Türk, Denise, Müller, Fabian, Fromm, Martin F., Selzer, Dominik, Dallmann, Robert and Lehr, Thorsten (2022) Renal transporter‐mediated drug‐biomarker interactions of the endogenous substrates creatinine and N 1 ‐methylnicotinamide : a PBPK modeling approach. Clinical Pharmacology & Therapeutics, 112 (3). pp. 687-698. doi:10.1002/cpt.2636 ISSN 0009-9236.
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Abstract
Endogenous biomarkers for transporter-mediated drug-drug interaction (DDI) predictions represent a promising approach to facilitate and improve conventional DDI investigations in clinical studies. This approach requires high sensitivity and specificity of biomarkers for the targets of interest, e.g., transport proteins, as well as rigorous characterization of their kinetics, which can be accomplished utilizing physiologically based pharmacokinetic (PBPK) modeling. Therefore, the objective of this study was to develop PBPK models of the endogenous organic cation transporter (OCT) 2 and multidrug and toxin extrusion protein (MATE) 1 substrates creatinine and N1-methylnicotinamide (NMN). Additionally, this study aimed to predict kinetic changes of the biomarkers during administration of the OCT2 and MATE1 perpetrator drugs trimethoprim, pyrimethamine and cimetidine. Whole-body PBPK models of creatinine and NMN were developed utilizing studies investigating creatinine or NMN exogenous administration and endogenous synthesis. The newly developed models accurately describe and predict observed plasma concentration-time profiles and urinary excretion of both biomarkers. Subsequently, models were coupled to the previously built and evaluated perpetrator models of trimethoprim, pyrimethamine and cimetidine for interaction predictions. Increased creatinine plasma concentrations and decreased urinary excretion during the drug-biomarker interactions with trimethoprim, pyrimethamine and cimetidine were well described. An additional inhibition of NMN synthesis by trimethoprim and pyrimethamine was hypothesized, improving NMN plasma and urine interaction predictions. To summarize, whole-body PBPK models of creatinine and NMN were built and evaluated to better assess creatinine and NMN kinetics while uncovering knowledge gaps for future research. The models can support investigations of renal transporter-mediated DDIs during drug development.
| Item Type: | Journal Article |
|---|---|
| Subjects: | Q Science > QP Physiology R Medicine > R Medicine (General) R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
| Library of Congress Subject Headings (LCSH): | Biochemical markers , Drug interactions , Carrier proteins, Cations, Pharmacokinetics |
| Journal or Publication Title: | Clinical Pharmacology & Therapeutics |
| Publisher: | Wiley |
| ISSN: | 0009-9236 |
| Official Date: | September 2022 |
| Dates: | Date Event September 2022 Published 8 May 2022 Available 8 May 2022 Accepted |
| Volume: | 112 |
| Number: | 3 |
| Page Range: | pp. 687-698 |
| DOI: | 10.1002/cpt.2636 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Restricted or Subscription Access |
| Date of first compliant deposit: | 12 May 2022 |
| Date of first compliant Open Access: | 8 May 2023 |
| RIOXX Funder/Project Grant: | Project/Grant ID RIOXX Funder Name Funder ID 031L0161C (“OSMOSES”) Bundesministerium für Bildung und Forschung UNSPECIFIED |
| URI: | https://wrap.warwick.ac.uk/165364/ |
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