Mahmoud Tareq Abdelwahab1, Richard Court 1, Daniel Everitt4, Andreas Diacon5,6, Rodney Dawson7, Elin M. Svensson8,9, Gary Maartens1,2, Paolo Denti1
1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 2) Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa 3) Divisions of General Internal Medicine & Infectious Diseases, Albert Einstein College of Medicine, New York, United States of America 4) Global Alliance for TB Drug Development, New York, New York 5) Division of Medical Physiology, MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research 6) Task Applied Science, Bellville, South Africa 7) Division of Pulmonology and Department of Medicine, University of Cape Town Lung Institute, Mowbray, Cape Town, South Africa 8) Department of Pharmacy, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands 9) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives:
Clofazimine is recommended by the World Health Organization and the American Thoracic Society for patients with rifampicin-resistant tuberculosis (TB). Clofazimine is highly protein bound and undergoes duration-dependent accumulation in fat tissues and macrophages resulting in extremely long terminal half-life (around 40 days). Different dosing regimen with or without loading dose are currently being investigated to optimize average daily concentrations above 0.25 mg/L1. Cardiac QT prolongation, which can cause fatal arrhythmias, has been described for several anti-TB drugs, including clofazimine, but there is no information about the exposure-response risk. We used population pharmacokinetic/pharmacodynamic modelling to describe effects of clofazimine concentrations on QT prolongation in South African patients with drug-susceptible TB.
Methods:
Adult treatment-naïve drug-susceptible TB patients were enrolled in a 14-day phase 2A study of early bactericidal activity of clofazimine, alone or in combination with other TB drugs. 105 patients were randomized into 7 treatment arms2. Clofazimine was administered as loading dose of 300 mg 3 days, followed by 100 mg until day 14. Triplicate ECGs were performed predose, 5 and 10 hours before treatment initiation +/- 15 minutes of time point relative to when dosing is scheduled to occur then at pre-dose, 5 and 10 hours after observed dose on days 1, 2, 3, 8, and 14. Additional ECGs were performed on day 28. A previously developed population pharmacokinetic model3 was used to predict individual concentrations concomitant to each ECG measurement. Different cosine functions were tested to describe the diurnal variation of the QTcF with time shift relative to clock time. We used the final model to simulate QTcF prolongation for different dosing regimens: 200 or 300 mg daily for two weeks followed by 100 mg QD. Data were analysed using NONMEM 7.4 with FOCE-I; PsN was used for model run execution and R software was used for data preparation. Xpose4 and Pirana were used for post-processing results, precision of the parameters was obtained by bootstrap.
Results:
Pre-treatment QTcF data from all 7 arms (105 patients, 524 observations) were used to characterize the circadian variation in QTcF and pooled with the data from the clofazimine monotherapy arm (199 ECGs) to characterise the PK/PD relationship, after averaging the triplicate ECG measurement at each time point. Patients had median age of 30 years (range: 18 – 62), median weight of 53.8 kg (40 – 86.6) and a median fat-free mass of 42.7 kg (27.3 – 64.8). The data included 65 male patients and 12 HIV positive. A baseline model for QTcF with three cosine functions was found to best describe the circadian rhythm of QTcF. Age and sex were tested as covariate on the baseline model and were not statistically significant. The model estimated (95% CI) a baseline QTcF value of 391(387 – 396) ms with 3.7% (3.2 – 4.2) between subject variability. The QTcF-clofazimine concentration relationship was best described by an Emax model, with an Emax value of 26 (11.7 – 67.7) ms increase of QTcF for the typical patient. and a clofazimine EC50 of 0.28 (0.01 – 0.992) mg/L. After two weeks of treatment, the proportions of times the change from baseline was above 30 ms were 5, 20 and 35% for 100, 200 and 300 mg dosing regimens, respectively. At steady state these proportions reaches 38% for all regimens. The proportions of absolute QTcF interval above 450 ms reached 5 % for all simulated regimen at steady state. For other cut-off points the proportions were negligible.
Conclusions:
We present the first population pharmacokinetic/pharmacodynamic model characterizing the effect of clofazimine concentrations on QTcF prolongation in South African TB patients. Our simulation shows that clofazimine mono-therapy has a significant QTc prolongation effect. Our PK/PD model can be used to inform exposure-efficacy and -safety analysis of clofazimine as a part of proposedTB multiple-drug regimen.
References:
[1] Adamson, J. et al. Clofazimine Contributes Sustained Antimicrobial Activity after Treatment Cessation in a Mouse Model of Tuberculosis Chemotherapy. Antimicrob. Agents Chemother. 60, 2864–2869 (2016).
[2] Diacon, A. H. et al. Bactericidal Activity of Pyrazinamide and Clofazimine Alone and in Combinations with Pretomanid and Bedaquiline. Am. J. Respir. Crit. Care Med. 191, 943–953 (2015).
[3] Abdewahab, M. T., Wasserman, S., Brust, J. C. M., Maartens, G. & Denti, P. Clofazimine population pharmacokinetics in South African patients with drug resistant tuberculosis. in (Presented at 28th Annual Meeting Population Approach Group Europe (PAGE), Stockholm, Sweden,11-14 June 2019).
Reference: PAGE () Abstr 9494 [www.page-meeting.org/?abstract=9494]
Poster: Drug/Disease Modelling - Infection