PanACEA-MAMS-TB-01 - Virology Education

PanACEA-MAMS-TB-01 - Virology Education

Pharmacokinetics of high dose rifampicin,
moxifloxacin and first-line TB drugs
in the PanACEA-MAMS-TB-01 trial
Rob Aarnoutse & Angela Colbers
Radboudumc, Nijmegen, The Netherlands
on behalf of the PanACEA consortium
17th September 2015
8th International Workshop on Clinical Pharmacology of TB drugs, San Diego, USA
PanACEA: a consortium of consortia
Focus: treatment shortening in drug sensitive TB
Started in 2007 with 3 subconsortia:
• REMox: bring moxifloxacin beyond phase III
• HIGHRIF: bring high dose rifampicin beyond phase II
• SQ109: bring SQ109 beyond phase II
The three drugs brought
together:
PanACEA-MAMS-TB-01
PanACEA-MAMS-TB-01: African
and European partner institutes
Albert-SchweitzerHospital
Medical Research Unit
Makarere University
Tuberculosis Unit NTLP
KEMRI
Kentya Medical Research Institute
KCRI
Kibong’oto National
Tuberculosis Hospital
Northern European partners:
•Sponsor: University of Munich
•CI: Radboudumc, Nijmegen
•University College London
•MRC CTU at UCL, UK
•University of St. Andrews, UK
IHI
Bagamoyo branch of
Ifakara Health Institute
MMRP
Mbeya Medical Research
Programme
UNZA
University of Zambia
Medical School
US Partner:
•Sequella, Inc., Washington DC
WITS
University of
Witwatersrand
AURUM
Aurum Institute for
Health Research
UCT
University of Cape
Town
SQ109
Stellenbosch
Stellenbosch
University/TASK
Washington, 21/09/15
4
PanACEA-MAMS-TB-01: randomisation scheme
All drugs at standard doses unless otherwise stated
8 weeks
Control
RHZQ
Isoniazid
Rifampicin 10mg/kg
Pyrazinamide
Ethambutol
Isoniazid
Rifampicin 10mg/kg
Pyrazinamide
SQ109
12 weeks
Isoniazid
Rifampicin 10mg/kg
Isoniazid
Rifampicin 10mg/kg
R20ZQ
Isoniazid
Rifampicin 20mg/kg
Pyrazinamide
SQ109
Isoniazid
Rifampicin 10mg/kg
R20ZM
Isoniazid
Rifampicin 20mg/kg
Pyrazinamide
Moxifloxacin
Isoniazid
Rifampicin 10mg/kg
R35ZHE
Isoniazid
Rifampicin 35mg/kg
Pyrazinamide
Ethambutol
Isoniazid
Rifampicin 10mg/kg
26 weeks
Design of PanACEA-MAMS-TB-01 and PK substudy
Overarching trial
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Open label, randomized, controlled, phase II MAMS trial
Primary endpoint: time to stable culture conversion to negative in liquid media up to 12
weeks
Sample size: n=372, n=62 in each arm, n=124 in the control arm
FDCs and loose drugs combined: WHO prequalified and approved
Weight bands 30-37, 38-54, 55-70 and > 70 kgs
PK substudy
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Overall aim: to substantiate dosing of individual drugs and in combination
Objectives: describe PK, assess predictors of PK, PK-PD
Intensive PK sampling in 20 patients in each arm in week 4 of treatment (n=100 PK curves)
PK sampling in Mbeya and Moshi (Tanzania), Cape Town and Johannesburg (SA): 25 PK
