DDMODEL00000085: Midazolam_PK_Morbidly_obese_Healthy_volunteers

  public model
Short description:
Model comprised of files: Output_simulated_mdz_PK_MO_HV.lst, Output_real__mdz_PK_MO_HV.lst, Simulated_data_MDZ.csv, Command.txt, Executable_mdz_PK_MO_HV.mod
Original code
  • Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: a comparison with healthy volunteers.
  • Brill MJ, van Rongen A, Houwink AP, Burggraaf J, van Ramshorst B, Wiezer RJ, van Dongen EP, Knibbe CA
  • Clinical pharmacokinetics, 10/2014, Volume 53, Issue 10, pages: 931-941
  • Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
  • BACKGROUND: While in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bioavailability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers. METHODS: Twenty morbidly obese patients [mean body weight 144 kg (range 112-186 kg) and mean body mass index 47 kg/m(2) (range 40-68 kg/m(2))] participated in the study. All patients received a midazolam 7.5 mg oral and 5 mg intravenous dose (separated by 159 ± 67 min) and per patient 22 samples over 11 h were collected. Data from 12 healthy volunteers were available for a population pharmacokinetic analysis using NONMEM(®). RESULTS: In the three-compartment model in which oral absorption was characterized by a transit absorption model, population mean clearance (relative standard error %) was similar [0.36 (4 %) L/min], while oral bioavailability was 60 % (13 %) in morbidly obese patients versus 28 % (7 %) in healthy volunteers (P < 0.001). Central and peripheral volumes of distribution increased substantially with body weight (both P < 0.001) and absorption rate (transit rate constant) was lower in morbidly obese patients [0.057 (5 %) vs. 0.130 (14 %) min(-1), P < 0.001]. CONCLUSIONS: In morbidly obese patients, systemic clearance of midazolam is unchanged, while oral bioavailability is increased. Given the large increase in volumes of distribution, dose adaptations for intravenous midazolam should be considered. Further research should elucidate the exact physiological changes at intestinal and hepatic level contributing to these findings.
Margreke Brill
Context of model development: Patient Population Selection and Bridging between Population (Pediatrics, Elderly, Obese); Variability sources in PK and PD (CYP, Renal, Biomarkers);
Long technical model description: See publication.;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: This is a pharmacokinetic model which was developed to evaluate the influence of morbid obesity on CYP3A-mediated clearance and oral bioavailability of midazolam when studied after semisimultaneous oral and intravenous administration. The model consists of 3 compartment + a depot compartment for the oral dose and 3 transit compartment in order to describe the delay in midazolam absorption. The model was developed using midazolam plasma concentrations from morbidly obese patient and healthy volunteers. Twenty morbidly obese patients that were undergoing a bariatric procedure were included on the study. First they received an oral midazolam dose followed by an intravenous dose 2-3 hours later. On average 22 blood samples were collected to measure midazolam concentrations. In addition, similar data from 12 non-obese healthy volunteers was available for analysis.;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Metabolism;
Annotations are correct.
This model is not certified.
  • Model owner: Margreke Brill
  • Submitted: Dec 10, 2015 1:09:52 PM
  • Last Modified: Jun 1, 2016 8:57:36 AM
  • Version: 9 public model Download this version
    • Submitted on: Jun 1, 2016 8:57:36 AM
    • Submitted by: Margreke Brill
    • With comment: Updated model annotations.
  • Version: 7 public model Download this version
    • Submitted on: Dec 11, 2015 10:06:23 AM
    • Submitted by: Margreke Brill
    • With comment: Edited model metadata online.
  • Version: 3 public model Download this version
    • Submitted on: Dec 10, 2015 1:09:52 PM
    • Submitted by: Margreke Brill
    • With comment: Adding output files, simulated data file and command.txt file