Journal article
Incorporating Pharmacological Target-Mediated Drug Disposition (TMDD) in a Whole-Body Physiologically Based Pharmacokinetic (PBPK) Model of Linagliptin in Rat and Scale-up to Human
The AAPS journal, Vol.22(6), pp.125-125
09/29/2020
DOI: 10.1208/s12248-020-00481-w
PMID: 32996028
Abstract
Linagliptin demonstrates substantial nonlinear pharmacokinetics due to its saturable binding to its pharmacological target dipeptidyl peptide 4 (DPP-4), a phenomenon known as target-mediated drug disposition (TMDD). In the current study, we established a novel whole-body physiologically-based pharmacokinetic (PBPK)-TMDD model for linagliptin. This comprehensive model contains plasma and 14 tissue compartments, among which TMDD binding process was incorporated in 9 of them, namely the plasma, kidney, liver, spleen, lung, skin, salivary gland, thymus, and reproductive organs. Our final model adequately captured the concentration-time profiles of linagliptin in both plasma and various tissues in both wildtype rats and DPP4-deficient rats following different doses. The association rate constant (k(on)) in plasma and tissues were estimated to be 0.943 and 0.00680 nM(-1) h(-1), respectively, and dissociation rate constant (k(off)), in plasma and tissues were estimated to be 0.0698 and 0.00880 h(-1), respectively. The binding affinity of linagliptin to DPP-4 (Kd) was predicted to be higher in plasma (0.0740 nM) than that in tissue (1.29 nM). When scaled up to a human, this model captured the substantial and complex nonlinear pharmacokinetic behavior of linagliptin in human adults that is characterized by less-than dose-proportional increase in plasma exposure, dose-dependent clearance and volume of distribution, as well as long terminal half-life with minimal accumulation after repeated doses. Our modeling work is not only novel but also of high significance as the whole-body PBPK-TMDD model platform developed using linagliptin as the model compound could be applied to other small-molecule compounds exhibiting TMDD to facilitate their optimal dose selection.
Details
- Title: Subtitle
- Incorporating Pharmacological Target-Mediated Drug Disposition (TMDD) in a Whole-Body Physiologically Based Pharmacokinetic (PBPK) Model of Linagliptin in Rat and Scale-up to Human
- Creators
- Nan Wu - University of IowaGuohua An - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The AAPS journal, Vol.22(6), pp.125-125
- Publisher
- Springer Nature
- DOI
- 10.1208/s12248-020-00481-w
- PMID
- 32996028
- ISSN
- 1550-7416
- eISSN
- 1550-7416
- Number of pages
- 17
- Grant note
- University of Iowa Pharmaceutics Development Consortium
- Language
- English
- Date published
- 09/29/2020
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984365877002771
Metrics
4 Record Views