Cardiovascular Safety Pharmacology Study of a Single ... · CUMI was administered intravenously to four dogs al doses of 13.2, 6.6 or 3.3 ug/kg. There were no electrocardiographs

Cardiovascular Safety Pharmacology Study of a Single Intravenous Dose of CUMI in Conscious Beagle Dogs

SRI Study No. M748-10

Appendix F

CARDIOLOGY

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Appendix F-1

CARDIOLOGY REPORT AND INDIVIDUAL HEART RATE

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ELECTROCARDIOGRAPHY REPORT

FOR

SRI INTERNATIONAL


Study No. M748-10

Author: Jeffrey W. Richig, DVM ANILAB, LLC 500 Rt. 33 West, Suite LLA Millstone Township, NJ 08535 Document Status: Final Release date: Number of pages: 7

CONFIDENTIAL

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ECG Report for: Page 2 SRI International

Cardiovascular Safety Pharmacology Study of a Single Intravenous Dose of CUMI in Conscious Beagle Dogs Study No.: M748-10 _____________________________________________________________________________________ Table of Contents 1. Material and Methods .....................................................................................................3

1.1. Experimental Design ........................................................................................3

1.2. Electrocardiography and Blood Pressure Evaluations ......................................4

2. Results ..............................................................................................................................4

2.1. Electrocardiographic Evaluation and Blood Pressure Results ..........................4

3. Conclusion .......................................................................................................................5

4. Summary ..........................................................................................................................7

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Cardiovascular Safety Pharmacology Study of a Single Intravenous Dose of CUMI in Conscious Beagle Dogs Study No.: M748-10 _____________________________________________________________________________________ 1. Material and Methods 1.1. Experimental Design Test Article: CUMI Study Director: James Bakke, B.S. Testing started: May 24, 2010 Testing completed: June 29, 2010 Species: Canine, Beagle Route of Test Article Administration: Intravenous (iv); slow bolus Table 1. Dosing Schedule

Group A

Target Dose B Dose Level C

(µg/m2)

Dose Level

(µg/kg) Concentration

(µg/ml) No. Dogs

Evaluated C

1 100x

Human Dose

264.2 13.2 26.4 1M/1F

2 50x Human Dose 132.1 6.6 13.2 1M/1F

3 25x Human Dose 66.1 3.3 6.6 1M/1F

4 25x

(Confirm NOAEL)

66.1 3.3 6.6 1M/1F

A Each group was staggered each started on a new Day 1. B One male and one female dog was initially treated at a dose of 100x human dose (xHD). If no effect was observed at 100x HD, the dose level was escaled to 500x HD for Group 2. No further escalation was required after testing 500x HD. If an effect was observed at 100x HD, the dose level was de-escalated to 50x HD for Group 2. If an effect was observed at 50x HD, further de-escalation to 25x HD was tested for Group 3. However, if no effect was observed at 50x HD, then further de-escalation was not required. Testing was concluded by proceeding to confirm the NOAEL. Two animals (1 sex) previously not used for the escalation/de-escalation groups were used to confirm NOAEL. C Maximum human dose was 5 µg per 70 kg person. 5 µg/70kg = 0.0714 µg/kg x 37 (human surface area conversion) = 2.642 µg/m2. Scaling for the dog gave 2.642 µg/m2 / 20 (dog surface area conversion) = 0.132 µg/kg for the equivalent human dose in dog.

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Cardiovascular Safety Pharmacology Study of a Single Intravenous Dose of CUMI in Conscious Beagle Dogs Study No.: M748-10 _____________________________________________________________________________________ 1.2. Electrocardiography and Blood Pressure Evaluations Electrocardiograms (ECG), blood pressure (BP and heart rate (HR) were recorded from all animals at predose and approximately 0.5, 1, 2, 4 and 24 hours after each dose administration. A Schiller electrocardiograph was utilized to record the electrocardiograms. Six leads (Leads I, II, III, aVR, aVL, and aVF) were qualitatively evaluated for abnormalities. Blood pressure data were generated by SRI International and were evaluated by ANILAB for any treatment-related changes. 2. Results 2.1. Electrocardiographic Evaluation and Blood Pressure Results All electrocardiograms and mean blood pressure values were within normal limits for all dogs at all time points with the exception of the following:

Animal Number/ID Group Dose

Interval

Finding

001/0442 Group 1 30 Minutes Post-Dose Hypotension

001/0442 Group 1 2 Hours Post-Dose Sinus tachycardia

002/2445 Group 1 30 minutes Post-Dose

Occasional ventricular premature complexes

002/2445 Group 1 2 Hours Post-Dose and 4 Hours Post-

Dose

Hypotension

004/2445 Group 2 Predose and 4 Hours Post-

Dose

Hypotension Ventricular premature complex

004/2445 Group 2 30 Minutes Post-Dose and 1 Hour Post-

Dose

Hypotension

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Cardiovascular Safety Pharmacology Study of a Single Intravenous Dose of CUMI in Conscious Beagle Dogs Study No.: M748-10 _____________________________________________________________________________________ 2.1 Electrocardiographic Evaluation and Blood Pressure Results (continued)

