Clinical Significance of Drug–Drug Interaction Studies During Therapeutic Peptide Drug Development: Follow‐Up Investigation of Therapeutic Peptides Approved Between 2021 and 2024

ABSTRACT

The risk of clinically relevant drug–drug interactions (DDIs) for therapeutic peptides remains unclear, mandating a comprehensive analysis for this modality. In our prior study, we analyzed DDIs for 31 peptide drugs approved between January 2008 and August 2021. Here, we analyze DDI data for an additional nine peptide drugs (trofinetide, nirmatrelvir, danicopan, odevixibat, rezafungin, motixafortide, zilucoplan, vosoritide, and tirzepatide) approved from September 2021 to September 2024, focusing on in vitro and clinical DDI data for metabolism‐ and transporter‐based interactions. All nine peptides investigated CYP inhibition in human liver microsomes (HLMs), with low risk identified for larger peptides (> 2 kDa). Likewise, all nine peptides assessed CYP induction in human hepatocytes, with one peptide showing a risk in vitro (danicopan). Phenotyping investigations varied from standard studies (e.g., HLMs with selective CYP inhibitors) to submission packages without classical phenotyping studies. All nine peptides included information related to in vitro transporter properties, but the level of detail varied between submitted packages. Clinical studies investigating metabolism‐ or transporter‐mediated DDIs were performed for four peptides (all < 2 kDa). Area under the curve changes attributed to the peptide drug were < 2.3 fold. Our expanded dataset now includes 40 therapeutic peptides approved since 2008, providing a unique resource for drug developers. The findings reinforce our previous conclusions regarding the low likelihood of DDIs for larger peptides and a higher risk for smaller peptides with xenobiotic structural properties. This collective data will be invaluable in developing clear and meaningful DDI guidelines for therapeutic peptides.

Abbreviations

AUC

area under the curve

BCRP

breast cancer resistance protein

CYP

Cytochrome P450

DDI

drug–drug interaction

EMA

European Medicines Agency

FDA

US Food and Drug Administration

HLMs, human liver microsomes

MATE

multidrug and toxin extrusion

OATP

organic anion transporting polypeptides

P‐gp

P‐glycoprotein

PK

pharmacokinetics

UGT

uridine diphosphate‐glucuronosyltransferases

Summary.

• What is the current knowledge on the topic?

  • ○
    The potential for clinically relevant DDIs for therapeutic peptides is not yet well understood, and there are currently no detailed DDI guidelines for therapeutic peptides. This presents a challenge for drug developers to plan peptide DDI studies that are both feasible and meaningful.
• What question did this study address?

  • ○
    Peptides approved between 2021 and 2024 included substantial in vitro packages for all nine peptides, independent of the type of peptide. No clinical effects > 2.5 fold were observed due to the peptide drug in the performed clinical DDI studies. We build on our previous analysis of DDI studies available for approved drugs between 2008 and 2021 by assessing DDI studies performed for more recently approved peptides from 2021 to 2024.
• What does this study add to our knowledge?

  • ○
    This study provides a powerful resource for drug developers. As we have now in total assessed 40 therapeutic peptides approved from 2008 to 2024, we identify trends associated with the presence or absence of DDI risk among different types of peptide drugs. Namely, DDI is highest for low‐molecular‐weight peptides, especially those with significant non‐peptide structural motifs.
• How might this change clinical pharmacology or translational science?

  • ○
    By benchmarking the current DDI landscape of approved peptides, we present novel findings for assessing DDI risk guidance for this heterogeneous class of molecules that will be important for initiating discussions with regulatory authorities to establish meaningful DDI guidelines in the future.

1. Introduction

The absence of detailed drug–drug interaction (DDI) guidelines for therapeutic peptides makes it difficult to identify when and what types of DDI studies are most or least informative for this heterogeneous class of molecules. Our cross‐industry working group was formed under the sponsorship of the European Federation of Pharmaceutical Industries and Associations to investigate the landscape of peptide DDI activities across the industry. We previously compiled a database containing DDI data from submission packages for 31 peptide drugs approved between January 2008 and August 2021. Our findings were reported in a White Paper [1], where we describe diverse challenges arising from an absence of informative DDI guidance during peptide drug development. Among other observations, our analysis of submission packages from 2008 to 2021 suggests that DDI likelihood is low for larger peptides (> 2 kDa) and greater for low molecular weight peptides, especially those with significant non‐peptide structural motifs (e.g., nitrogen‐containing heterocycles, hydroxylated oxanes, and sulphoxides). In line with recommendations from the Editor‐in‐Chief of Clinical Pharmacology and Therapeutics [2], we stress that much more peptide DDI data from diverse molecules with different sizes, structures, and modes of action will be required to establish clear guidelines for peptide DDI studies that are both feasible and meaningful.

