Download VetACE Bioavailability and Pharmacodynamic Effect

®
VetACE Bioavailability and Pharmacodynamic Effect
Jurox Pty Limited recognises the concern that veterinarians face when making a decision to
change an older pet on important disease modifying drugs like benazepril from one formulation to
another. The main factor to be considered when making this decision is whether both
formulations will give the same therapeutic effect. With benazepril, the therapeutic effect of
vasodilation occurs due to decreased production of the vasopressor peptide Angiotensin II,
through inhibition of Angiotensin Converting Enzyme (ACE).
Jurox recently performed a Study (JX0507-K006) in healthy mixed breed dogs to assess whether
or not the administration of VetACE 2.5 mg tablets resulted in different pharmacodynamic
activity of benazeprilat (the active metabolite of benazepril) when compared to the pioneer
Fortekor* 2.5 (2.5 mg benazepril tablets, Novartis Animal Health Australasia Pty Limited).
Study Design
Dogs were physically examined and randomly assigned to receive either
1. Fortekor for two consecutive doses, 24 hours apart, followed by VetACE for two
consecutive doses 24 hours apart; or
2. VetACE for two consecutive doses, 24 hours apart, followed by Fortekor for two
consecutive doses 24 hours apart.
Dogs were clinically examined at three (3) hours after drug administration (the expected time of
peak drug effect) for signs of adverse effects on cardiovascular and respiratory function. Blood
samples were also collected at three (3) and twenty three (23) hours after administration of each
dose to assess the Angiotensin Converting Enzyme activity associated with administration of each
dose. Statistical analysis of ACE activity at these time points was made using a method to
investigate non-inferiority (i.e. whether administration of VetACE resulted in equal or greater
suppression of ACE activity compared to administration of Fortekor).
Results
There were no adverse events in the study or noticeable changes in clinical parameters associated
with the administration of either VetACE or Fortekor tablets. Dogs remained healthy throughout
the study period. Physical examination parameters fell within clinically acceptable values
throughout the study period. Table 1. shows mean (+/- sd) values for vital signs recorded three (3)
hours after administration of either Fortekor or VetACE at the registered label dose of 0.25 mg/kg.
Table 1. Mean (+/- sd) values for measured clinical parameters three (3) hours after administration
of either VetACE or Fortekor.
®
Examination Tim e
Poin t
Heart Rate
(beats per minute)
Respiratory Rate
Temperature
(breaths per minute) (degrees C)
Prior to treatment
129 (20)
16 (8)
38.1 (0.2)
3 hours after
Fortekor
administration
125 (14)
16 (8)
37.1 (2.9)
3 hours after
VetACE
administration
125 (13)
24 (21)
38.0 (0.3)
VetACE is a registered trademark of Jurox Pty Ltd. *Fortekor is a registered trademark of Novartis Animal Health
Statistical non-inferiority analysis of the two formulations revealed that VetACE administration
resulted in equal or lower levels of ACE activity at three (3) hours after administration of each
dose when compared to Fortekor. VetACE also produced equal or lower levels of ACE activity
23 hours after the first dose, but not 23 hours after the second dose. Figures 1 to 4 show the
individual dog’s percentage reduction in ACE activity compared to their baseline value for
Fortekor and VetACE at 3 and 23 hours after each dose, respectively.
% of Baseline ACE Activity
Figure 1. Percentage of Baseline ACE Activity
3 Hours After First Dose
120%
100%
80%
Fortekor
60%
V etACE
40%
20%
0%
Archy
B lue
Du ck
B oomer
Boon
Ike
Su rf
Anim al
% of Baseline ACE
Activity
Figure 2. Percentage of Baseline ACE Activity 23
Hours After First Dose
120%
100%
80%
60%
40%
20%
0%
Fortekor
VetACE
Archy
Blue
Duck
Boomer
Boon
Anim al
Ike
Surf
% of Baseline ACE
Activity
Figure
3. Percentage
of Baseline
ACEACE
Activity
Three
Figure
3. Percentage
of Baseline
Activity
(3)
Hours
After
Second
Dose
3 Hours After Second Dose
120%
100%
80%
60%
40%
20%
0%
Fortekor
VetACE
Archy
Blue
Duck
Boomer
Boon
Ike
Surf
Anim al
% of Baseline ACE
Activity
Figure 4. Percentage of Baseline ACE Activity
23 Hours After Second Dose
120%
100%
80%
60%
40%
20%
0%
Fortekor
VetACE
Archy
Blue
Duck
Boomer
Boon
Ike
Surf
Anim al
Figure 5 shows the mean ACE activities with 95% Confidence Interval limits. Time points have
been altered slightly to improve clarity of the values. Arrows (  ) indicate time of dose
administration.
ACE Activity
Figure 5. Mean (95% CI bars) ACE activity displayed as individual lines relating to treatment and
sequence.
Conclusions
This in vivo study measured the inhibition of plasma ACE activity as an indicator of the
pharmacodynamically important effect of benazeprilat when benazepril is administered for the
treatment of hypertension associated with cardiac or renal disease.
The results of this in vivo study showed that administration of VetACE produced equal or greater
suppression of serum Angiotensin Converting Enzyme activity at the expected time of peak effect
compared to the pioneer product, Fortekor.
VetACE can be used with confidence where inhibition of ACE activity and a resultant decrease in
Angiotensin II levels are desired therapeutic outcomes, such as with congestive heart failure and
chronic renal disease.