Animal Number/ID Group Dose

Interval

Finding

004/2445 Group 2 2 Hours Post-Dose

Hypotension Occasional ventricular premature complexes

004/2445 Group 2 24 Hours Post-Dose

Occasional ventricular premature complexes

003/0442 Group 2 30 Minutes Post-Dose, 2 Hours Post-Dose and 4 Hours Post-

Dose

Hypotension

006/2445 Group 3 Predose, 30 Minutes Post-

Dose and 1 and 2 Hours Post-

Dose

Hypotension

005/0442 Group 3 30 Minutes Post-Dose and 2 Hours Post-

Dose

Hypotension

008/5376 Group 4 4 Hours Post-Dose Sinus tachycardia

3. Conclusion Dog 001/0442 (Group 1) had hypotension at 30 minutes post-dose and sinus tachycardia at 2 hours post-dose. The heart rate was 164 beats per minute. The upper limit of normal, for dogs, is 160 beats per minute. Sinus tachycardia can be a normal variant attributable to excitement or stress. Dog 002/2445 (Group 1) at 30 minutes post-dose had occasional ventricular premature complexes. Single (isolated) or occasional ventricular premature complexes can be a normal variant.

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Cardiovascular Safety Pharmacology Study of a Single Intravenous Dose of CUMI in Conscious Beagle Dogs Study No.: M748-10 _____________________________________________________________________________________ 3. Conclusion (continued) Dog 002/2445 (Group 1) also demonstrated hypotension at both 2 and 4 hours post-dose. Dog 004/2445 (Group 2) had hypotension at 30 minutes post-dose and 1 hour post-dose. Dog 003/0442 (Group 2) had hypotension at 30 minutes post-dose, 2 hours post-dose and 4 hours post-dose. Dog 004/2445 (Group 2) had hypotension and ventricular premature complexes at predose and 4 hours post-dose and had hypotension and occasional ventricular premature complexes at 2 hours post-dose and occasional ventricular premature complexes at 24 hours post-dose. Dog 006/2445 (Group 3) had hypotension at predose, 30 minutes post-dose and 1 and 2 hours post-dose. Dog 005/0442 (Group 3) had hypotension at 30 minutes post-dose and at 2 hours post-dose. Dog 008/5376 (Group 4) had sinus tachycardia at 4 hours post-dose. The heart rate was 167 beats per minute. Sinus tachycardia can be a normal variant attributable to excitement or stress. Hypotension noted during the course of this study was not considered to be treatment related. The finding was noted at various time-points throughout the course of the study in Groups 1, 2 and 3. The finding was not evident in Group 4 which was at a dose equal to Group 3. Hypotension was also noted, on occasion, at predose in dog (2445). There was no hard evidence to warrant labeling hypotension as a treatment-related effect. Ventricular premature complex(es) noted in dog (2445) during the course of this study were not considered to be treatment related. Single (isolated) ventricular premature complexes can be a normal variant. There was no evidence of ventricular premature complexes coupled or with increased frequency. A ventricular premature complex was also noted at predose in the same dog (2445). The fact that this dog may have already had underlying occasional ventricular premature complexes is a possibility. There was no clear evidence to warrant labeling ventricular premature complex(es) as a treatment-related effect. Therefore, there were no qualitative or quantitative electrocardiographic findings, including heart rate, or adverse effects on blood pressure that were attributable to the single intravenous dose administration of CUMI during Study M748-10.

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ECG Report for: Page 7

SRI International


Study No.: M748-10

4. Summary

CUMI was administered intravenously to four dogs al doses of 13.2, 6.6 or 3.3 ug/kg. There

were no electrocardiographs findings or adverse effects on blood pressure that were

attributable to the intravenous administration of CUMI.

V.JeTfrey^V. Richig, DVM (f Dale

ANILAB. LLC

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STUDY NUMBER: M748-10

STUDY INTERVAL: Predose

ECG DATA SHEET

Animal

Number

Heart

Rate in

beats per

minute

Heart

Rate in

beats per

minute

Heart

Rate in

beats per

minute

Heart

Rate in

beats per

minute

Heart

Rate in

beats per

minute

Comments

Signature: Date:'/?.?.(, I/O

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Appendix F-2

INDIVIDUAL ANIMAL BLOOD PRESSURE

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ID1st 2nd 3rd 4th 5th Avg 1st 2nd 3rd 4th 5th Avg 1st 2nd 3rd 4th 5th Avg

001/0442 % 101 130 110 147 136 124.8 75 86 86 63 88 79.6 85 107 94 101 110 99.4

003/0442 % 114 127 119 133 113 121.2 93 90 75 112 65 87.0 102 107 87 121 84 100.2

005/0442 % 98 164 92 61 129 108.8 50 146 64 39 82 76.2 73 154 76 47 95 89.0

007/1996 % 132 129 127 136 126 130.0 72 70 80 78 72 74.4 98 95 97 104 93 97.4Group 4: CUMI 25x Human Dose IV

