DDMODEL00000295: Executable_CMS_colistin_PK_CRRT

  public model
Short description:
The model describes the pharmacokinetics of colistimethate (CMS, prodrug of colistin) and colistin (active moiety) in patients receiving continuous renal replacement therapy (CRRT). It was fitted to observations collected in 10 intensive care patients providing 96 pre-filter and 15 post-filter plasma samples together with 12 effluent samples for CMS and colistin determination. The systemic disposition of both molecules was described with a single compartment model, estimating the clearance and the distribution volume of each moiety. The exchanges occurring in the CRRT device were modelled according to a physiologically-inspired model extension, taking into account real blood and filtrate-dialysate flow rates, actual filter and cartridge volumes and patients' haematocrit, and estimating the sieving coefficients of CMS and colistin. The model predicts that a CMS loading dose of 9 MU followed after 8 h by a maintenance dosage of 3 MU 8-hourly will achieve therapeutic colistin concentration exposure (>2.5 mg/L over the whole dosing interval) in patients undergoing CVVHD using low blood flows.
Original code
  • Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy.
  • Leuppi-Taegtmeyer AB, Decosterd L, Osthoff M, Mueller NJ, Buclin T, Corti N
  • Antimicrobial agents and chemotherapy, 2/2019, Volume 63, Issue 2, pages: e01957-18
  • Department of Clinical Pharmacology and Toxicology, University & University Hospital of Basel, Basel, Switzerland.
  • Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100?ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60?kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5?mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8?h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.).
Thierry Buclin
Context of model development: Dose & Schedule Selection and Label Recommendation;
Discrepancy between implemented model and original publication: None - this is the model presented in the original publication;
Long technical model description: CMS and colistin pharmacokinetics were assessed prospectively in 10 critically ill patients requiring CRRT. Extensive pharmacokinetic sampling was performed on treatment day 1, 3 and 5 after administration of a loading dose of CMS, followed by a maintenance dosage every eight hours. The disposition of CMS and colistin was described using a 6-compartment model with first-order transfer rates for metabolic transformation of CMS into colistin, metabolic elimination of colistin and exchanges of both compounds within the filter and cartridge compartments of CRRT apparatus. The systemic distributions of CMS and colistin were assumed to correspond to a single-compartment volume each (VCMS and VCol). The fraction of the CMS dose escaping elimination through CRRT was assumed to be completely transformed into colistin through metabolic clearance (CLM CMS); then colistin in turn was considered to be eliminated through both CRRT and metabolic clearance (CLM Col). Both compounds were assumed to be transferred into a CRRT filter of fixed volume (Vfilter = 0.2 L) at the flow rate read on the CRRT device (Qblood), corrected for the patient's hematocrit (1 - Ht), set to the average HT value (0.25) when unknown. Non-filtered amounts of CMS and colistin were driven back into the patient's circulation with the same blood flow, while filtered amounts passed into the filter cartridge (Vcartridge = 0.3 L), continuously rinsed with the effluent rate read on the CRRT device (Qeffl). Sieving coefficients were assumed to characterize the filter permeability for CMS and colistin (SCMS and Scol), multiplying Qeffl to give the respective filtration clearances.;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Interpretation of concentration results of a prospective observational study aimed to clarify the dosage adaptation required for CMS/colistin in CRRT patients;
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: Thierry Buclin
  • Submitted: Nov 13, 2018 6:29:03 PM
  • Last Modified: Nov 13, 2018 6:43:21 PM
  • Version: 12 public model Download this version
    • Submitted on: Nov 13, 2018 6:43:21 PM
    • Submitted by: Thierry Buclin
    • With comment: Updated model annotations.
  • Version: 11 public model Download this version
    • Submitted on: Nov 13, 2018 6:29:03 PM
    • Submitted by: Thierry Buclin
    • With comment: Model revised without commit message