2. Methods

In the present study, we revisit the PepTherDia database [3] to identify nine additional peptide drugs that have been approved between September 2021 and September 2024 for further analysis. As with our previous study [1], inclusion/exclusion criteria for selecting peptides in our analysis are in line with D'Aloisio et al. [4], with the exception that we excluded diagnostic peptides and set a 40‐amino‐acid upper cutoff as per the FDA definition of a peptide. The reported pharmacokinetic interaction data focused on metabolism‐based and transporter‐based DDIs (excluding, e.g., pharmacodynamic interactions) for these recently approved peptides. The data were subsequently collected from FDA and EMA submission packages. Included information for analysis also encompassed peptide size, structure, administration route, and indication.

3. Results

According to the PepTherDia database, nine therapeutic peptide drugs were approved between September 2021 and September 2024: trofinetide (size = 0.32 kDa; structure = linear), nirmatrelvir (0.5 kDa; linear), danicopan (0.58 kDa; linear), odevixibat (0.74 kDa; linear), rezafungin (1.23 kDa; cyclic), motixafortide (2.16 kDa; cyclic), zilucoplan (3.56 kDa; cyclic), vosoritide (4.10 kDa; cyclic), and tirzepatide (4.81 kDa; linear). In Figure 1, we visualize how these nine new peptides compare in size/type/administration route to the 31 peptides we previously analyzed. Next, we analyzed DDI studies performed for each of the newly approved peptides (Table 1).

FIGURE 1.

Properties of therapeutic peptides approved between January 2008 and September 2024. The previous set includes peptides approved between January 2008 and August 2021 that we have previously analyzed for DDI risk [1]. The new set includes nine therapeutic peptides approved between September 2021 and September 2024. Graphs depict the numbers of peptides based on (A) size, (B) structure, and (C) route of administration.

TABLE 1.

Peptide drugs approved September 2021 to September 2024.

