Concomitant evaluation of cardiovascular, respiratory

Concomitant evaluation of cardiovascular, respiratory and central nervous system functions
following a single administration of a candidate drug in the cynomolgus monkey
Abdel-Ilah El Amrani, Stéphane Loriot, Francine El Amrani, Olivier Foulon, Roy Forster
CiToxLAB in France, 27005 Evreux, France
Figure 1: Plasma exposure
450
400
Plasma BM
45
350
40
300
35
250
200
Test item Dose 1
Test item Dose 2
150
30
100
25
Figure 5: Effects of TI on respiratory function
20
∆ TV (mL)
Vehicle
10
0
24
48
72
96
120
144
0
168
24
Test item Dose 1
48
72
Time (h)
96
Test item Dose 2
120
144
168
Time (h)
Cardiovascular function
When compared to controls, no noticeable changes in heart rate, mean, systolic and
diastolic arterial blood pressure, ECG parameters (PQ, QRS, QT, QTcb and QTcf) or body
temperature were observed on Day 1 or Day 7 after single intravenous administration
of TI (see figures 3 and 4). No treatment-related arrhythmias were reported at the
observation time-points in this study on Day 1 or Day 7.
HR (bpm)
HR (bpm)
Day 1
250
20
0
-10
-10
-20
-20
Vehicle
TI dose 1
TI dose 2
-30
-40
0
200
800
1000
150
50
0
200
400
600
800
1000
1200
Test item Dose 2
1400
0
200
400
600
800
SAP (mmHg)
Day 1
200
1500
1000
1000
500
500
0
0
1200
-2000
0
400
600
1000
Vehicle
Test item Dose 1
Test item Dose 2
0
200
400
600
800
1000
1200
1400
Vehicle
Test item Dose 1
25
0
200
400
600
10
0
300
300
250
250
800
1000
0
200
100
1200
400
600
400
325
325
400
600
800
1000
1200
1400
-30
Vehicle
TI dose 1
TI dose 2
0
200
400
600
0
200
400
600
800
1000
1200
1400
Day 7
1000
1200
1400
Autonomic domain
5
BD
4h
TI - Dose 1
168 h
6
3
0
BD
4h
168 h
Time
TI - Dose 2
Vehicle
10
5
BD
TI - Dose 1
TI - Dose 2
4h
168 h
Central Nervous System
(Functional Observation Battery FOB)
TI (at dose 1 and dose 2) had no relevant
effect on the neurologic, autonomic or
behavioral domains on Day 1 or Day 7 after
dosing (see figure 6).
Time
Vehicle
TI - Dose 1
TI - Dose 2
Vehicle
Test item Dose 1
Test item Dose 2
100
800
9
Test item Dose 2
175
1400
1400
Time (min)
Test item Dose 1
Test item Dose 2
200
1200
15
Vehicle
250
Test item Dose 1
1200
Behavioral domain
Vehicle
175
1000
10
0
250
1000
*** : p < 0.001 vs. Vehicle
Neurologic domain
Vehicle
QTcf (ms)
Day 1
800
1400
Time (min)
400
800
***
Time
Time (min)
QTcf (ms)
600
Figure 6: Effects of TI on Central Nervous System (1)
0
150
100
400
Day 7
-20
15
200
Test item Dose 2
200
-10
Vehicle
TI dose 1
TI dose 2
350
Test item Dose 1
0
30
0
Day 7
400
Vehicle
Vehicle
TI dose 1
TI dose 2
*: p < 0.05 vs. Vehicle
Time (min)
Day 1
Test item Dose 2
QT (ms)
150
1400
10
Time (min)
Day 1
400
Day 7
Time (min)
Figure 4: Effects of TI on ECG parameters
QT (ms)
1200
20
-30
50
0
1400
∆ f (breath/min)
-20
Time (min)
0
800
20
75
25
100
200
30
100
50
1200
*
-1500
-10
125
75
1000
-1000
1400
150
100
800
-500
Vehicle
TI dose 1
TI dose 2
175
125
600
Day 7
200
175
0
1000
Time (min)
Time (min)
SAP (mmHg)
400
2000
Severity Scores
0
200
∆ MV (mL/min)
1500
∆ f (breath/min)
Test item Dose 1
Test item Dose 2
0
0
Time (min)
Vehicle
Test item Dose 1
-50
Time (min)
Day 1
2000
-2000
Vehicle
50
1400
∆ MV (mL/min)
100
100
1200
-40
Time (min)
-1500
200
0
200
400
600
Time (min)
Plasma exposure (PK) and circulating biomarker (BM):
TI was quantified in plasma samples at pre-dose, 4, 24, 72 and 168 hours after
treatment. Cmax was reached at 4 hours after administration of TI and increased
dose- dependently (see figure 1). Single intravenous administration of TI produced
sustained and dose dependent increases in plasma biomarker (BM, see figure 2).
