CLINICAL PHARMACOLOGY
Mechanism Of Action
Cangrelor is a direct P2Y12 platelet
receptor inhibitor that blocks ADP-induced platelet activation and aggregation.
Cangrelor binds selectively and reversibly to the P2Y12 receptor to prevent
further signaling and platelet activation.
Pharmacodynamics
Cangrelor inhibits activation
and aggregation of platelets. After administration of a 30 mcg/kg IV bolus
followed by a 4 mcg/kg/min IV infusion, platelet inhibition occurs within 2
minutes.
Figure 2 shows the effect on
platelet activity, and its relation to cangrelor plasma concentration, of
administering a 30 mcg/kg IV bolus, followed by a 1-hour 4 mcg/kg/min IV
infusion, of cangrelor. The anti-platelet effect is maintained for the duration
of the infusion. After discontinuation of the infusion, the anti-platelet
effect decreases rapidly and platelet function returns to normal within 1 hour.
Figure 2: Cangrelor PD Characteristics
Pharmacokinetics
KENGREAL administered
intravenously has linear pharmacokinetics in both healthy volunteers and
patients. KENGREAL is rapidly distributed and metabolized, reaching Cmax within
2 minutes after administration of an intravenous bolus followed by infusion.
Distribution
In a study in healthy
volunteers, KENGREAL administration at a dose of 30 mcg/kg bolus plus 4
mcg/kg/min showed a volume of distribution of 3.9 L. Plasma protein binding of
KENGREAL is about 97-98%.
Metabolism
KENGREAL is deactivated rapidly
in the circulation by dephosphorylation to its primary metabolite, a
nucleoside, which has negligible anti-platelet activity. KENGREAL's metabolism
is independent of hepatic function and it does not interfere with other drugs
metabolized by hepatic enzymes.
Elimination
Following IV administration of
[3H] KENGREAL 58% of radioactivity was recovered in urine. The
remaining 35% of radioactivity was in feces, presumably following biliary
excretion. The average elimination half-life of KENGREAL is about 3-6 minutes.
Specific Populations
KENGREAL pharmacokinetics are
not affected by sex, age, renal status or hepatic function. No dose adjustment
is needed for these factors [see Use In Specific Populations].
Weight
Although weight was a
significant covariate for PK with higher clearance in heavier patients, the
impact of weight on drug exposure is accounted by the use of weight-based
dosing.
Drug-Drug Interactions
Co-administration of cangrelor with unfractionated
heparin, aspirin, and nitroglycerin was formally studied in healthy subjects,
with no evidence of an effect on the PK/PD of cangrelor.
In clinical trials cangrelor has been co-administered
with bivalirudin, low molecular weight heparin, clopidogrel, prasugrel, and
ticagrelor without clinically detectable interactions.
The expected antiplatelet effect of a 600 mg loading dose
of clopidogrel or a 60 mg loading dose of prasugrel was blocked when clopidogrel
or prasugrel was administered during a cangrelor infusion [see DRUG
INTERACTIONS].
In contrast, the antiplatelet effect of a 180 mg
ticagrelor loading dose was not altered significantly when ticagrelor was
administered during cangrelor infusion [see DRUG INTERACTIONS].
Figure 3: Inhibition (Mean) of 20 μM ADP-induced
Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after
Cangrelor 30 mcg/kg Bolus and 120-minute 4 mcg/kg Infusion with Transition to
Other Oral P2Y12 Platelet Inhibitors.
 |
As shown in Figure 3,
discontinuation of cangrelor infusion, followed by administration of the
irreversible P2Y12 platelet inhibitors clopidogrel and prasugrel led to a
1-hour decrease in IPA followed by an increase in inhibition of platelet
aggregation beginning at about one hour. This time course of platelet
inhibition reflects the pharmacokinetics of cangrelor (offset) followed by the
absorption and metabolism of clopidogrel and prasugrel to active metabolites
(onset). Administration of ticagrelor, a reversible P2Y12 platelet
inhibitor, during the cangrelor infusion led to minimal decrease in platelet
inhibition for approximately 0.5 hours following discontinuation of the
cangrelor infusion. Administering ticagrelor during cangrelor infusion does not
attenuate the anti-platelet effect of ticagrelor.
In vitro studies suggest that
neither cangrelor nor its major metabolites inhibit the activity of the hepatic
CYP isoenzymes at therapeutic concentrations. Therefore, cangrelor
administration is not expected to interfere with the hepatic metabolism of
other concomitantly administered therapeutic agents.
Clinical Studies
Champion Phoenix Trial
The CHAMPION PHOENIX trial was intended to test whether
faster platelet inhibition with cangrelor at the time of PCI would reduce the
rate of periprocedural thrombotic events compared to a drug with a slower
antiplatelet effect, clopidogrel, given at about the time of PCI. It was a
randomized, double-blind study in which patients with coronary artery disease
(stable angina, UA/NSTEMI, STEMI) requiring PCI and receiving standard therapy
including aspirin and heparin or bivalirudin were randomized 1:1 to KENGREAL
(n=5472) or to clopidogrel 300 or 600 mg (n=5470). Patients who had already
taken an oral P2Y12 platelet inhibitor were not eligible to enroll. Patients
administered glycoprotein IIb/IIIa inhibitors (GPI) or for whom GPI use was
planned were also not eligible to enroll. PHOENIX was thus a study of people
undergoing PCI who had not been previously treated with anti-platelet therapy
other than aspirin.