Name (kDa) structure route of administration	Indication (first approval year)	Available in vitro enzyme inhibition data	Available in vitro enzyme induction data	Available in vitro transporter inhibition/substrate data	Available enzyme phenotyping data	Available clinical DDI data a	References
Odevixibat (0.74) Linear Oral	Treatment of pruritus in progressive familial intrahepatic cholestasis (2021)	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 investigated in recombinant CYP enzymes, HLMs, and human hepatocytes No clinically relevant inhibition, except risk of intestinal CYP3A4 inhibition	CYP1A2, 2B6, and 3A4 investigated in human hepatocytes. Not an inducer at clinically relevant concentrations	P‐gp substrate. Not a BCRP substrate. Not an inhibitor of P‐gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2‐K at clinically relevant concentrations	Metabolized via mono‐hydroxylation in human hepatocytes. Information on involved enzyme is not identified	Midazolam (CYP3A4 probe) AUC decreased by approximately 30% Odevixibat AUC increased by approximately 65%, following co‐administration with itraconazole (P‐gp and CYP3A4 inhibitor)	[5, 6]
Vosoritide (4.10) Cyclic sc	Achondroplasia in children from 5 years (2021)	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 investigated in HLMs. Not an inhibitor at clinically relevant concentrations	CYP1A2, 2B6, and 3A4/5 investigated in human hepatocytes. Not an inducer at clinically relevant concentrations	Potential for interactions with OAT1, OAT3, OCT 1, OCT 2, MATE 1, MATE2‐K, BCRP, Pg‐P, BSEP, OATP1B1, and OATP1B3 is low at clinically relevant concentrations b	In vitro microsome stability study showed that CYP enzymes were not involved in the elimination	No clinical DDI studies identified	[7, 8, 9, 10]
Tirzepatide (4.81) Linear sc	Type 2 diabetes (2022) Obesity (2023)	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 investigated in HLMs. Not an inhibitor at clinically relevant concentrations	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5 investigated in human hepatocytes. Not an inducer	Not an inhibitor of P‐gp, BCRP, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2‐K at clinically relevant concentrations. Slight inhibition of OATP1B1 and OATP1B3 observed in the presence of 0.1% fatty acid‐free human serum albumin, inhibition markedly reduced in the presence of 4% fatty acid‐free human serum albumin (physiologic concentration). OATP inhibition concluded not to be clinically relevant	Observed metabolic pathways include proteolytic cleavage of the peptide backbone, β‐oxidation of the C20 fatty acid, and amide hydrolysis in the linker region. Enzyme phenotyping data not identified	No clinical DDI studies identified	[11, 12]
Trofinetide (0.32) Linear Oral/Gastrostomy	Rett Syndrome (2023)	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 investigated in HLMs. No clinically relevant inhibition except potential intestinal CYP3A inhibition Inconclusive data on CYP2B6 TDI potential c UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B15, and 2B17 inhibition investigated. In vitro inhibition potential on UGT1A9, 2B7 and 2B15 observed	CYP1A2, 2B6 and 3A4 investigated in human hepatocytes. Not an inducer at clinically relevant concentrations	Not a substrate of P‐gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2‐K. Not an inhibitor of P‐gp, BCRP, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2‐K at clinically relevant concentrations. Inhibits OATP1B1 and OATP1B3 in vitro c	Not a CYP or UGT substrate based on investigations in HLMs and recombinant enzymes	No clinically DDI studies identified c	[13]
Rezafungin (1.23) Cyclic iv	Antifungal (2023)	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 investigated in recombinant human CYP isoenzymes and HLMs. Inhibitor of CYP2C8 and CYP3A4/5 at clinically relevant concentrations	CYP1A2, 2B6, and 3A4/3A5 investigated in human hepatocytes. Not and inducer at clinically relevant concentrations	Not a substrate of P‐gp, BCRP, OATP1B1, OATP1B3, MRP2, OCT1, OCTN1, and OCTN2 Not an inhibitor of BSEP, OATP1B1, OAT1/3, OCT1/2, and MATE2‐K. Inhibitor potential for Pg‐p, BCRP, OATP1B3, and MATE1 in vitro	No relevant contribution by CYPs as investigated in HLMs and human hepatocytes in vitro. Minimal biotransformation in vivo, mainly by hydrolysis	Minimal AUC increase (< 20%) of repaglinide (CYP2C8 and OATP probe) and rosuvastatin (BCRP and OATP probe), minimal AUC decrease (< 20%) of tacrolimus (CYP3A4, P‐gp). No effect on exposure of metformin (OCT, MATEs), pitavastatin (OATP), caffeine (CYP1A2), efavirenz (CYP2B6), midazolam (CYP3A4), digoxin (P‐gp), cyclosporine (CYP3A4, P‐gp), ibrutinib (CYP3A4, P‐gp), and venetoclax (CYP3A4, P‐gp)	[14]
