Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice
Introduction: Fusion of the fragment crystallizable (Fc) to protein therapeutics is commonly used to extend the circulation time by enhancing neonatal Fc-receptor (FcRn)-mediated endosomal recycling and slowing renal clearance. This study applied kinetic modeling to gain insights into the cellular p...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1352842/full |
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| author | Heechun Kwak Heechun Kwak Min-Soo Kim Suyong Kim Jiyoung Kim Yasunori Aoki Yasunori Aoki Suk-Jae Chung Hyun-Ja Nam Wooin Lee |
| author_facet | Heechun Kwak Heechun Kwak Min-Soo Kim Suyong Kim Jiyoung Kim Yasunori Aoki Yasunori Aoki Suk-Jae Chung Hyun-Ja Nam Wooin Lee |
| author_sort | Heechun Kwak |
| collection | DOAJ |
| description | Introduction: Fusion of the fragment crystallizable (Fc) to protein therapeutics is commonly used to extend the circulation time by enhancing neonatal Fc-receptor (FcRn)-mediated endosomal recycling and slowing renal clearance. This study applied kinetic modeling to gain insights into the cellular processing contributing to the observed pharmacokinetic (PK) differences between the novel recombinant ADAMTS13 fragment (MDTCS) and its Fc-fusion protein (MDTCS-Fc).Methods: For MDTCS and MDTCS-Fc, their plasma PK profiles were obtained at two dose levels following intravenous administration of the respective proteins to mice. The plasma PK profiles of MDTCS were fitted to a kinetic model with three unknown protein-dependent parameters representing the fraction recycled (FR) and the rate constants for endocytosis (kup, for the uptake into the endosomes) and for the transfer from the plasma to the interstitial fluid (kpi). For MDTCS-Fc, the model was modified to include an additional parameter for binding to FcRn. Parameter optimization was done using the Cluster Gauss-Newton Method (CGNM), an algorithm that identifies multiple sets of approximate solutions (“accepted” parameter sets) to nonlinear least-squares problems.Results: As expected, the kinetic modeling results yielded the FR of MDTCS-Fc to be 2.8-fold greater than that of MDTCS (0.8497 and 0.3061, respectively). In addition, MDTCS-Fc was predicted to undergo endocytosis (the uptake into the endosomes) at a slower rate than MDTCS. Sensitivity analyses identified the association rate constant (kon) between MDTCS-Fc and FcRn as a potentially important factor influencing the plasma half-life in vivo.Discussion: Our analyses suggested that Fc fusion to MDTCS leads to changes in not only the FR but also the uptake into the endosomes, impacting the systemic plasma PK profiles. These findings may be used to develop recombinant protein therapeutics with extended circulation time. |
| first_indexed | 2024-04-24T19:47:17Z |
| format | Article |
| id | doaj.art-533464e8e3404804a59918ca828f80c3 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-24T19:47:17Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-533464e8e3404804a59918ca828f80c32024-03-25T04:58:42ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-03-011510.3389/fphar.2024.13528421352842Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in miceHeechun Kwak0Heechun Kwak1Min-Soo Kim2Suyong Kim3Jiyoung Kim4Yasunori Aoki5Yasunori Aoki6Suk-Jae Chung7Hyun-Ja Nam8Wooin Lee9College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of KoreaDiscovery Unit, Research and Early Development Department, GC Biopharma Corp, Yongin-si, Republic of KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of KoreaDiscovery Unit, Research and Early Development Department, GC Biopharma Corp, Yongin-si, Republic of KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of KoreaLaboratory of Quantitative System Pharmacokinetics/Pharmacodynamics, Josai International University, Tokyo, JapanDrug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of KoreaDiscovery Unit, Research and Early Development Department, GC Biopharma Corp, Yongin-si, Republic of KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of KoreaIntroduction: Fusion of the fragment crystallizable (Fc) to protein therapeutics is commonly used to extend the circulation time by enhancing neonatal Fc-receptor (FcRn)-mediated endosomal recycling and slowing renal clearance. This study applied kinetic modeling to gain insights into the cellular processing contributing to the observed pharmacokinetic (PK) differences between the novel recombinant ADAMTS13 fragment (MDTCS) and its Fc-fusion protein (MDTCS-Fc).Methods: For MDTCS and MDTCS-Fc, their plasma PK profiles were obtained at two dose levels following intravenous administration of the respective proteins to mice. The plasma PK profiles of MDTCS were fitted to a kinetic model with three unknown protein-dependent parameters representing the fraction recycled (FR) and the rate constants for endocytosis (kup, for the uptake into the endosomes) and for the transfer from the plasma to the interstitial fluid (kpi). For MDTCS-Fc, the model was modified to include an additional parameter for binding to FcRn. Parameter optimization was done using the Cluster Gauss-Newton Method (CGNM), an algorithm that identifies multiple sets of approximate solutions (“accepted” parameter sets) to nonlinear least-squares problems.Results: As expected, the kinetic modeling results yielded the FR of MDTCS-Fc to be 2.8-fold greater than that of MDTCS (0.8497 and 0.3061, respectively). In addition, MDTCS-Fc was predicted to undergo endocytosis (the uptake into the endosomes) at a slower rate than MDTCS. Sensitivity analyses identified the association rate constant (kon) between MDTCS-Fc and FcRn as a potentially important factor influencing the plasma half-life in vivo.Discussion: Our analyses suggested that Fc fusion to MDTCS leads to changes in not only the FR but also the uptake into the endosomes, impacting the systemic plasma PK profiles. These findings may be used to develop recombinant protein therapeutics with extended circulation time.https://www.frontiersin.org/articles/10.3389/fphar.2024.1352842/fullADAMTS13kinetic modelingpharmacokineticsFc-fusionrecombinant proteins |
| spellingShingle | Heechun Kwak Heechun Kwak Min-Soo Kim Suyong Kim Jiyoung Kim Yasunori Aoki Yasunori Aoki Suk-Jae Chung Hyun-Ja Nam Wooin Lee Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice Frontiers in Pharmacology ADAMTS13 kinetic modeling pharmacokinetics Fc-fusion recombinant proteins |
| title | Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice |
| title_full | Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice |
| title_fullStr | Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice |
| title_full_unstemmed | Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice |
| title_short | Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice |
| title_sort | kinetic modeling of the plasma pharmacokinetic profiles of adamts13 fragment and its fc fusion counterpart in mice |
| topic | ADAMTS13 kinetic modeling pharmacokinetics Fc-fusion recombinant proteins |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1352842/full |
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