DDMODEL00000130: Executable_CMS_colistin_PK_v2

  public model
Short description:
The model includes 4 compartments describing the disposition of CMS and its intermediates, as well as 1 compartment for colistin. The model is based on 3 studies in critically ill patients. The model includes CrCL as a covariate for CMS and considers the differences in availability in the formulation used in the new study versus the older studies. Model comprised of files: Output_simulated_CMS_colistin_PK.lst, Output_real_CMS_colistin_PK.lst, Simulated_CMS_colistin_PK_data.csv, Model_Accommodations.txt, Executable_CMS_colistin_PK_v2.mod, Command.txt
Original code
  • Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients.
  • Karaiskos I, Friberg LE, Pontikis K, Ioannidis K, Tsagkari V, Galani L, Kostakou E, Baziaka F, Paskalis C, Koutsoukou A, Giamarellou H
  • Antimicrobial agents and chemotherapy, 12/2015, Volume 59, Issue 12, pages: 7240-7248
  • 6th Department of Internal Medicine, Hygeia General Hospital, Athens, Greece iliaskaraiskos@gmail.com.
  • Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241- 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (?270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.
Lena Friberg
Context of model development: Mechanistic Understanding; Dose & Schedule Selection and Label Recommendation; Variability sources in PK and PD (CYP, Renal, Biomarkers);
Long technical model description: CMS (CMS and the intermediates) were described by 4 compartments for disposition and elimination. Colistin was described by a one-compartment model. The apparent higher concentrations of the A and B forms in the latest study was explained by a higher availability (F) for this study. The original analysis was performed using FOCE-I in NONMEM. Inter-occasion variability was considered.;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Characterize CMS and colistin PK for an analysis of pooled data from 3 different studies;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Anti-infectives;
Annotations are correct.
This model is not certified.
  • Model owner: Lena Friberg
  • Submitted: Mar 4, 2016 1:19:39 PM
  • Last Modified: Aug 27, 2016 7:53:08 AM
  • Version: 9 public model Download this version
    • Submitted on: Aug 27, 2016 7:53:08 AM
    • Submitted by: Lena Friberg
    • With comment: Updated model annotations.
  • Version: 7 public model Download this version
    • Submitted on: Mar 4, 2016 1:19:39 PM
    • Submitted by: Lena Friberg
    • With comment: Edited model metadata online.