Motixafortide (2.16) Cyclic sc	Hematopoietic stem cell mobilizer for multiple myeloma Approved in combination with filgrastim (2023)	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and CYP3A4 investigated in HLMs. Follow‐up studies for CYP2B6, 2C8, and 3A4 using human hepatocytes, but not an inhibitor at clinically relevant concentrations	CYP3A4, 1A2, and 2B6 investigated in human hepatocytes. Not an inducer at clinically relevant concentrations	No transporter substrate data identified. Not an inhibitor of P‐gp, BCRP, BSEP, MATE1, MATE2‐K, OATP1B1, OAT1B3, OAT1, OAT3, OCT1, OCT2, PEPT1, and PEPT2 at clinically relevant concentrations	Identified metabolites were hydrolysis and/or disulfide bond cleavage products	No clinically DDI studies identified	[15, 16]
Nirmatrelvir (0.50) Linear Oral (co‐packed with ritonavir)	Mild‐to‐moderate COVID‐19 (2023)	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A/5 investigated in HLMs. Reversible and time‐dependent inhibitor of CYP3A4	CYP1A2, 2B6, 2C9, 2C19 and 3A4 investigated in human hepatocytes (activity). Not an inducer at clinically relevant concentrations	P‐gp substrate. Not a substrate of BCRP, MATE1/2 K, NTCP, OAT1/2/3, OCT1/2, PEPT1, OATP1B1/1B3/2B1/4C1. P‐gp and OATP1B1 inhibitor. Not an inhibitor of BCRP, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2‐K	Primarily metabolized by CYP3A4 in HLMs. When dosed with ritonavir (potent CYP3A4 inhibitor), metabolic clearance is minimal resulting in increased nirmatrelvir plasma concentrations	All clinical DDI studies performed in combination with ritonavir d (potent CYP3A4 inhibitor) Midazolam (CYP3A4 substrate) AUC increased 14.3‐fold Dabigatran (P‐gp substrate) AUC increased 1.94‐fold Nirmatrelvir AUC decreased 0.45‐fold with carbamazepine (CYP3A4 inducer) and increased 1.39‐fold with itraconazole (P‐gp and CYP3A4 inhibitor)	[17, 18]
Zilucoplan (3.56) Cyclic sc	Myasthenia gravis (Compliment inhibitor) (2023)	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and 4F investigated in HLMs e UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, and 2B15 investigated in recombinant enzymes. Not an inhibitor at clinically relevant concentrations	CYP3A4, 1A2, and 2B6 investigated in human hepatocytes. Not an Inducer. mRNA downregulation observed	Not a substrate of Pgp, BCRP, OATP1B1, and OATP1B3. Not an inhibitor e of P‐gp, BCRP, MATE1, MATE2‐K, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 and OCT2 at clinically relevant concentrations	Not a CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A substrate based on investigations in HLMs and recombinant enzymes Peptide hydrolysis identified as the predominant metabolic pathway in human hepatocytes. Two major metabolites in human plasma include RA102758 and RA103488. RA102758 formed by protease mediated degradation. Active metabolite RA103488 is formed mainly due to CYP4F2. Minor contributions by CYP4A11, CYP4F3A, and CYP4F3B	No clinical DDI studies identified	[19]
Danicopan (0.58) Linear Oral	Add‐on therapy to ravulizumab or eculizumab for treatment of extravascular hemolysis in Paroxysmal nocturnal hemoglobinuria (2024)	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A, UGT1A1 and 2B7 investigated in HLMs. Not an inhibitor at clinically relevant concentrations.	CYP1A2, 2B6, 2C8, 2C9 and 3A4/3A5 investigated in human hepatocytes. Not an inducer of 1A2, 2B6 and 2C9. Potential to induce CYP3A4 and 2C8 in vitro	P‐gp substrate. Not a substrate of BCRP, OATP1B1/1B3, OAT1/3 and OCT2 Inhibitor of P‐gp, BCRP. Not an inhibitor of OATP1B1/1B3, MATE‐1/2‐K, OAT1/3, OCT2, BSEP, and MRP2 at clinically relevant concentrations.	Minimal contribution of CYP enzymes based on studies in HLMs and human hepatocytes Likely no relevant contribution of aldehyde oxidase 1 in vitro Amide hydrolysis identified as major pathway in human hepatocytes	Midazolam (CYP3A4 substrate) AUC increased 1.23‐fold Cyclosporine (CYP3A4 and P‐gp substrate) AUC increased 1.20‐fold Tacrolimus (CYP3A4 and P‐gp substrate) AUC increased 1.49‐fold Mycophenolate mofetil (UGT1A7 and UGT2B7 substrate) no relevant effect on exposure Fexofenadine (P‐gp substrate) AUC increased 1.62‐fold Rosuvastatin (BCRP substrate) AUC increased 2.25‐fold Warfarin (CYP2C9 substrate): no relevant effect on exposure Bupropion (CYP2B6 substrate) no relevant effect on exposure Ethinyl estradiol (EE) /norethindrone (NET) (oral contraceptives) EE AUC increased 1.24‐fold, no relevant effect on NET	[20]

