Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling
Abstract Introduction Icotrokinra (formerly JNJ-77242113 or PN-21235) is a targeted oral peptide that selectively inhibits interleukin-23 receptor signaling. The studies described here assessed its absorption, distribution, metabolism, and excretion (ADME), and potential for drug–drug interactions (...
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Adis, Springer Healthcare
2025-07-01
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| Series: | Dermatology and Therapy |
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| Online Access: | https://doi.org/10.1007/s13555-025-01454-7 |
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| author | Beverly Knight Brinda Tammara Nishit B. Modi Shannon Dallas Saro Mardirosian Jianyao Wang Aline Laenen Laurent Leclercq Karen DiLoreto Lieve Adriaenssen Darren Moss David Polidori Siladitya Ray Chaudhuri Seonghee Park Carlo Sensenhauser Anthony Ndifor Siddharth Sukumaran Tristan Baguet Yifan Shi Shefali Patel Brian Geist Anne Fourie Raymond Patch Chengzao Sun Stephanie A. Barros Sandeep Somani Mario Monshouwer |
| author_facet | Beverly Knight Brinda Tammara Nishit B. Modi Shannon Dallas Saro Mardirosian Jianyao Wang Aline Laenen Laurent Leclercq Karen DiLoreto Lieve Adriaenssen Darren Moss David Polidori Siladitya Ray Chaudhuri Seonghee Park Carlo Sensenhauser Anthony Ndifor Siddharth Sukumaran Tristan Baguet Yifan Shi Shefali Patel Brian Geist Anne Fourie Raymond Patch Chengzao Sun Stephanie A. Barros Sandeep Somani Mario Monshouwer |
| author_sort | Beverly Knight |
| collection | DOAJ |
| description | Abstract Introduction Icotrokinra (formerly JNJ-77242113 or PN-21235) is a targeted oral peptide that selectively inhibits interleukin-23 receptor signaling. The studies described here assessed its absorption, distribution, metabolism, and excretion (ADME), and potential for drug–drug interactions (DDI). Methods In vitro assays evaluated permeability, plasma protein binding, blood-to-plasma partitioning, metabolic stability, and interactions with drug transporters and metabolic enzymes. The nonclinical pharmacokinetic properties of icotrokinra were studied in vivo in rats and monkeys. Phase 1 studies evaluated the pharmacokinetic profile, metabolic profile and excretion in healthy volunteers. Results Icotrokinra demonstrated oral bioavailability of 0.1–0.3% in animals, with evidence of systemic pharmacodynamic activity, without the use of an absorption enhancer. The compound was stable across species in plasma, gastrointestinal matrices, and hepatocytes. Protein binding was low across species (~ 50% in human plasma), and icotrokinra distributed freely to tissues, including skin, joints, and gastrointestinal tissues. Following oral dosing in both rats and monkeys, fecal excretion of unabsorbed drug was the primary elimination route, and metabolite levels were low (each < 2% of dose) in plasma and excreta, with unchanged icotrokinra being the main circulating component. Icotrokinra was neither a substrate nor an inhibitor of prototypical drug transporters or cytochrome P450 enzymes. Icotrokinra exhibited dose-proportional pharmacokinetics from 25 mg to 1000 mg in a first-in-human study, and no serious adverse events were identified following single and multiple dose administrations. Unchanged icotrokinra was the only drug-related component in human plasma. Conclusions Icotrokinra exhibited high stability and an ADME profile consistent with that of a small peptide, with no risk of DDI identified on the basis of in vitro studies. Clinical data demonstrated linear pharmacokinetics and no major metabolites. Trial Registration Number ClinicalTrials.gov, NCT04621630. Euclinicaltrials.eu, EUCT: 2023-504720-26-00. A Graphical Abstract is available for this article. Graphical abstract |
| format | Article |
| id | doaj-art-3b8f0c56b27f414da09ce323fea02c3a |
| institution | Kabale University |
| issn | 2193-8210 2190-9172 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Adis, Springer Healthcare |
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| series | Dermatology and Therapy |
