DDMODEL00000244: Non-linear saturable pharmacokinetic model for high dose rifampicin in tuberculosis patients

  public model
Short description:
The model follows one-compartment disposition and the transit absorption compartment model describes absorption. The model includes an enzyme turnover model to account for autoinduction as well as saturable (Michaelis-Menten) elimination. In addition, the model includes a dose-dependent bioavailability.
Original code
  • A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses.
  • Svensson RJ, Aarnoutse RE, Diacon AH, Dawson R, Gillespie SH, Boeree MJ, Simonsson USH
  • Clinical pharmacology and therapeutics, 6/2017
  • Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
  • Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time-dependent elimination due to autoinduction, concentration-dependent clearance, and dose-dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis-Menten relationship. The relationship between bioavailability and dose was described using an Emax relationship. The model will be key in determining exposure-response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high-dose rifampicin.
Robin Svensson
Context of model development: Mechanistic Understanding;
Discrepancy between implemented model and original publication: No difference;
Long technical model description: The pharmacokinetics of high dose rifampicin was described using one-compartment disposition kinetics. The absorption was described using the transit absorption compartment model. The data included several non-linearities. Firstly, an enzyme tunr-over model was included to take into account the autoinduction for rifampicin. A Michaelis-Menten relationship was included for clearance in addition to a dose-dependency in the bioavailability where the bioavailability increased at higher doses.;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Mechanistic Understanding, Dose & Schedule Selection and Label Recommendation, Variability Sources in PK and PD (CYP, Renal, Biomarkers);
Modelling task in scope: estimation;
Nature of research: Early clinical development (Phases I and II);
Therapeutic/disease area: Anti-infectives;
Annotations are correct.
This model is not certified.
  • Model owner: Robin Svensson
  • Submitted: Aug 11, 2017 11:49:13 AM
  • Last Modified: Aug 11, 2017 11:49:13 AM
  • Version: 3 public model Download this version
    • Submitted on: Aug 11, 2017 11:49:13 AM
    • Submitted by: Robin Svensson
    • With comment: Updated model annotations.