A Physiologically-based Quantitative Systems Pharmacology model of the incretin hormones GLP-1 and GIP
Pavel Balazki (1, 2), Stephan Schaller (2), Thomas Eissing (3), Thorsten Lehr (1)
(1) Clinical Pharmacy, Saarland University, Saarbrucken, Germany, (2) esqLABS GmbH, Saterland, Germany, (3) Clinical Pharmacometrics, Bayer AG, Leverkusen, Germany
Objectives:
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are crucial for the regulation of postprandial glucose. Their therapeutic effects are mainly achieved by potentiation of insulin secretion (GLP-1 and GIP) and by slowing down the gastric emptying rate (GLP-1) [1]. Most of the available data on concentrations of GLP-1 and GIP do not distinguish between the intact forms of the peptides and their primary metabolites due the use of non-specific assays, and only few sources report the concentrations of the biologically active forms. Our objective is to develop a physiologically-based (PB) model of metabolization and secretion of the two hormones that accounts for the pharmacokinetics (PK) of both, parent and metabolite of the two peptides.
Methods:
The PBPK models for GLP-1 and GIP were developed with PK-Sim® and MoBi® as part of the Open Systems Pharmacology Suite (OSPS), version 7.2 [2]. An extensive literature research was performed to identify the processes involved in the metabolism of GLP-1 and GIP [excerpt: 1,3–5]. Mean model parameters were estimated by fitting simulation results to concentration-time profiles of intact GLP-1 and GIP, their primary metabolites, and/or “total peptide”.
Data used for characterization of degradation and elimination processes include incubation of human plasma with GLP-1 and/or GIP [6–8], bolus injections [9,10], and continuous intravenous infusions of the peptides. Contribution of kidneys to the total elimination of GLP-1, GIP, and their primary metabolites, was estimated with the datasets reported by Idorn et al. [11] and Asmar et al. [12,13] and Albrechtsen et al. [14].
Parameters governing the secretion of the hormones were estimated by fitting the model to data from intraduodenal infusions of glucose [15–17].
Results:
The model includes degradation of the active hormones by the enzyme dipeptidyl-peptidase 4 (DPP-4), glomerular filtration, and active secretion into renal tubulus. Degradation of the peptides occurs in tissue’s interstitial space through membrane-located DPP-4, and in plasma through free-floating and endothelium-located DPP-4. The primary metabolites are eliminated via tubular secretion and degradation by the enzyme neutral endopeptidase (NEP, also known as membrane metallo-endopeptidase, MME).
GLP-1 is secreted from the L-Cells located in mucosa of ileum and colon. The basal secretion rate is enhanced by oral glucose load in a biphasic nature. The first phase is dependent on the concentration of glucose in the duodenum, the second phase is coupled to glucose uptake through sodium-glucose co-transporter 1 (SGLT1) in the direct proximity of the L-Cells.
Secretion of GIP is implemented in the duodenum and jejunum and is coupled to SGLT1-mediated glucose uptake in the respective region.
The model successfully mimics the complex behavior of incretin secretion and degradation while being consistent with reported concentrations of intact hormones and their primary metabolites. The expression of endothelial DPP-4 was identified as the most important factor to describe highly variable data from all 28 sources gathered for model assessment.
Conclusions:
We here present the first PB model of the two most important incretin hormones including both, the intact forms and their primary metabolites. The advantage of such a model is that it can reproduce the majority of reported data on incretin concentrations, regardless of the applied assays, e.g., the model could be used to estimate the concentration of intact peptides from “total” concentration data. In a next step, the model will be integrated into the physiologically based pharmacokinetics and pharmacodynamics (PBPK/PD) Quantitative Systems Pharmacology (QSP) Diabetes Platform [18,19] to couple the PK to the PD on gastric emptying, glucose metabolism and insulin and glucagon secretion.
References:
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