Target-mediated drug disposition

Target-mediated drug disposition (TMDD) is the process in which a drug binds with high affinity to its pharmacological target (for example, a receptor) to such an extent that this affects its pharmacokinetic characteristics. Various drug classes can exhibit TMDD, most often these are large compounds (biologics such as antibodies, cytokines or growth factors^[1]) but also smaller compounds can exhibit TMDD (such as warfarin and CHK-336).^[2] A typical TMDD pattern of antibodies displays non-linear clearance and can be seen at concentration ranges that are usually defined as 'mid-to-low'. In this concentration range, the target is partly saturated.^[3]^[4]

References

^ Berends, Sophie E.; van Steeg, Tamara J.; Ahsman, Maurice J.; Singh, Sharat; Brandse, Johannan F.; D’Haens, Geert R. A. M.; Mathôt, Ron A. A. (December 2019). "Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients". Journal of Pharmacokinetics and Pharmacodynamics. 46 (6): 543–551. doi:10.1007/s10928-019-09652-5. ISSN 1567-567X. PMC 6868113. PMID 31489538.
^ Cox, Jennifer H.; Boily, Marc-Olivier; Caron, Alexandre; Sheng, Tao; Wu, Joyce; Ding, Jinyue; Gaudreault, Samuel; Chong, Oliver; Surendradoss, Jayakumar; Gomez, Robert; Lester, Jeffrey; Dumais, Valerie; Li, Xingsheng; Gumpena, Rajesh; Hall, Matthew D. (2025-04-07). "Characterization of CHK-336, A First-in-Class, Liver-Targeted, Small Molecule Lactate Dehydrogenase Inhibitor for Hyperoxaluria Treatment". Journal of the American Society of Nephrology. doi:10.1681/ASN.0000000690. ISSN 1046-6673.
^ Dua, P; Hawkins, E; van der Graaf, Ph (2015-04-10). "A Tutorial on Target-Mediated Drug Disposition (TMDD) Models: A Tutorial on Target-Mediated Drug Disposition (TMDD) Models". CPT: Pharmacometrics & Systems Pharmacology. 4 (6): 324–337. doi:10.1002/psp4.41. PMC 4505827. PMID 26225261.
^ An, Guohua (February 2020). "Concept of Pharmacologic Target-Mediated Drug Disposition in Large-Molecule and Small-Molecule Compounds". The Journal of Clinical Pharmacology. 60 (2): 149–163. doi:10.1002/jcph.1545. ISSN 0091-2700. PMC 7472685. PMID 31793004.

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[1] Berends, Sophie E.; van Steeg, Tamara J.; Ahsman, Maurice J.; Singh, Sharat; Brandse, Johannan F.; D’Haens, Geert R. A. M.; Mathôt, Ron A. A. (December 2019). "Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients". Journal of Pharmacokinetics and Pharmacodynamics. 46 (6): 543–551. doi:10.1007/s10928-019-09652-5. ISSN 1567-567X. PMC 6868113. PMID 31489538.

[:2-2] Cox, Jennifer H.; Boily, Marc-Olivier; Caron, Alexandre; Sheng, Tao; Wu, Joyce; Ding, Jinyue; Gaudreault, Samuel; Chong, Oliver; Surendradoss, Jayakumar; Gomez, Robert; Lester, Jeffrey; Dumais, Valerie; Li, Xingsheng; Gumpena, Rajesh; Hall, Matthew D. (2025-04-07). "Characterization of CHK-336, A First-in-Class, Liver-Targeted, Small Molecule Lactate Dehydrogenase Inhibitor for Hyperoxaluria Treatment". Journal of the American Society of Nephrology. doi:10.1681/ASN.0000000690. ISSN 1046-6673.

[3] Dua, P; Hawkins, E; van der Graaf, Ph (2015-04-10). "A Tutorial on Target-Mediated Drug Disposition (TMDD) Models: A Tutorial on Target-Mediated Drug Disposition (TMDD) Models". CPT: Pharmacometrics & Systems Pharmacology. 4 (6): 324–337. doi:10.1002/psp4.41. PMC 4505827. PMID 26225261.

[4] An, Guohua (February 2020). "Concept of Pharmacologic Target-Mediated Drug Disposition in Large-Molecule and Small-Molecule Compounds". The Journal of Clinical Pharmacology. 60 (2): 149–163. doi:10.1002/jcph.1545. ISSN 0091-2700. PMC 7472685. PMID 31793004.

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