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.
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%.
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.
Following IV administration of [3 H] 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.
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 ( 8)].
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.
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 ( 7.1)].
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 ( 7.1)].
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 P2Y 12 Platelet Inhibitors.
As shown in Figure 3, discontinuation of cangrelor infusion, followed by administration of the irreversible P2Y12 platelet inhibitors clopidogrel or 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 hour 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.
No carcinogenicity studies were conducted.
Cangrelor was non-mutagenic and non-clastogenic in genetic toxicology studies, including in vitro bacterial gene mutation assay, mouse lymphoma thymidine kinase assay, chromosome aberration assay in human peripheral lymphocytes, and in vivo bone marrow micronucleus assay in mice.
Impairment of Fertility
Cangrelor had no significant effect on male or female rats fertility treated by continuous infusion for 28 days, or on early embryonic development at steady state plasma concentration (Css) of approximately the same as that achieved in the PCI setting at the MRHD.
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.
|KENGREAL (N=5470) n (%)||Clopidogrel (N=5469) n (%)||KENGREAL vs. clopidogrel|
|OR (95% CI)||p-value|
|Primary EndpointDeath/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.
|n (%)||KENGREAL( N=5470 )||Clopidogrel( N=5469 )||KENGREAL vs. clopidogrelOR (95% CI)|
|Supplementary EndpointDeath/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 >ARC-ST)
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 Population a )
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.
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