NDLI: Target-mediated drug disposition model and its approximations for antibody

Content Provider	Springer Nature Link
Author	Gibiansky, Leonid Gibiansky, Ekaterina
Copyright Year	2013
Abstract	Antibody–drug conjugate (ADC) is a complex structure composed of an antibody linked to several molecules of a biologically active cytotoxic drug. The number of ADC compounds in clinical development now exceeds 30, with two of them already on the market. However, there is no rigorous mechanistic model that describes pharmacokinetic (PK) properties of these compounds. PK modeling of ADCs is even more complicated than that of other biologics as the model should describe distribution, binding, and elimination of antibodies with different toxin load, and also the deconjugation process and PK of the released toxin. This work extends the target-mediated drug disposition (TMDD) model to describe ADCs, derives the rapid binding (quasi-equilibrium), quasi-steady-state, and Michaelis–Menten approximations of the TMDD model as applied to ADCs, derives the TMDD model and its approximations for ADCs with load-independent properties, and discusses further simplifications of the system under various assumptions. The developed models are shown to describe data simulated from the available clinical population PK models of trastuzumab emtansine (T-DM1), one of the two currently approved ADCs. Identifiability of model parameters is also discussed and illustrated on the simulated T-DM1 examples.
Starting Page	35
Ending Page	47
Page Count	13
File Format	PDF
ISSN	1567567X
Journal	Journal of Pharmacokinetics and Pharmacodynamics
Volume Number	41
Issue Number	1
e-ISSN	15738744
Language	English
Publisher	Springer US
Publisher Date	2013-12-11
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Antibody–drug conjugates Target-mediated drug disposition Quasi-steady-state approximation Michaelis–Menten approximation Nonlinear pharmacokinetics Identifiability of model parameters Pharmacology/Toxicology Pharmacy Veterinary Medicine Biomedical Engineering Biochemistry
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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