Bedaquiline’s exposure-response relationship evaluated with data from the observational study C209
Lénaïg Tanneau (1), Mats O Karlsson (1), Elin M Svensson (1,2)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Department of Pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands
Objectives: To confirm a previously characterized relationship between bedaquiline (BDQ) exposure and the decline of mycobacterial load (MBL) during treatment of tuberculosis (TB) [1], and to further explore any study-dependent characteristics such as the duration of the individualized background regimen (BR).
Methods: Data were obtained from the TMC207-C209 phase IIb study (single-arm, open-label) enrolling 233 newly diagnosed or treatment-experienced multi-drug resistant (MDR-TB) subjects. The patients received 24 weeks of BDQ on top of an individualized BR. The trial was conducted in accordance with Good Clinical Practice standards and received ethical approval from appropriate local authorities. The applied model was first developed with data from the TMC207-C208 study enrolling exclusively newly diagnosed MDR-TB patients and receiving BDQ on top of an optimized BR initiated at the same time. The model consists of 3 parts: a longitudinal representation of MBL in patients, the probability of bacterial presence in sputum and a time-to-event model for time to positivity in mycobacterial growth tube. Evaluation of the previously developed model’s performance was tested with a set of 500 bootstrapped datasets of individual profiles, stratified by the TB status. It has been carried out by using fixed population parameters from the C208 study, with inclusion of a BDQ effect either by a treatment effect or by an exposure effect described by an Emax function. Analysis of covariate effects was conducted on parameters of the MBL model and the impact of the TB status, the presence and the duration of the previous BR was explored.
Results: The model with the BDQ exposure effect has shown to described the new data better than the model with solely a BDQ treatment effect, with a difference in OFV of -17.1 points (bootstrapped 95%PI = -45 to 10). The evaluation of patient related characteristics revealed that patients with extensively drug-resistant (XDR) TB and pre-XDR TB clear the bacteria slower than patients with MDR TB, resulting in 127% (RSE 36%) and 44% (RSE 21%) longer MBL half-life, respectively. A significant impact of the presence and duration of previous BR was not detected.
Conclusions: The previously developed model including a relationship between BDQ exposure and decrease in MBL describes the data from the C209 study better than a model with only a treatment effect. This supports the use of the model for exploration of potential BDQ dose optimization.
References:
[1] E. M. Svensson & M. O. Karlsson, ‘Bedaquiline's exposure-response relationship revealed through modeling of mycobacterial load’, PAGE 25 (2016) Abstr 5937
Acknowledgement: The research was funded by the Swedish Research Council and the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement n°115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.
