DDMODEL00000036: Executable_BDQ_M2_PK_DDI_with_LPV-RTV

  public model
Short description:
A population PK model of the anti-tuberculosis drug bedaquiline and its metabolite M2 in healthy volunteers, with and without lopinavir/ritonavir co-administration.
Original code
  • Impact of lopinavir-ritonavir or nevirapine on bedaquiline exposures and potential implications for patients with tuberculosis-HIV coinfection.
  • Svensson EM, Dooley KE, Karlsson MO
  • Antimicrobial agents and chemotherapy, 11/2014, Volume 58, Issue 11, pages: 6406-6412
  • Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden elin.svensson@farmbio.uu.se.
  • Concomitant treatment of tuberculosis (TB) and HIV is recommended and improves outcomes. Bedaquiline is a novel drug for the treatment of multidrug-resistant (MDR) TB; combined use with antiretroviral drugs, nevirapine, or ritonavir-boosted lopinavir (LPV/r) is anticipated, but no clinical data from coinfected patients are available. Plasma concentrations of bedaquiline and its M2 metabolite after single doses were obtained from interaction studies with nevirapine or LPV/r in healthy volunteers. The antiretrovirals' effects on bedaquiline and M2 pharmacokinetics were assessed by nonlinear mixed-effects modeling. Potential dose adjustments were evaluated with simulations. No significant effects of nevirapine on bedaquiline pharmacokinetics were identified. LPV/r decreased bedaquiline and M2 clearances to 35% (relative standard error [RSE], 9.2%) and 58% (RSE, 8.4%), respectively, of those without comedication. As almost 3-fold (bedaquiline) and 2-fold (M2) increases in exposures during chronic treatment with LPV/r are expected, dose adjustments are suggested for evaluation. Efficacious, safe bedaquiline dosing for MDR-TB patients receiving antiretrovirals is important. Modeling results suggest that bedaquiline can be coadministered with nevirapine without dose adjustments. The predicted elevation of bedaquiline and M2 levels during LPV/r coadministration may be a safety concern, and careful monitoring is recommended. Further data are being collected in coinfected patients to determine whether dose adjustments are needed. (These studies have been registered at ClinicalTrials.gov under registration numbers NCT00828529 [study C110] and NCT00910806 [study C117].).
Elin Svensson
Context of model development: Variability sources in PK and PD (CYP, Renal, Biomarkers); Mechanistic Understanding;
Long technical model description: Final PK model of bedaquiline and the primary metabolite M2 in 16 healthy volunteers taking two separate singel doses of 400 mg bedaquiline, with and without concomitant adminsitartion of lopinavir/ritonavir;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Aiming to characterize the drug-drug interaction between bedaquiline and lopinavir/ritonavir;
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: Elin Svensson
  • Submitted: Dec 10, 2015 4:03:18 PM
  • Last Modified: Jun 1, 2016 11:27:02 AM
  • Version: 14 public model Download this version
    • Submitted on: Jun 1, 2016 11:27:02 AM
    • Submitted by: Elin Svensson
    • With comment: Model revised without commit message
  • Version: 8 public model Download this version
    • Submitted on: Dec 10, 2015 4:03:18 PM
    • Submitted by: Elin Svensson
    • With comment: Edited model metadata online.