Pharmacokinetics-pharmacodynamics analysis of bicyclic 4

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Pharmacokinetics-pharmacodynamics analysis of bicyclic 4-nitroimidazole analogs in a
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murine model of tuberculosis.
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Suresh B. Lakshminarayana1#, Helena I. M. Boshoff2, Joseph Cherian1,a, Sindhu Ravindran1,b,
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Anne Goh1, Jan Jiricek1, Mahesh Nanjundappa1, Amit Nayyar2,c, Meera Gurumurthy1,d,
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Ramandeep Singh2, e, Thomas Dick1,d, Francesca Blasco1, Clifton E. Barry III2, Paul C. Ho3
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and Ujjini H. Manjunatha1#
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1
Novartis Institute for Tropical Diseases, Singapore, Singapore
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2
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute
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of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United
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States of America
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Department of Pharmacy, National University of Singapore, Singapore, Singapore
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#
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Suresh B. Lakshminarayana
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Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos
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Singapore, 138670
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Email: suresh.b_lakshminarayana@novartis.com; Phone: +65 67222991
Corresponding Authors SBL & UHM
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Ujjini H. Manjunatha
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Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos,
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Singapore, 138670
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Email: manjunatha.ujjini@novartis.com ; Phone: +65 67222976
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Key words: Tuberculosis, Pharmacokinetics, Pharmacodynamics, PA-824, Nitroimidazoles
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Present address:
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a
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b
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c
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d
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system, National University of Singapore, Singapore
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e
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Experimental Therapeutics Centre, Singapore
National University Health System, Singapore
AMRI Singapore Research Center, Singapore
Department of Microbiology, Yong Loo Lin School of Medicine, National University Health
Translational Health Science and Technology Institute, Gurgaon, Haryana, India
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Table S1. Correlation of PK parameters with in vivo efficacy in mice for bicyclic 4-nitroimidazole analogs.
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Compound ID
PA-824
NI-622
NI-644
NI-135
NI-136
NI-182
NI-297
Spearman
correlation with
efficacy
Dose
(mg/kg)
25
25#
25#
25
25
25
25
Plasma PK
Total concentration
Cmax (µg/mL) AUC (µg.h/mL)
6
50.9
7.4
54.2
8.1
44.8
1.2
4.8
2
10.7
3.5
22.5
6
99.1
rs = -0.52
rs = 0.11
Lung PK
Free concentration
fCmax (µg/mL)
fAUC (µg.h/mL)
0.6
5.1
0.2
1.6
0.8
4.5
0.1
0.4
0.3
1.8
0.3
2.0
0.1
1.8
rs = -0.58
rs = -0.16
Total concentration
Cmax (µg/g)
AUC (µg.h/g)
17.8
139.9
5.1
35.6
3.8
19
5.5
18.6
7.2
39.8
11.4
73.2
16.3
233.4
rs = 0.76
Mean log lung
CFU reduction
± SEM
1.48 ± 0.09
0.89 ± 0.08
0.48 ± 0.03
1.48 ± 0.07
1.31 ± 0.06
1.23 ± 0.14
1.56 ± 0.11
rs = 0.52
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PK parameters obtained from single dose PK data. Free concentrations in plasma were calculated using in vitro plasma protein binding. #PK
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parameters derived from 50 mg/kg. rs = Spearman correlation coefficient. ∆ Mean log lung CFU reduction compared to untreated controls. Each
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data represents mean value ± SEM from 5 animals.
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Table S2. Correlation of PK-PD indices with in vivo efficacy in mice for bicyclic 4-nitroimidazole analogs.
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Compound ID
PA-824
NI-622
NI-644
NI-135
NI-136
NI-182
NI-297
Spearman
correlation
with efficacy
Plasma PK-PD indices
Dose
(mg/kg)
25
25#
25#
25
25
25
25
Total concentration
Cmax/MIC
AUC/MIC %T>MIC
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170
66
41
301
65
90
498
93
40
160
66
67
357
65
175
1125
66
300
4955
100
rs = -0.05
rs = -0.05
rs =
0.30
Lung PK-PD indices
Free concentration
fCmax/MIC
fAUC/MIC
fT>MIC
2.0
17
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1.1
8.9
17
8.9
50
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3.3
13.3
16
10
60
49
15
100
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5.0
90
98
Total concentration
Cmax/MIC AUC/MIC
%T>MIC
59
466
96
28
198
64
42
211
84
183
620
95
240
1327
89
570
3660
75
815
11670
100
rs = -0.16
rs = 0.63
rs = 0.16
rs = 0.07
rs = 0.63
Mean log
lung CFU
reduction ±
SEM
1.48 ± 0.09
0.89 ± 0.08
0.48 ± 0.03
1.48 ± 0.07
1.31 ± 0.06
1.23 ± 0.14
1.56 ± 0.11
rs = 0.88
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PK-PD indices were calculated using PK parameters obtained from single dose PK data and in vitro potency. Free concentrations in plasma were
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calculated using in vitro plasma protein binding. #PK parameters derived from 50 mg/kg. rs = Spearman correlation coefficient . ∆ Mean log lung
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CFU reduction compared to untreated controls. Each data represents mean value ± SEM from 5 animals.
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Figure S1: Plasma concentration time profiles of representative bicyclic 4-nitroimidazole
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analogs following a single 25 mg/kg dose in mice
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Mean Conc. +/- SD (ng/mL)
100000
PA-824
10000
NI-147
NI-135
1000
NI-297
NI-302
100
10
1
0
10
20
Time (h)
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57
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