| spelling | doaj-art-3b8f0c56b27f414da09ce323fea02c3a2025-08-20T04:01:43ZengAdis, Springer HealthcareDermatology and Therapy2193-82102190-91722025-07-011592495252010.1007/s13555-025-01454-7Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits SignalingBeverly Knight0Brinda Tammara1Nishit B. Modi2Shannon Dallas3Saro Mardirosian4Jianyao Wang5Aline Laenen6Laurent Leclercq7Karen DiLoreto8Lieve Adriaenssen9Darren Moss10David Polidori11Siladitya Ray Chaudhuri12Seonghee Park13Carlo Sensenhauser14Anthony Ndifor15Siddharth Sukumaran16Tristan Baguet17Yifan Shi18Shefali Patel19Brian Geist20Anne Fourie21Raymond Patch22Chengzao Sun23Stephanie A. Barros24Sandeep Somani25Mario Monshouwer26Johnson & JohnsonJohnson & JohnsonProtagonist Therapeutics, IncJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonJohnson & JohnsonAbstract Introduction Icotrokinra (formerly JNJ-77242113 or PN-21235) is a targeted oral peptide that selectively inhibits interleukin-23 receptor signaling. The studies described here assessed its absorption, distribution, metabolism, and excretion (ADME), and potential for drug–drug interactions (DDI). Methods In vitro assays evaluated permeability, plasma protein binding, blood-to-plasma partitioning, metabolic stability, and interactions with drug transporters and metabolic enzymes. The nonclinical pharmacokinetic properties of icotrokinra were studied in vivo in rats and monkeys. Phase 1 studies evaluated the pharmacokinetic profile, metabolic profile and excretion in healthy volunteers. Results Icotrokinra demonstrated oral bioavailability of 0.1–0.3% in animals, with evidence of systemic pharmacodynamic activity, without the use of an absorption enhancer. The compound was stable across species in plasma, gastrointestinal matrices, and hepatocytes. Protein binding was low across species (~ 50% in human plasma), and icotrokinra distributed freely to tissues, including skin, joints, and gastrointestinal tissues. Following oral dosing in both rats and monkeys, fecal excretion of unabsorbed drug was the primary elimination route, and metabolite levels were low (each < 2% of dose) in plasma and excreta, with unchanged icotrokinra being the main circulating component. Icotrokinra was neither a substrate nor an inhibitor of prototypical drug transporters or cytochrome P450 enzymes. Icotrokinra exhibited dose-proportional pharmacokinetics from 25 mg to 1000 mg in a first-in-human study, and no serious adverse events were identified following single and multiple dose administrations. Unchanged icotrokinra was the only drug-related component in human plasma. Conclusions Icotrokinra exhibited high stability and an ADME profile consistent with that of a small peptide, with no risk of DDI identified on the basis of in vitro studies. Clinical data demonstrated linear pharmacokinetics and no major metabolites. Trial Registration Number ClinicalTrials.gov, NCT04621630. Euclinicaltrials.eu, EUCT: 2023-504720-26-00. A Graphical Abstract is available for this article. Graphical abstracthttps://doi.org/10.1007/s13555-025-01454-7ADMEIL-23Targeted oral peptidePharmacokineticsPsoriasisIcotrokinra |
| spellingShingle | Beverly Knight Brinda Tammara Nishit B. Modi Shannon Dallas Saro Mardirosian Jianyao Wang Aline Laenen Laurent Leclercq Karen DiLoreto Lieve Adriaenssen Darren Moss David Polidori Siladitya Ray Chaudhuri Seonghee Park Carlo Sensenhauser Anthony Ndifor Siddharth Sukumaran Tristan Baguet Yifan Shi Shefali Patel Brian Geist Anne Fourie Raymond Patch Chengzao Sun Stephanie A. Barros Sandeep Somani Mario Monshouwer Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling Dermatology and Therapy ADME IL-23 Targeted oral peptide Pharmacokinetics Psoriasis Icotrokinra |
| title | Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling |
| title_full | Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling |
| title_fullStr | Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling |
| title_full_unstemmed | Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling |
| title_short | Translational Pharmacokinetics of Icotrokinra, a Targeted Oral Peptide that Selectively Blocks Interleukin-23 Receptor and Inhibits Signaling |
| title_sort | translational pharmacokinetics of icotrokinra a targeted oral peptide that selectively blocks interleukin 23 receptor and inhibits signaling |
| topic | ADME IL-23 Targeted oral peptide Pharmacokinetics Psoriasis Icotrokinra |
| url | https://doi.org/10.1007/s13555-025-01454-7 |
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