curves/site, first 5 patients in each arm are sampled
Samples collected prior to and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24 h after intake of TB drugs with a
light meal, analyzed by validated UPLC methods
Standard two-stage approach with non-compartmental PK methods
Results - patient characteristics
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98 valid PK curves recorded
Total
N
Gender (male)
98
70
Control
HRZE
19
84
Age (year)
34 (18-56)
36 (25-51)
36 (20-44)
37 (18-56)
33 (20-56)
33 (18-50)
Weight (kg)
54 (35-80)
53 (42-60)
54 (42-80)
55 (41-70)
53 (42-72)
52 (35-59)
Race (black,
mixed)
Country Tz /
SA
HIV-infected
87 / 13
95 / 5
84 / 16
90 / 10
79 / 21
86 / 14
55 / 45
53/47
53 / 47
60 / 40
53 /47
57 / 43
2 / 98
0 / 19
1 / 19
0 / 20
0 / 19
1 / 21
4.9
9.8
26.3
18.0
4.9
9.8
26.1
4.8
19.1
25.5
4.7
18.8
25.1
4.8
32.7
25.6
17.6
Drug dose
(mg/kg)
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol
Moxifloxacin
SQ109
HRZQ
HR20ZQ
HR20ZM
HR35ZE
19
74
20
75
19
63
21
57
7.4 (400 mg)
Results - rifampicin
Results - rifampicin
Rifampicin
(geom. means)
AUCtau
(h*mg/L)
control
HRZE
HRZQ
HR20ZQ
HR20ZM
HR35ZE
24.2
17.4
68
58
170
Cmax (mg/L)
5.8
3.4
11.7
11.3
26.7
Tmax (h)
3.1
4.0
4.0
3.1
4.0
CL/F (L/h)
21.3
29.5
15.5
17.5
9.7
Vd/F (L)
53.8
78.2
46.2
45.9
35.3
T1/2 (h)
1.8
1.8
2.1
1.8
2.5
Results - rifampicin
Rifampicin
(geom. means)
AUCtau
(h*mg/L)
control
HRZE
HRZQ
HR20ZQ
HR20ZM
HR35ZE
24.2
17.4
68
58
170
Cmax (mg/L)
5.8
3.4
11.7
11.3
26.7
Tmax (h)
3.1
4.0
4.0
3.1
4.0
CL/F (L/h)
0.41
0.59
0.29
0.35
0.21
Vd/F (L)
1.04
1.58
0.87
0.91
0.75
T1/2 (h)
1.8
1.8
2.1
1.8
2.5
Results - rifampicin
Rifampicin
(geom. means)
AUCtau
(h*mg/L)
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Low exposures with rifampicin 10 mg/kg
More than dose-proportional increase in
average exposure (AUC, Cmax) with the dose
One-way ANOVA: no difference in AUC0-24 at
the same rifampicin dose levels
Large interindividual variability in PK,
eg min-max with 35 mg/kg is 103-266 h*mg/L,
GCV is 37-66-37-51-26%
Minimum exposure recorded in each group
increased with the dose administered
control
HRZE
HRZQ
HR20ZQ
HR20ZM
HR35ZE
24.2
17.4
68
58
170
Cmax (mg/L)
5.8
3.4
11.7
11.3
26.7
Tmax (h)
3.1
4.0
4.0
3.1
4.0
CL/F (L/h)
21.3
29.5
15.5
17.5
9.7
Vd/F (L)
53.8
78.2
46.2
45.9
35.3
T1/2 (h)
1.8
1.8
2.1
1.8
2.5
Results - rifampicin
Rifampicin
(geom. means)
Control
HRZE
HRZQ
HIGH
RIF1
HIGH
RIF2
HR20ZM
HIGH
RIF1
HIGH
RIF2
HR35ZE
HIGH
RIF1
AUCtau
(h*mg/L)
24.2
17.4
26.3
23.9
58
113
73.8
170
235
5.8
3.4
7.4
5.3
11.3
21.6
13.6
26.7
35.2
Cmax (mg/L)
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Higher exposures in HIGHRIF1 (South African patients only, sampling at week
2 instead of week 4) at 20 mg/kg and 35 mg/kg compared to current study
Effect of ethnicity or sampling time (auto-induction) ?
