Concept of Pharmacologic Target-Mediated Drug Disposition in Large-Molecule and Small-Molecule Compounds

Overview

Journal J Clin Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2019 Dec 4

PMID 31793004

Citations 31

Authors

Guohua An

Affiliations

Soon will be listed here.

Abstract

Target-mediated drug disposition (TMDD) is a term to describe a nonlinear pharmacokinetic (PK) phenomenon that is caused by high-affinity binding of a compound to its pharmacologic targets. As the interaction between a drug and its pharmacologic target belongs to the process of pharmacodynamics (PD), TMDD can be viewed as a consequence of "PD affecting PK." Although there are numerous TMDD-related articles in the literature, most of them focus on characterizing TMDD using various mathematical models, which may not be suitable for those readers who have little interest in mathematical modeling and only want to have an understanding of the basic concept. The goal of this review is to serve as a "primer" on TMDD. This review explains (1) how TMDD happens; (2) why large-molecule and small-molecule compounds exhibiting TMDD demonstrate substantially different nonlinear PK behaviors; (3) what nonlinear PK profiles look like in large-molecule and small-molecule compounds exhibiting TMDD, using pegfilgrastim, erythropoietin, ABT-384, and linagliptin as case examples; and (4) how to identify whether the nonlinear PK of a compound is because of TMDD.

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References

Smith D, van Waterschoot R, Parrott N, Olivares-Morales A, Lave T, Rowland M . Importance of target-mediated drug disposition for small molecules. Drug Discov Today. 2018; 23(12):2023-2030. DOI: 10.1016/j.drudis.2018.06.010. View

Francis R, Brown A, Kler L, Fasanella dAmore T, Nussberger J, Waeber B . Pharmacokinetics of the converting enzyme inhibitor cilazapril in normal volunteers and the relationship to enzyme inhibition: development of a mathematical model. J Cardiovasc Pharmacol. 1987; 9(1):32-8. View

Mager D, Krzyzanski W . Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Pharm Res. 2005; 22(10):1589-96. DOI: 10.1007/s11095-005-6650-0. View

Yan X, Lowe P, Fink M, Berghout A, Balser S, Krzyzanski W . Population pharmacokinetic and pharmacodynamic model-based comparability assessment of a recombinant human Epoetin Alfa and the Biosimilar HX575. J Clin Pharmacol. 2011; 52(11):1624-44. PMC: 3483448. DOI: 10.1177/0091270011421911. View

Till A, Gomez H, HICHENS M, Bolognese J, McNabb W, Brooks B . Pharmacokinetics of repeated single oral doses of enalapril maleate (MK-421) in normal volunteers. Biopharm Drug Dispos. 1984; 5(3):273-80. DOI: 10.1002/bdd.2510050309. View

Peletier L, Gabrielsson J . Dynamics of target-mediated drug disposition: characteristic profiles and parameter identification. J Pharmacokinet Pharmacodyn. 2012; 39(5):429-51. PMC: 3446204. DOI: 10.1007/s10928-012-9260-6. View

Dua P, Hawkins E, van der Graaf P . A Tutorial on Target-Mediated Drug Disposition (TMDD) Models. CPT Pharmacometrics Syst Pharmacol. 2015; 4(6):324-37. PMC: 4505827. DOI: 10.1002/psp4.41. View

Bauer R, Gibbons J, BELL D, Luo Z, Young J . Nonlinear pharmacokinetics of recombinant human macrophage colony-stimulating factor (M-CSF) in rats. J Pharmacol Exp Ther. 1994; 268(1):152-8. View

Widness J, Schmidt R, Hohl R, Goldman F, Al-Huniti N, Freise K . Change in erythropoietin pharmacokinetics following hematopoietic transplantation. Clin Pharmacol Ther. 2007; 81(6):873-9. PMC: 2880326. DOI: 10.1038/sj.clpt.6100165. View

10.

An G, Liu W, Katz D, Marek G, Awni W, Dutta S . Population pharmacokinetics of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor ABT-384 in healthy volunteers following single and multiple dose regimens. Biopharm Drug Dispos. 2014; 35(7):417-29. DOI: 10.1002/bdd.1912. View

11.

DCunha R, Widness J, Yan X, Schmidt R, Veng-Pedersen P, An G . A Mechanism-Based Population Pharmacokinetics Model of Erythropoietin in Premature Infants and Healthy Adults Following Multiple Intravenous Doses. J Clin Pharmacol. 2019; 59(6):835-846. PMC: 7485325. DOI: 10.1002/jcph.1368. View

12.

DCunha R, Schmidt R, Widness J, Mock D, Yan X, Cress G . Target-mediated disposition population pharmacokinetics model of erythropoietin in premature neonates following multiple intravenous and subcutaneous dosing regimens. Eur J Pharm Sci. 2019; 138:105013. PMC: 6733583. DOI: 10.1016/j.ejps.2019.105013. View

13.

Jin F, Krzyzanski W . Pharmacokinetic model of target-mediated disposition of thrombopoietin. AAPS PharmSci. 2004; 6(1):E9. PMC: 2750944. DOI: 10.1208/ps060109. View

14.

Lee K, Yang J, Niu J, Ng C, Wagner K, Dong H . Drug-Target Residence Time Affects Target Occupancy through Multiple Pathways. ACS Cent Sci. 2019; 5(9):1614-1624. PMC: 6764161. DOI: 10.1021/acscentsci.9b00770. View

15.

Johnston E, Crawford J, Blackwell S, Bjurstrom T, Lockbaum P, Roskos L . Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol. 2000; 18(13):2522-8. DOI: 10.1200/JCO.2000.18.13.2522. View

16.

Brazzell R, Mayer P, DOBBS R, McNamara P, Teng R, Slattery J . Dose-dependent pharmacokinetics of the aldose reductase inhibitor imirestat in man. Pharm Res. 1991; 8(1):112-8. DOI: 10.1023/a:1015850911382. View

17.

Meijer R, Koopmans R, ten Berge I, Schellekens P . Pharmacokinetics of murine anti-human CD3 antibodies in man are determined by the disappearance of target antigen. J Pharmacol Exp Ther. 2001; 300(1):346-53. DOI: 10.1124/jpet.300.1.346. View

18.

van Waterschoot R, Parrott N, Olivares-Morales A, Lave T, Rowland M, Smith D . Impact of target interactions on small-molecule drug disposition: an overlooked area. Nat Rev Drug Discov. 2018; 17(4):299. DOI: 10.1038/nrd.2018.26. View

19.

Kakkar T, Sung C, Gibiansky L, Vu T, Narayanan A, Lin S . Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL4 receptor. Pharm Res. 2011; 28(10):2530-42. DOI: 10.1007/s11095-011-0481-y. View

20.

Weber C, Schmitt R, Birnboeck H, Hopfgartner G, van Marle S, Peeters P . Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther. 1996; 60(2):124-37. DOI: 10.1016/S0009-9236(96)90127-7. View