^a Metabolism‐ and transporter‐based DDIs (excluding e.g., pharmacodynamic interactions).

^b Conflicting data between FDA review document and drug label as to whether in vitro studies were performed.

^c Issued post‐marketing requirements: Evaluate time‐dependent inhibition of CYP2B6 and clinical DDI study evaluating effect of trofinetide on OATP1B1/1B3.

^d No additional effect of nirmatrelvir on midazolam PK or dabigatran PK beyond that caused by ritonavir alone in either study.

^e Metabolite RA102758 also investigated.

All peptides had been investigated for cytochrome P450 (CYP) inhibition using a standard CYP panel (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A) in human liver microsomes (HLMs), while some (e.g., odevixibat, rezafungin, motixafortide) submission packages included additional studies (e.g., hepatocytes or recombinant enzyme investigations). There were potential risks of relevant CYP inhibition identified for four out of the five smallest peptides (i.e., trofinetide, nirmatrelvir, odevixibat, and rezafungin; all < 2 kDa in size), while danicopan (0.6 kDa) and the four largest peptides (motixafortide, zilucoplan, vosoritide, and tirzepatide; >2 kDa) did not identify any CYP inhibition risk at clinically relevant concentrations. In addition, three peptides assessed the risk of UGT inhibition (trofinetide, danicopan, and zilucoplan) where trofinetide identified a potential risk of UGT1A9, 2B7, and 2B15 inhibition in vitro. RA102758, a pharmacologically active metabolite of zilucoplan, was also included in the overall in vitro inhibition assessment.

All peptides had been investigated for CYP induction, including standard CYP panel (CYP1A2, CYP2B6, and CYP3A4) in human hepatocytes, but the majority (with the exception of danicopan) were found not to be inducers of the investigated CYPs at clinically relevant concentrations.

In line with findings from our previously published industry survey [1], there was a major discrepancy in terms of phenotyping studies performed for the nine new peptides. Phenotyping investigations varied from standard studies (e.g., HLMs in the presence of selective CYP inhibitors) to submission packages without classical phenotyping studies (e.g., motixafortide, odevixibat, and tirzepatide).

Similar to observations made during our previously published industry survey [1], drug transporter studies (substrate and inhibition properties) varied from peptide to peptide. Potential clinically relevant risks were identified for all of the smaller peptides (< 2 kDa): trofinetide inhibited organic anion transporting polypeptides (OATP) 1B1 and 1B3 in vitro; nirmatrelvir inhibited P‐glycoprotein (P‐gp) and OATP1B1 in vitro; rezafungin showed in vitro inhibitor potential against P‐gp, breast cancer resistance protein (BCRP), OATP1B3, and multidrug and toxin extrusion (MATE) 1; danicopan inhibited P‐gp and BCRP in vitro; while danicopan, odevixibat, and nirmatrelvir were also identified as P‐gp substrates in vitro.

Clinical studies investigating metabolism‐ or transporter‐mediated DDIs were performed for four small peptides (nirmatrelvir, danicopan, odevixibat, and rezafungin; all < 2 kDa). However, results attributed to the peptide drug showed only weak–moderate or minimal changes in PK parameters. Notably, nirmatrelvir is co‐administered with the small molecule drug ritonavir and together showed 1.94‐fold and 14.3‐fold area under the curve (AUC) increases for P‐gp substrate dabigatran and CYP3A4 substrate midazolam, respectively. However, it was concluded that no additional effect of nirmatrelvir was identified beyond that caused by ritonavir alone. The clinical significance of the in vitro OATP1B1 inhibition flag for nirmatrelvir has not been explored, likely due to the R value slightly exceeding 1.1 (ICH M12). Among the other peptides (which are administered alone), the most potent perpetrator effects were a 1.62‐fold AUC increase of fexofenadine (P‐gp substrate) and a 2.25‐fold AUC increase of rosuvastatin (BCRP substrate) by danicopan. The strongest victim DDI effect was an increase of approximately 65% in odevixibat AUC following co‐administration with itraconazole (P‐gp and CYP3A4 inhibitor), but the observed change was not considered clinically relevant, and no dose adjustments were recommended. The effect of rezafungin was assessed in the clinical setting with > 10 probe substrates. Based on these results, the clinical DDI risk for rezafungin was concluded to be low compared to other FDA‐approved antifungal drug products currently indicated to treat candidemia and invasive candidiasis (i.e., azole and echinocandin).

4. Discussion

Building on our published study [1], we have now in total assessed 40 therapeutic peptides approved between January 2008 and September 2024. By collecting and interpreting available in vitro and clinical DDI data for these approved peptide‐based therapies, we provide a unique and powerful resource for drug developers, especially due to the absence of clear guidelines from regulators. Overall, DDI results for the nine newly approved therapeutic peptides (September 2021–September 2024) were largely consistent with earlier observations from the 2008 to 2021 approved peptide dataset. Most notably, analyses here are consistent with our published observation that DDI likelihood is low for larger peptides (> 2 kDa), while smaller peptides, especially those with xenobiotic structural properties (e.g., danicopan), pose a higher DDI risk. Interestingly, high‐molecular‐weight peptides such as vosoritide and tirzepatide (both > 4 kDa) continue to be investigated for CYP in vitro inhibition potential, despite no evidence that large molecules like these would have such effects. Overall, this new information adds confidence to our previous conclusions and should serve as a starting point for drug developers to more strategically assess DDI risk profiles when planning DDI studies for their molecules and to better inform discussions with regulatory authorities.

