Margreke J.E. Brill (1), Elin M. Svensson (1), Mishal Pandie (2), Gary Maartens (2), Mats O. Karlsson (1)
(1) Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
Objectives: Cytochrome P450 3A4 (CYP3A4) inhibitors lopinavir/ritonavir or the moderate CYP3A4 inducer nevirapine may affect the exposure of the anti-tuberculosis drug bedaquiline and its metabolite M2. In this work we aimed to quantify lopinavir/ritonavir and nevirapine drug-drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis. The results were compared to model-based predictions from single-dose studies in subjects without tuberculosis.
Methods: An observational PK study was performed in three groups of MDR-TB patients during the bedaquiline maintenance dosing period: HIV-seronegative patients without antiretroviral treatment (ART) and HIV-infected patients using ART regimens containing either lopinavir/ritonavir or nevirapine. Bedaquiline and M2 samples were collected over 48 hours after a 200 mg dose [1]. A previously developed population PK model for patients was used as prior information to inform parameter estimation using the NWPRI functionality in NONMEM 7.3 [2,3]. The uncertainty of the model parameters were calculated using SIR [4].
Results: The final model was able to describe bedaquiline and M2 concentrations well for all three groups and the PK parameters estimates were close to their prior values. Lopinavir/ritonavir co-administration reduced bedaquiline clearance substantially to 25% (95% confidence interval, 17 – 35%) and M2 clearance to 59% (44 – 69%) of their original values. Nevirapine co-administration altered bedaquiline clearance to 82% (67 – 99%) and M2 clearance to 119% (95 – 156%) of their original values.
Conclusions: This work confirms earlier model-based prediction of lopinavir/ritonavir and nevirapine interaction effects on bedaquiline and M2 clearance from single-dose studies for MDR-TB and HIV co-infected patients receiving long-term treatments [3]. To normalize bedaquiline exposure in patients with concomitant lopinavir/ritonavir therapy, an adjusted bedaquiline dosing regimen is proposed.
References:
[1] Pandie, M. et al. Drug–drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV-infected patients with drug-resistant TB. J. Antimicrob. Chemother. dkv447 (2016). doi:10.1093/jac/dkv447
[2] Svensson, E. M., Dosne, A.-G. & Karlsson, M.O. Population pharmacokinetics of bedaquiline and metabolite M2 in drug-resistant tuberculosis patients – the effect of time-varying weight and albumin. (Submitted).
[3] Svensson, E. M., Dooley, K. E. & Karlsson, M. O. Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection. Antimicrob. Agents Chemother. 58, 6406–6412 (2014).
[4] Dosne, A.-G., Bergstrand, M. & Karlsson, M. O. Application of Sampling Importance Resampling to estimate parameter uncertainty distributions. PAGE (2013).
Acknowledgements: MP acknowledges funding in the form of a FIDSSA-GSK Research Fellowship and a Discovery Foundation Academic Fellowship Award. GM was supported in part by the National Research Foundation of South Africa (grant specific unique reference numbers 85810 and 90729, respectively). ES and MK were supported by the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) (grant agreement 115337 to ES and MK) for the PreDiCT-TB consortium.
Reference: PAGE 25 (2016) Abstr 5919 [www.page-meeting.org/?abstract=5919]
Poster: Drug/Disease modeling - Infection