600
Vehicle
TI dose 1
TI dose 2
-30
-500
150
350
RESULTS
400
-1000
200
200
10
0
Severity Scores
Study Design
20
Day 7
250
150
Parameters:
- Cardiovascular parameters: implanted telemetry
Heart Rate: HR, Arterial blood pressure parameters: DAP, SAP and MAP, Body
temperature, ECG parameters: PQ, QRS, QT, QTcb and QTcF, Arrhythmia monitoring.
- R espiratory parameters: Jacket external telemetry (JET) & Respiratory Inductive
Plethysmography (RIP). Respiration rate, Tidal volume and Minute volume.
- CNS - Functional observation Battery (FOB) including 33 parameters covering the
following domains: Neurologic, Autonomic and Behavioral
30
Severity Scores
Twelve cynomolgus monkeys in total (Le Tamarinier, Mauritius) implanted with
telemetry transmitters (TL11M2-D70-PCT), Data Sciences International, Saint
Paul, (USA) were equipped with JET devices including Respiratory Inductive
Plethysmography (RIP). Implanted telemetry data were recorded and analyzed with
HEM, Notocord software. JET data were recorded and analyzed with DSI Ponemah
software. After a randomization, animals were allocated to three groups of 2 males
and 2 females: Vehicle group, TI dose 1 and TI dose 2. After an acclimation period,
animals were monitored by IT and JET, for 2 hours before and 24h after dosing.
Each animal received one single intravenous administration of TI or vehicle over a
period of 45 sec.
40
30
-50
Day 7
50
40
10
Figure 3: Effects of TI on heart rate and systolic arterial pressure
MATERIALS AND METHODS
∆ TV (mL)
Day 1
50
15
50
0
Respiratory function
With the exception of slight and isolated changes which were mainly related to
individual variations on day 7, TI (at dose 1 and dose 2) had no effect on respiratory
parameters up to 7 days after treatment (see figure 5).
Figure 2: Circulating biomarker (BM)
PK (Plasma exposure)
Circulating BM
Evaluation of the potential effects of new drug candidates on cardiovascular (CV),
respiratory (Res) and central nervous system (CNS) functions is a part of the safety
pharmacology core battery (ICH S7). These investigations are usually conducted
separately in conscious non-restrained rodents (for Res and CNS) and non-rodents
(for CV). A combination of implanted and jacketed (1, 2) external telemetry enables
investigation of all safety pharmacology core battery parameters within a single
study. Using a minimum number of animals, this approach allows collection of a
maximum amount of relevant scientific data and simultaneous investigation of any
possible interaction between different vital functions in the same animal. Therefore,
this approach may improve the safety pharmacology assessment bringing scientific,
economic and ethical benefits.
The purpose of the present study was to evaluate the feasibility of this approach
and to investigate the effect of one single administration of a test item (a biological
drug candidate, TI) simultaneously on CV, Res and CNS functions in the conscious
non restrained cynomolgus monkey using implanted (IT) and jacketed external
telemetry (JET).
Plasma concentration
Introduction
800
1000
1200
1400
Time (min)
BIBLIOGRAPHIC REFERENCES
(1) Chui, R. W., Fosdick, A., Conner, R., Jiang, J., Bruenner, B. A., Vargas, H. M., (2009). Assessment of two external
telemetry systems (PhysioJacketTM and JETTM) in beagle dogs with telemetry implants. Journal of pharmacological
and toxicological methods, 60, pp. 58-68.
(2) Vargas HM, Amouzadeh HR, Engwall MJ. (2013). Nonclinical strategy considerations for safety pharmacology:
evaluation of biopharmaceuticals. Expert Opin Drug Saf. 12(1):91-102.
www.citoxlab.com
Conclusion
In this study we have demonstrated the feasibility of combining implanted and jacketed
external telemetry to investigate the effect of one single administration of a test item
simultaneously on CV, Res and CNS functions in the conscious non restrained cynomolgus
monkey. The results confirm the efficacy of combining implanted and external telemetry in
one single investigation in safety pharmacology assessment.
This combination approach can be recommended for the evaluation of potential adverse
effects of drug candidates. It is a convenient approach for drugs with long lasting systemic
exposure, and it brings scientific, economical and ethical benefits.

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