Current study: Tanzanians lower rifampicin AUC0-24 only at 35 mg/kg
(GM 145 vs 206 h*mg/L, n=11 vs n=9, p=0.001)
Results - moxifloxacin
Moxifloxacin
AUCtau
(h*mg/L)
Cmax (mg/L)
Tmax (h)
CL/F (L/h)
Vd/F (L)
T1/2 (h)
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GCV for AUC tau: 27%
control
HRZE
HRZQ
HR20ZQ
HR20ZM HR35ZE
23.5
2.6
3.0
17.0
151
6,1
Results - moxifloxacin
Comparison to historical PK data
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Moxifloxacin is metabolized only by phase II metabolism: glucuronidation and sulphation
Rifampicin lowers exposure to moxifloxacin by about 30% (Nijland et al, Clin Infect Dis 2007 & Weiner et al,
AAC 2007)
Other PK data using the same analytical method are available (Magis et al, Int J Antimicrob Agents. 2014)
Exposure to moxi in PanACEA-MAMS-TB-01 is low:
Moxifloxacin
Nijland et al, 2007
Magis et al, 2014
Weiner et al, 2007
HR20ZM
Indonesian patients,
n=19
moxi
AUCtau
(h*mg/L)
Cmax (mg/L)
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Mixed population
n=5 and n=7
moxi + RIF
moxi
48.2
33.3
4.7
3.2
moxi + RIF
38.1
28.1
Healthy volunteers,
mixed population,
n=16
moxi
moxi+RIF
Africans, n=19
moxi + RIF
38.7
28.4
23.5
3.7
3.5
2.6
Clinical relevance ?
In-vitro studies and animal studies suggest higher dose of moxi for TB (Gumbo et al, JID 2004 & Almeida
et al, AAC 2007)
PK interaction involved in suboptimal effect moxi in REMOX study ? (Alffenaar, Gumbo, Aarnoutse, N Engl J
Med 2015)
Results - isoniazid
Isoniazid
AUCtau
(h*mg/L)
Cmax (mg/L)
Tmax (h)
CL/F (L/h)
Vd/F (L)
T1/2 (h)
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One-way ANOVA: no difference in AUC0-24
between arms
Metabolized by acetylation (NAT2),
hydrolysis, oxidation (CYP2E1) and
conjugation (GSTM1)
No apparent strong effect of high dose
rifampicin on exposure to INH
control
HRZE
11.1
2.4
3.0
23.2
106.9
3.2
HRZQ
11.3
1.9
3.9
22.7
124.4
3.8
HR20ZQ
HR20ZM
8.4
1.6
3.2
31.6
143.3
3.1
10.3
1.8
3.3
24.5
133.1
3.8
HR35ZE
9.1
2.0
3.0
26.4
124.7
3.3
Results - pyrazinamide
Pyrazinamide
AUCtau
(h*mg/L)
Cmax (mg/L)
Tmax (h)
CL/F (L/h)
Vd/F (L)
T1/2 (h)
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One-way ANOVA: no difference in AUC024 between arms
Metabolized to pyrazinoic acid and 5hydroxypyrazinoic acid
No apparent strong effect of high dose
rifampicin on exposure to PZA
2.0-2.7 fold difference in AUC0-24,
GCV: 21-30%
control
HRZE
361
33.5
3.0
3.8
38.7
7.1
HRZQ
339
27.8
4.0
4.1
39.8
6.8
HR20ZQ HR20ZM HR35ZE
324
27.3
4.0
4.4
42.1
6.7
350
30.1
4.0
3.0
38.7
6.7
306
31.3
3.0
4.1
34.8
5.8
Results - ethambutol
Ethambutol
AUCtau
(h*mg/L)
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Control
HRZE
HRZQ
HR20ZQ
HR20ZM
HR35ZE
19.1
17.9
Cmax (mg/L)
2.4
2.2
Tmax (h)
4.0
4.0
CL/F (L/h)
49.9
49.7
Vd/F (L)
657
681
T1/2 (h)
9.2
9.5
T-test: no difference in AUC0-24
between arms
Cleared both hepatically and renally,
pathways in hepatic clearance
unknown
No apparent strong effect of high
dose rifampicin on exposure to
ethambutol
Results – predictors /determinants of PK
• Gender: isoniazid: higher AUC0-24 in females versus men (GM 9.2 vs 12.2 h*mg/L, p=0.02)
rifampicin, ethambutol, moxifloxacin: no differences in AUC0-24
• Acetylator status: fast/intermediate vs slow acetylator based on T1/2: 6.4 vs 11.0 h*mg/L, p<0.001
In multivariate analyses, both gender and acetylator status affect INH AUC0-24
• Age:
no significant correlations with AUC and Cmax
• Weight / BMI: pending
• ‘Ethnicity’ (Tanzanians vs South Africans)
rifampicin:
Tanzanians lower rifampicin AUC0-24 only at 35 mg/kg
(GM 145 vs 206 h*mg/L, n=11 vs n=9, p=0.001)
pyrazinamide: Tanzanians lower pyrazinamide AUC0-24
(GM 317 vs 360 h*mg/L, n=53 vs n=41, p=0.02)
• HIV status: numbers too small
Results – predictors /determinants of PK
Proportion of patients experiencing AEs
*Hepatic AEs resulting in a change of treatment,
pending final safety review.
