Journal article
A Quantitative Systems Pharmacology Model of the Incretin Hormones GIP and GLP1, Glucagon, Glucose, Insulin, and the Small Molecule DPP-4 Inhibitor, Linagliptin
Journal of pharmaceutical sciences, Vol.113(1), pp.278-289
01/2024
DOI: 10.1016/j.xphs.2023.09.006
PMID: 37716531
Abstract
In the current study, we established a comprehensive quantitative systems pharmacology (QSP) model using linagliptin as the model drug, where drug disposition, drug intervention on dipeptidyl peptidase-4 (DPP-4), glucose-dependent insulinotropic peptide (GIP), Glucagon-like peptide-1 (GLP-1), glucagon, glucose, and insulin are integrated together with the cross talk and feedback loops incorporated among the whole glycemic control system. In the final linagliptin QSP model, the complicated disposition of linagliptin was characterized by a 2-compartment pharmacokinetic (PK) model with an enterohepatic cycling (EHC) component as well as target-mediated drug disposition (TMDD) processes occurring in both tissues and plasma, and the inhibitory effect of linagliptin on DPP-4 was determined by the linagliptin-DPP-4 complex in the central compartment based on target occupancy principle. The integrated GIP-GLP1-glucagon-glucose-insulin system contains five indirect response models as the “skeleton” structure with 12 feedback loops incorporated within the glucose control system. Our model adequately characterized the substantial nonlinear PK of linagliptin, time course of DPP-4 inhibition, as well as the kinetics of GIP, GLP-1, glucagon and glucose simultaneously in human. Our model provided valuable insights on linagliptin pharmacokinetics/pharmacodynamics and complicated glucose homeostasis. Since the glucose regulation modeling framework within the QSP model is “drug-independent”, our model can be easily adopted by others to evaluate the effect of other DPP-4 inhibitors on glucose control system. In addition, our QSP model, which contains more components than other reported glucose regulation models, can potentially be used to evaluate the effect of combination antidiabetic therapy targeting different components of glucose control system.
Details
- Title: Subtitle
- A Quantitative Systems Pharmacology Model of the Incretin Hormones GIP and GLP1, Glucagon, Glucose, Insulin, and the Small Molecule DPP-4 Inhibitor, Linagliptin
- Creators
- Nan WuGuohua An
- Resource Type
- Journal article
- Publication Details
- Journal of pharmaceutical sciences, Vol.113(1), pp.278-289
- DOI
- 10.1016/j.xphs.2023.09.006
- PMID
- 37716531
- NLM abbreviation
- J Pharm Sci
- ISSN
- 0022-3549
- eISSN
- 1520-6017
- Language
- English
- Electronic publication date
- 09/14/2023
- Date published
- 01/2024
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984466698402771
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