo PK studies of the new moieties to characterize their metabolism and elimination pathways.

• If sufficient in vitro and/or in vivo ADME data or literature is provided to demonstrate the safety of the novel unnatural amino acids or organic moieties, radiolabeled metabolism and excretion studies may not be required.

Figure 2. Industry recommendations for ADME studies of therapeutic peptides. Adapted from reference ^[1]

Final thoughts

Radiolabeling technology provides a powerful tool for DMPK studies of peptide drugs, characterizing their metabolism and elimination patterns. WuXi AppTec DMPK has technical platforms for synthesizing radiolabeled compounds, mass balance, tissue distribution, and metabolite profiling and identification. With over a decade of experience in radioactive project research and hundreds of radiolabeled compound submissions to the NMPA and the FDA, we assist global clients in rapidly advancing the development process of peptide drugs.

Figure 3. Peptide platform of WuXi AppTec DMPK

Committed to accelerating drug discovery and development, we offer a full range of discovery screening, preclinical development, and clinical drug metabolism and pharmacokinetic (DMPK) platforms and services. With research facilities in the United States (New Jersey) and China (Shanghai, Suzhou, Nanjing, and Nantong), 1,000+ scientists, and over fifteen years of experience in Investigational New Drug (IND) application, our DMPK team at WuXi AppTec are serving 1,600+ global clients, and have successfully supported 1,500+ IND applications.  

Talk to a WuXi AppTec expert today to get the support you need to achieve your drug development goals.

Authors: Lian Guo, Jia Xue, Lingling Zhang