Time to stable culture conversion on MGIT
liquid media over 12 weeks
Control
Included in
123
analysis
Median
62 days
time
Adj. HR1
(95% CI)
Q
20RQ
20RM
35R
58
56
63
63
63 days
66 days
55 days
48 days
0.82
0.73
1.42
1.75
(0.55 - 1.24) (0.48 - 1.13) (0.98 - 2.05) (1.21 - 2.55)
p=0.35
p=0.16
p=0.07
p=0.003
Analysis has been adjusted for: HIV status; baseline GeneXpert CT; centre; baseline culture
(using TTP).
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Time to stable culture conversion on MGIT
liquid media over 12 weeks
Control
Included in
123
analysis
Median
62 days
time
Adj. HR1
(95% CI)
Q
20RQ
20RM
35R
58
56
63
63
63 days
66 days
55 days
48 days
1.42
(0.98 - 2.05)
1.75
(1.21 - 2.55)
p=0.07
p=0.003
0.82
0.73
(0.55 - 1.24) (0.48 - 1.13)
p=0.35
p=0.16
Censoring data at 8 weeks (to mimic previous TB phase II trials)
Adj. HR
(95% CI)1
1.05
0.91
1.69
1.99
(0.60 - 1.83) (0.50 - 1.68) (1.02 - 2.80) (1.21 - 3.29)
p=0.88
p=0.78
p=0.04
p=0.007
Analysis has been adjusted for: HIV status; baseline GeneXpert CT; centre; baseline culture
(using TTP).
1
Time to stable culture conversion on MGIT
liquid media
Conclusions
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Increasing the dose of rifampicin increases average and minimum
exposures effectively
Large interindividual variability in exposure to rifampicin
Relatively low exposure to moxifloxacin with co-administered (high dose)
rifampicin: suggestion to increase the moxi dose to 600 mg or 800 mg QD
No apparent effect of high dose rifampicin on exposure to isoniazid,
pyrazinamide and ethambutol
Lower exposure to high dose rifampicin in TZ vs SA patients
 high dose rifampicin to be evaluated in other populations
High dose (35 mg/kg) rifampicin + concomitant drugs is reasonably well
tolerated for 3 months in African TB patients
High dose rifampicin (35 mg/kg ) and 20 mg/kg plus moxifloxacin resulted
in an increased likelihood of, and shorter time to, culture conversion in
liquid media, not in solid
PK results for SQ109 and PK-PD analyses are pending
Acknowledgements
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South Africa
– Aurum, Tembisa: Gavin Churchyard, Solome Charalambous, Robert Wallis
– CHRU, University of Witwatersrand, Johannesburg: Ian Sanne, Karla Mellet
– TASK, University of Stellenbosch: Andreas Diacon, Jeannine Du Bois, Armour Venter
– The Lung Institute, University of Cape Town: Rod Dawson, Kim Narunsky
– Triclinium
Tanzania
– IHI, Bagamoyo: Klaus Reither, Lilian Tina Minja
– KCRI, Moshi: Gibson Kibiki, Hadija Semvua, Stellah Mpagama, Charles Mtabho
– MMRC, Mbeya: Nyanda Ntinginya, Leonard Maboko
United States
– Sequella inc.: Carol Nacy, Lisa Beth Ferstenberg
United Kingdom
– University of St Andrews: Stephen Gillespie
– University of London, MRC CTU: Sunita Rehal, Patrick Phillips, Andrew Nunn
– University of London: Tim Mc Hugh
Germany
– Ludwig Maximilian University, Munich: Michael Hoelscher, Norbert Heinrich, Anka Mekota, Sonja
Henne
The Netherlands
– Radboudumc, Nijmegen: Martin Boeree, Georgette Plemper van Balen, Marloes Weijers, technicians
All other PanACEA site collaborators