caa a22 4500 44531303X CHVBK 20180317142636.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s11095-011-0471-0 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0471-0 Theoretical Analysis of Interplay of Therapeutic Protein Drug and Circulating Soluble Target: Temporal Profiles of ‘Free' and ‘Total' Drug and Target [Elektronische Daten] [Cuyue Tang, Thomayant Prueksaritanont] ABSTRACT: Purpose: 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. Method: 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 (KD), target baseline (Rss), target turnover, and drug dose level. Two sets of published experimental data were compared with the simulated results. 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 KD and Rss, 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. Conclusions: 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. Springer Science+Business Media, LLC, 2011 pharmacodynamics nationallicence pharmacokinetics nationallicence soluble target nationallicence target mediated drug disposition nationallicence therapeutic protein drug nationallicence C : free drug concentration nationallicence Ctot : total drug concentration nationallicence KD : dissociation constant nationallicence PD : pharmacodynamics nationallicence PK : pharmacokinetics nationallicence R : free target concentration nationallicence RB-TMDD : rapid binding approximation of TMDD model nationallicence RC : target-drug complex nationallicence Rss : target baseline concentration nationallicence Rtot : total target concentration nationallicence TMDD : target-mediated drug disposition nationallicence Tang Cuyue Department of Drug metabolism and Pharmacokinetics, WP75A-203, Merck Research Laboratories, 19486, West Point, Pennsylvania, USA aut Prueksaritanont Thomayant Department of Drug metabolism and Pharmacokinetics, WP75A-203, Merck Research Laboratories, 19486, West Point, Pennsylvania, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2447-2457 0724-8741 28:10<2447 2011 28 11095 https://doi.org/10.1007/s11095-011-0471-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0471-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tang Cuyue Department of Drug metabolism and Pharmacokinetics, WP75A-203, Merck Research Laboratories, 19486, West Point, Pennsylvania, USA aut NATIONALLICENCE 700 1- Prueksaritanont Thomayant Department of Drug metabolism and Pharmacokinetics, WP75A-203, Merck Research Laboratories, 19486, West Point, Pennsylvania, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2447-2457 0724-8741 28:10<2447 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer