Midazolam-Model

Whole-body PBPK model of midazolam.

This repository contains:

• a PK-Sim snapshot (*.json) file of the current PBPK model
• static content (e.g. text blocks, *.md files) as inputs for an evaluation plan
• an evaluation plan (evaluation-plan.json) to create an evaluation report using the snapshot and static text blocks to display the performance of the model

The latest release of the snapshot of the model, the evaluation plan and the static content can be found here.

The latest release of the PK-Sim project model file and the respective evaluation report can be found here.

This midazolam model is intended to be used as victim drug in CYP3A4-mediated drug-drug interactions (DDI).

This whole-body PBPK model of midazolam has been developed using in particular published pharmacokinetic clinical data by Hohmann et al. 2015 [1], Hyland et al. 2009 [2] and Thummel et al. 1996 [3]. The model has then been evaluated simulating a large number of clinical studies and comparing with respective observed data.

The presented model represents an update of the midazolam model presented by Hanke et al. [4]. Additional features in this update are:

• direct UGT1A4 metabolism,
• a decrease in the permeability between the intracellular and interstitial space (parameters "P (intracellular->interstitial)" and "P (interstitial->intracellular)") in intestinal mucosa to optimize quantitatively the extent of gut wall metabolism,
• and binding to a hypothetical binding partner in the brain to optimize a late redistribution phase in midazolam plasma concentrations.

Code of conduct

Everyone interacting in the Open Systems Pharmacology community (codebases, issue trackers, chat rooms, mailing lists etc...) is expected to follow the Open Systems Pharmacology code of conduct.

Contribution

We encourage contribution to the Open Systems Pharmacology community. Before getting started please read the contribution guidelines. If you are contributing code, please be familiar with the coding standard.

License

The model code is distributed under the GPLv2 License.

References

[1] Hohmann N, Kocheise F, Carls A, Burhenne J, Haefeli WE, Mikus G. Midazolam microdose to determine systemic and pre-systemic metabolic CYP3A activity in humans. Br J Clin Pharmacol (2015)

[2] Hyland R, Osborne T, Payne A, Kempshall S, Logan YR, Ezzeddine K, Jones B. In vitro and in vivo glucuronidation of midazolam in humans. Br J Clin Pharmacol (2009)

[3] Thummel KE, O'Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD, Wilkinson GR. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther (1996)

[4] Hanke N, Frechen S, Moj D, Britz H, Eissing T, Wendl T, Lehr T. PBPK models for CYP3A4 and P-gp DDI prediction: a modeling network of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil and digoxin. CPT: Pharmacometrics & Systems Pharmacology (2018)