Group 3: CUMI 25x Human Dose IV


MAP (mmHg)Predose, Males

Systolic (mmHg) Diastolic (mmHg)


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001/0442 % 96 85 99 81 85 89.2 39 24 26 34 33 31.2 67 54 62 56 59 59.6

003/0442 % 91 89 108 80 101 93.8 64 40 57 15 26 40.4 76 64 81 47 62 66.0

005/0442 % 79 85 73 82 82 80.2 19 38 28 27 37 29.8 49 60 50 54 59 54.4


30 min, MalesSystolic (mmHg) Diastolic (mmHg) MAP (mmHg)




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001/0442 % 88 138 100 103 110 107.8 68 112 59 48 36 64.6 77 123 78 75 71 84.8

003/0442 % 166 90 132 54 90 106.4 147 67 107 29 37 77.4 155 77 118 41 62 90.6

005/0442 % 109 106 90 122 90 103.4 74 39 65 81 61 64.0 90 71 74 100 71 81.2


1 hr, MalesSystolic (mmHg) Diastolic (mmHg) MAP (mmHg)




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001/0442 % 118 92 87 97 78 94.4 40 39 36 64 51 46.0 78 65 61 79 64 69.4

003/0442 % 107 96 99 99 100 100.2 63 62 72 35 56 57.6 84 76 81 66 76 76.6

005/0442 % 66 85 97 78 87 82.6 24 62 47 41 56 46.0 44 68 71 59 66 61.6






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001/0442 % 124 40 105 48 118 87.0 76 19 61 25 82 52.6 97 29 81 36 94 67.4

003/0442 % 82 101 91 92 92 91.6 20 23 68 46 45 40.4 51 62 78 68 68 65.4

005/0442 % 106 119 70 151 122 113.6 83 82 38 132 95 86.0 88 96 54 140 106 96.8






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001/0442 % 114 56 121 170 108 113.8 91 26 83 141 28 73.8 101 41 98 154 67 92.2

003/0442 % 109 107 111 124 142 118.6 61 77 69 63 106 75.2 83 90 87 90 111 92.2

005/0442 % 121 118 121 114 117 118.2 63 58 58 90 68 67.4 86 81 83 101 86 87.4






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002/2445 & 139 121 133 133 118 128.8 83 77 83 84 85 82.4 108 96 97 97 92 98.0

004/2445 & 97 103 87 78 81 89.2 38 33 40 28 41 36.0 67 68 63 53 60 62.2

006/2445 & 104 102 95 101 103 101.0 40 37 45 46 77 49.0 71 69 69 73 84 73.2

008/5376 & 154 161 129 128 128 140.0 115 42 75 76 66 74.8 131 101 100 97 95 104.8Group 4: CUMI 25x Human Dose IV

Predose, FemalesSystolic (mmHg) Diastolic (mmHg) MAP (mmHg)




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002/2445 & 113 115 118 95 91 106.4 81 67 67 48 38 60.2 88 89 90 71 63 80.2

004/2445 & 130 83 97 105 94 101.8 109 62 12 33 19 47.0 116 71 54 67 56 72.8

006/2445 & 99 81 85 92 88 89.0 60 39 62 59 45 53.0 73 59 71 72 65 68.0


30 min, FemalesSystolic (mmHg) Diastolic (mmHg) MAP (mmHg)




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002/2445 & 105 106 133 115 109 113.6 62 52 24 74 170 76.4 81 79 77 91 178 101.2

004/2445 & 89 99 103 119 107 103.4 46 50 28 64 43 46.2 67 74 65 90 72 73.6

006/2445 & 69 71 83 68 99 78.0 49 25 15 35 31 31.0 58 47 48 51 64 53.6


1 hr, FemalesSystolic (mmHg) Diastolic (mmHg) MAP (mmHg)




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002/2445 & 92 94 65 79 81 82.2 48 38 15 59 51 42.2 69 65 40 64 65 60.6

004/2445 & 98 104 78 98 103 96.2 75 61 38 44 45 52.6 84 79 58 70 74 73.0

006/2445 & 80 90 92 73 109 88.8 34 47 30 31 19 32.2 54 67 60 51 63 59.0






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002/2445 & 93 101 84 75 88 88.2 43 34 31 36 36 36.0 67 67 51 54 62 60.2

004/2445 & 75 87 95 108 119 96.8 26 64 25 59 60 46.8 49 74 59 81 87 70.0

006/2445 & 104 95 102 104 105 102.0 27 41 57 61 57 48.6 63 67 73 78 78 71.8






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002/2445 & 101 101 97 98 92 97.8 42 31 59 46 38 43.2 71 65 69 71 65 68.2

004/2445 & 118 123 114 125 108 117.6 92 36 71 83 63 69.0 104 78 90 102 81 91.0

006/2445 & 117 119 110 105 123 114.8 79 64 28 61 63 59.0 93 90 67 81 84 83.0






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Documents

Cardiovascular Safety Pharmacology Study of a Single ... · CUMI was administered intravenously to four dogs al doses of 13.2, 6.6 or 3.3 ug/kg. There were no electrocardiographs