Helen McIlleronDivision of Clinical PharmacologyUniversity of Cape Town

The clinical pharmacology and drug interactions of bedaquiline

7TH FIDSSA 2017

20 years ▷ ▷ ▷ 2 drugs

▷

conditional approval based on phase IIbclinical data in drug-resistant TB:

Time to sputum-culture conversion

Diacon AH et al. N Engl J Med 2014;371:723-732

• 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: 1700387)

• development of resistance is a concern, and is potentially an indicator of sub-optimal use

median time to culture conversion(CC): 60 (33-90)d3 month CC: 81%end of treatment CC: 92%

(limited) ‘roll-out’

basics

PK in patients

PK-PD

DDIs

diarylquinoline

lipophilic, basic

cationic amphiphilic (CAD) ➝phospholipidosis

protein binding >99.9%

M2

CYP3A4CYP2C8, -18, -19CYP1A1

N-didesmethyl BDQ (M3)hydroxyl metabolitesM6 (aldehyde)

Smyej et al., Toxicologic Pathology 2017, Vol. 45(5) 663-675; Nan Zheng et al. J Pharmacol Exp Ther 2011;336:661-671

bedaquiline

Image: Dheda et al., Int J Tuberc Lung Dis 2016; 20(12):S24–S32

bedaquiline’s target - mycobacterial ATP synthase

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: 684–690; Pang et al., Antimicrob Agents Chemother 2017; 61:e00900-17.

MIC, mg/L

2-3%

0

20

40

60

80

100

120

140

160

180

0.0

3

0.0

6

0.1

2

0.2

4

0.4

8

1

Andries K, PLoS ONE 9(7): e102135; image- Dheda et al., Int J Tuberc Lung Dis 2016; 20(12):S24–S32

resistance mechanisms- target mutations in atpE- nontarget mutations in Rv0678

Svensson EM et al., CPT Pharmacometrics Syst. Pharmacol. 2016; 5: 682–691

Healan AM et al., AntimicrobAgents Chemother 2017; doi:10.1128/AAC.00855-17

PK – high variability in plasma concentrations

terminal t1/2 ± 5 months

Loading dose (400 mg/d x 14 d)➝ maintenance (200 mg 3 x/week) to 6-months

post-treatment exposures

concomitant FOOD

Svensson EM et al., CPT Pharmacometrics Syst. Pharmacol. 2016; 5: 682–691

albumin - ↓ exposure weight - ↓age - ↑African - ↓

+

PK

bedaquiline PK – efficacy

Bedaquiline AUC (mg.h/L)

in MDR-TB patients

OBR only 0

bedaquiline+

OBR

17.4 (L)

34.8

69.6 (H)

Svensson EM, Karlsson MO. J Antimicrob Chemother. 2017; doi: 10.1093/jac/dkx317.

safety…

12% 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

with delamanid - 2/5 patients had asymptomatic QT prolongation (Maryandyshev et al. Emerging Infect Dis 2017)

ACTG 5343 ongoing

Guglielmetti L et al., Eur Respir J 2017; 49: 1601799

Pym AS et al., Eur Resp J 2016 47: 564-574

Dia

con

et a

l., A

JRC

CM

20

15

; 19

1(8

): 9

43

-53

.

change in QTcB interval from baseline over time in combination regimens x 14 days

time-dependent QT-interval changes

PK drug-drug interactions

• 1st-line TB drugs • rifampicin, rifapentine, isoniazid/ pyrazinamide

• 2nd-line TB drugs• rifabutin

• ART• efavirenz, nevirapine, lopinavir/r

Adjusted doses with rifampicin: BDQ 1000 mg/d *14d then 1000 mg 3x/wk

Svensson EM et al., Antimicrob Chemother 2015; 70: 1106–1114

effects of rifampicin and rifapentine- in daily 600 mg doses

BDQ

BDQ+RIF

BDQ+RPE

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

↓ ↓↓

van

Hee

swijk

et a

l., IC

AA

C 2

00

7

PK of bedaquiline, by INH/PZA combined, in 22 HNVs

single dose bedaquiline, by rifabutin - AUC ↓ 10%

Healan AM et al., AntimicrobAgents Chemother 2017; doi:10.1128/AAC.00855-17

bedaquiline drug-drug interactions with ARVs - cumulative effects

18

Sven

sso

n E

M e

t a

l. A

AC

20

13

;57

(6):

27

80

-7

bedaquiline M2

efavirenz reduces bedaquiline exposure

by 18% for single dose, by >50% at steady

state!

Brill MJ et al., Int J Antimicrob Agents. 2017 Feb;49(2):212-217.

400 mg daily x 14 d ➝200 mg 3 x/week

300 mg daily x 14 d ➝ 100 mg 3 x/week

Bedaquiline and M2 concentrations over time, without ART, and with lopinavir- and nevirapine-based ART, respectively.

impact of DDIs on bedaquiline efficacy

20

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, 2016

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