NDLI: Theoretical Analysis of Interplay of Therapeutic Protein Drug and Circulating Soluble Target: Temporal Profiles of ‘Free’ and ‘Total’ Drug and Target

Content Provider	Springer Nature Link
Author	Tang, Cuyue Prueksaritant, Thomayant
Copyright Year	2011
Abstract	To systemically investigate, for a therapeutic protein with a circulating soluble target, how the interplay of target dynamics and drug pharmacokinetics defines the ‘total’ and ‘free’ drug and target temporal profiles.By extending the established rapid-binding target-mediated drug disposition (TMDD) pharmacokinetic model to circulating soluble targets, the temporal profiles of ‘total’ and ‘free’ drug and target were simulated with varying binding affinity (K$_{D}$), target baseline (R$_{ss}$), target turnover, and drug dose level. Two sets of published experimental data were compared with the simulated results.Binding to a circulating soluble target could lead to a divergence of the ‘free’ drug from the ‘total’ drug. Simulations show this divergent magnitude determined by K$_{D}$ and R$_{ss}$, with the temporal profile being defined by target turnover and drug dose level. As divergence proceeds, starting at the distribution phase, ‘free’ drug would decline faster but eventually parallel ‘total’ drug at the terminal phase, giving rise to a steeper distribution phase and comparable terminal half-life, relative to the ’total’ form. The model also allows for estimation of the dynamic change of ‘total’ and ‘free’ target in response to the treatment of a therapeutic protein drug, facilitating dose level and regimen design to achieve desired ‘free’ target suppression. Model predictions compared favorably with two sets of published experimental data.Theoretical analyses identified key variables governing the different temporal profiles of ‘total’ and ‘free’ drug and target. The rapid-binding TMDD model reasonably captured the features of the interplay of drug pharmacokinetics and target dynamics for two reported cases.
Starting Page	2447
Ending Page	2457
Page Count	11
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	28
Issue Number	10
e-ISSN	1573904X
Language	English
Publisher	Springer US
Publisher Date	2011-05-26
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacy Biomedical Engineering Medical Law Pharmacology/Toxicology Biochemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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