We identified a few interesting cases of potential clinical relevance during our analysis of DDI data for these nine new therapeutic peptides, most notably for the three smallest peptides: trofinetide, nirmatrelvir, and danicopan. For example, although in vitro studies showed that trofinetide inhibits OATP1B1 and 1B3, no clinical DDI studies investigating this potential risk were performed at submission, and a post‐marketing requirement was issued to investigate this in the clinic. Secondly, a comprehensive clinical DDI program was conducted for danicopan. Danicopan was identified as an inhibitor of P‐gp and BCRP in vitro, and clinical follow‐up studies identified this small peptide also as a clinically relevant inhibitor of P‐gp (fexofenadine AUC increased 1.62‐fold) and BCRP (rosuvastatin AUC increased 2.25‐fold). In addition, clinical DDI studies to assess the enzyme (CYP‐ and UGT) perpetrator profiles were performed, despite in vitro IC₅₀ values of low clinical relevance. Clinical DDI studies with nirmatrelvir on metabolism or transporters revealed that nirmatrelvir caused minimal changes in PK parameters, with the primary effects attributed to ritonavir (a potent CYP3A and P‐gp inhibitor). Nirmatrelvir did not have an effect beyond that of ritonavir. The main safety concern with this drug combination involves the risk of serious adverse reactions, including life‐threatening or fatal events, because of DDIs related to ritonavir. This DDI risk is clearly outlined in the labeling for nirmatrelvir/ritonavir, including a Boxed Warning alerting prescribers to this significant risk.

We note that classical in vitro systems designed to assess DDIs for small molecules were used for all peptides we have evaluated to date, with no submission packages including data from complex in vitro models (e.g., Hepatopac or liver‐on‐a‐chip) that have been shown to provide more clinically relevant results for peptide DDI studies potentially [21]. Additionally, ongoing research into humanized mice may offer an interesting alternative to cell‐based in vitro models, as testing peptides in such a model should better reflect complex physiological interactions. Moving forward, it will be interesting to see if more physiologically relevant models for studying peptide DDIs become more explored by the pharmaceutical industry for this modality.

We plan to continue benchmarking the evolving landscape of peptide DDI activities in the coming years. To utilize the most information possible for our analyses, we strongly encourage our colleagues to actively publish positive and negative results from peptide DDI studies and begin exploring more physiologically relevant models. As many drug programs do not reach final submission, it is important to emphasize that it is still valuable to publish DDI studies performed during drug development for molecules that fail to reach drug approval. Together, these data will be invaluable for us to gain a deeper scientific understanding of where real clinical DDI risk lies for therapeutic peptides.

Author Contributions

Wrote the manuscript: C.S., U.A., C.H., H.S., A.S., K.U., and K.W. Designed the research: C.S., U.A., C.H., H.S., A.S., K.U., and K.W. Performed the research: C.S., U.A., C.H., H.S., A.S., K.U., and K.W. Analyzed the data: C.S., U.A., C.H., H.S., A.S., K.U., and K.W.

Conflicts of Interest

C.S.: Employee and shareholder of Novo Nordisk. U.A.: Employee of the Gates Medical Research Institute. C.H.: Employee and shareholder of AstraZeneca. H.S.: Employee of Novartis Institutes for BioMedical Research and shareholder of Novartis. A.S.: Employee of Ferring Pharmaceuticals. K.U.: Employee of Roche. K.W.: Employee and shareholder of Johnson and Johnson Innovative Medicine.

Säll C., Argikar U., Hilgendorf C., et al., “Clinical Significance of Drug–Drug Interaction Studies During Therapeutic Peptide Drug Development: Follow‐Up Investigation of Therapeutic Peptides Approved Between 2021 and 2024,” Clinical and Translational Science 18, no. 7 (2025): e70288, 10.1111/cts.70288.