the clinical pharmacology and - fidssa · 2019-04-17 · division of clinical pharmacology...
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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
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