The primary outcome measure was the first occurrence of
any one of the composite endpoint of all-cause mortality, myocardial infarction
(MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) within
48 hours after randomization.
KENGREAL was administered as 30 mcg/kg bolus followed by
4 mcg/kg/min infusion for 2 to 4 hours. Clopidogrel 600 mg was administered
immediately at the end of the KENGREAL infusion in patients randomized to
KENGREAL. Clopidogrel 300 mg or 600 mg was administered shortly before PCI or
shortly afterward, in patients randomized to clopidogrel.
KENGREAL significantly reduced the occurrence of primary
composite endpoint events compared to clopidogrel (relative risk reduction
[RRR] 22%). Most of the effect was a reduction in post-procedural MIs detected
solely by elevations in CK-MB (type 4a MI). KENGREAL did not reduce the risk of
death. Table 2 shows the study results for the primary composite endpoint and
the contribution of each component to the primary endpoint.
Table 2: Primary Endpoint and Its Component Events at
48 Hours in CHAMPION PHOENIX (mITT populationa)
|
KENGREAL (N=5470) n (%) |
Clopidogrel (N=5469) n (%) |
KENGREAL vs. clopidogrel |
OR (95% CI) |
p-value |
Primary Endpoint Death/MI/IDR/ST |
257 (4.7) |
322 (5.9) |
0.78 (0.66,0.93) b |
0.005 |
Death |
18 (0.3) |
18 (0.3) |
|
|
MI |
202 (3.7) |
254 (4.6) |
|
|
IDR |
10 (0.2) |
14 (0.3) |
|
|
ST |
27 (0.5) |
36 (0.7) |
|
|
Note: if a subject had more
than one event at 48 hours, then worst outcome counted (death > MI > IDR
> ST)
 a The mITT population is all randomized subjects who received at
least one dose of study drug and underwent the index PCI procedure
b Based on logistic model adjusted for loading dose and baseline
patient status for primary endpoint |
A supplementary analysis was
also performed omitting two subcomponent events of the primary endpoint that
were of lesser clinical significance: intraprocedural stent thrombosis (defined
as a new or increasing thrombus within or adjacent to a deployed stent
occurring during the index PCI procedure), and myocardial infarction with less
than a 10-fold increase in CK-MB, or with less than a 5-fold increase in CK-MB
in the presence of new Q waves or new left bundle branch block (LBBB). These
results are shown in Table 3.
Table 3: Supplementary
Endpoint and Its Component Events at 48 Hours in CHAMPION PHOENIX (mITT
population)
n (%) |
KENGREAL
N=5470 |
Clopidogrel
N=5469 |
KENGREAL vs. clopidogrel OR (95% CI) |
Supplementary Endpoint Death/SCAI-MI/IDR/ARC-ST |
79 (1.4) |
114 (2.1) |
0.69 (0.52,0.92) |
Death |
18 (0.3) |
18 (0.3) |
|
SCAI-MIa |
48 (0.9) |
80 (1.5) |
|
IDR |
13 (0.2) |
16 (0.3) |
|
ARC-STb |
0 (0.0) |
0 (0.0) |
|
Note: if a subject had more
than one event at 48 hours, then worst outcome counted (death > SCAI-MI
> IDR > ARCST)
 a SCAI MI: CK-MB ≥ 10X ULN, or CK-MB ≥ 5X ULN with new Q
waves or new LBBB
 b ARC-ST defined according to the ARC definition [Cutlip et al.
2007] |
The effect of KENGREAL appeared to be consistent in a
variety of pre-specified and other clinically important subgroups (see Figure
4).
Figure 4: CHAMPION PHOENIX Study: Primary Efficacy
Endpoint by Subgroup (mITT Populationa)
a The mITT population is all randomized subjects who received
at least one dose of study drug and underwent the index PCI procedure. Note:
The figure above presents effects in various subgroups most of which are
baseline characteristics and most of which were pre-specified (patient
presentation and weight were not pre-specified subgroups). The 95% confidence
limits that are shown do not take into account how many comparisons were made,
nor do they reflect the effect of a particular factor after adjustment for all
other factors. Apparent homogeneity or heterogeneity among groups should not be
over-interpreted.
CHAMPION PCI And PLATFORM
Trials
Two additional concurrent
clinical trials of the effect of KENGREAL in patients undergoing percutaneous
coronary intervention, CHAMPION PCI and CHAMPION PLATFORM were conducted and
terminated early for futility. They were completed prior to the design and
conduct of CHAMPION PHOENIX. The comparative characteristics and outcomes of
each trial are shown in Table 4.
Table 4: Summary of the CHAMPION Trials
|
PCI |
PLATFORM |
PHOENIX |
Subjects Randomized (% of planned enrollment) |
8,846 (99%) |
5,346 (84%) |
11,145 (100%) |
Primary Endpoint at 48 hours |
Death, MI, or IDR |
Death, MI, or IDR |
Death, MI, IDR, or ST |
Outcome of primary analysis, OR (95% CI) |
1.05 (0.88, 1.24) |
0.87 (0.71, 1.07) |
0.78 (0.66, 0.93) |
Clopidogrel dose and time in clopidogrel arm |
600 mg immediately before PCI |
600 mg immediately after PCI |
300 or 600 mg shortly before or shortly after PCI |
Population enrolled (%) |
Stable angina |
15% |
5% |
58% |
UA/NSTEMI |
74% |
95% |
26% |
STEMI |
11% |
Excluded |
16% |