The clinical pharmacology and drug interactions of bedaquiline

Transcription

1 7 TH FIDSSA 2017 The clinical pharmacology and drug interactions of bedaquiline Helen McIlleron Division of Clinical Pharmacology University of Cape Town

2 20 years 2 drugs

3 conditional approval based on phase IIb clinical data in drug-resistant TB: Time to sputum-culture conversion Diacon AH et al. N Engl J Med 2014;371:

4 (limited) roll-out Indications - Pre-XDR, XDR, insufficient tolerated and effective drugs ± 8200 patients had bedaquiline before March 2017, 60% in South Africa scant use in children and adolescents (Achar et al., Emerging Infect Dis 2017) very few pregnant women outcomes - retrospective multicentre study, n=428, 46% XDR-TB (Borisov et al., Eur Respir J 2017; 49: ) median time to culture conversion(cc): 60 (33-90)d 3 month CC: 81% end of treatment CC: 92% development of resistance is a concern, and is potentially an indicator of sub-optimal use

5 basics PK in patients PK-PD DDIs

6 bedaquiline diarylquinoline lipophilic, basic cationic amphiphilic (CAD) phospholipidosis protein binding >99.9% M6 (aldehyde) M2 CYP3A4 CYP2C8, -18, -19 CYP1A1 N-didesmethyl BDQ (M3) hydroxyl metabolites Smyej et al., Toxicologic Pathology 2017, Vol. 45(5) ; Nan Zheng et al. J Pharmacol Exp Ther 2011;336:

7 bedaquiline s target - mycobacterial ATP synthase Image: Dheda et al., Int J Tuberc Lung Dis 2016; 20(12):S24 S32

8 % 0 MIC, mg/l MICs for baseline isolates from patients with DR-TB ( phase 2b studies, n=347; Chinese XDR-TB patients, n=90) Villellas C et al., J Antimicrob Chemother 2017; 72: ; Pang et al., Antimicrob Agents Chemother 2017; 61:e

9 resistance mechanisms - target mutations in atpe - nontarget mutations in Rv0678 Andries K, PLoS ONE 9(7): e102135; image- Dheda et al., Int J Tuberc Lung Dis 2016; 20(12):S24 S32

10 PK high variability in plasma concentrations Loading dose (400 mg/d x 14 d) maintenance (200 mg 3 x/week) to 6-months terminal t 1/2 ± 5 months Healan AM et al., Antimicrob Agents Chemother 2017; doi: /aac post-treatment exposures Svensson EM et al., CPT Pharmacometrics Syst. Pharmacol. 2016; 5:

11 concomitant FOOD PK + albumin - exposure weight - age - African - Svensson EM et al., CPT Pharmacometrics Syst. Pharmacol. 2016; 5:

12 bedaquiline PK efficacy Bedaquiline AUC (mg.h/l) in MDR-TB patients OBR only 0 bedaquiline + OBR 17.4 (L) (H) Svensson EM, Karlsson MO. J Antimicrob Chemother. 2017; doi: /jac/dkx317.

13 safety Guglielmetti L et al., Eur Respir J 2017; 49: % of 428 discontinued bedaquiline (Borisov et al. - multicentre retrospective study ) - 52% on clofazimine - 58% on moxifloxacin - 46% on amikacin/kanamycin - 82% on linezolid 1 cardiac arrythmia-related death/428 - hypokalaemia ±10% experience QTcF > 500 ms Pym AS et al., Eur Resp J : with delamanid - 2/5 patients had asymptomatic QT prolongation (Maryandyshev et al. Emerging Infect Dis 2017) ACTG 5343 ongoing

14 Diacon et al., AJRCCM 2015; 191(8): time-dependent QT-interval changes change in QTcB interval from baseline over time in combination regimens x 14 days

15 PK drug-drug interactions 1 st -line TB drugs rifampicin, rifapentine, isoniazid/ pyrazinamide 2 nd -line TB drugs rifabutin ART efavirenz, nevirapine, lopinavir/r

16 effects of rifampicin and rifapentine - in daily 600 mg doses BDQ BDQ +RIF BDQ +RPE Adjusted doses with rifampicin: BDQ 1000 mg/d *14d then 1000 mg 3x/wk Svensson EM et al., Antimicrob Chemother 2015; 70:

17 van Heeswijk et al., ICAAC 2007 single dose bedaquiline, by rifabutin - AUC 10% Healan AM et al., Antimicrob Agents Chemother 2017; doi: /aac PK of bedaquiline, by INH/PZA combined, in 22 HNVs BDQ AUC 13% M2 AUC 30% INH AUC 7% PZA AUC 8% daily doses: 5d >7d 10 d 5d PZA 2 g INH 300 mg BDQ 400 mg

18 Svensson EM et al. AAC 2013;57(6): bedaquiline drug-drug interactions with ARVs efavirenz reduces bedaquiline exposure by 18% for single dose, by >50% at steady state! - cumulative effects bedaquiline M2 18

19 Bedaquiline and M2 concentrations over time, without ART, and with lopinavir- and nevirapine-based ART, respectively. 400 mg daily x 14 d 200 mg 3 x/week 300 mg daily x 14 d 100 mg 3 x/week Brill MJ et al., Int J Antimicrob Agents Feb;49(2):

20 impact of DDIs on bedaquiline efficacy Proportion patients without SCC at 20 w 12.3% 16.3% 8.4% 19.8% 25.3% Svensson EM et al. 9th International Workshop on Clinical Pharmacology of TB Drugs, Liverpool,

21 conclusions Bedaquiline has transformed outcomes in patients with otherwise weak regimens Appears to be relatively safe Dosing, treatment duration and companion drugs need to be optimized to reduce the emergence of resistance Understanding the PK-PD relationships will contribute to optimized use