Chemical formula: C₁₇H₂₅Cl₂F₃N₅O₁₂P₃S₂ Molecular mass: 776.35 g/mol PubChem compound: 9854012
Cangrelor is a direct P2Y12 platelet receptor antagonist that blocks adenosine diphosphate (ADP)-induced platelet activation and aggregation in vitro and ex vivo. Cangrelor binds selectively and reversibly to the P2Y12 receptor to prevent further signalling and platelet activation.
Cangrelor exhibits inhibition of activation and aggregation of platelets as shown by aggregometry (light transmission and impedance), point-of care assays, such as the VerifyNow P2Y12 test, VASP-P and flow cytometry. Onset of P2Y12 inhibition occurs rapidly upon cangrelor administration.
Following the administration of a 30 microgram/kg bolus followed by a 4 microgram/kg/min infusion, platelet inhibition is observed within two minutes. The pharmacokinetic/pharmacodynamic (PK/PD) effect of cangrelor is maintained consistently for the duration of the infusion.
Irrespective of dose, following cessation of the infusion, blood levels decrease rapidly and platelet function returns to normal within one hour.
The bioavailability of cangrelor is complete and immediate. Cangrelor is rapidly distributed reaching Cmax within two minutes after administration of an intravenous bolus followed by infusion. The mean steady state concentration of cangrelor during a constant intravenous infusion of 4 micrograms/kg/min is 488 ng/mL.
Cangrelor has a volume of distribution of 3.9 L. Cangrelor is 97-98% plasma-protein bound.
Cangrelor is deactivated rapidly in the plasma by dephosphorylation to form its primary metabolite, a nucleoside. The metabolism of cangrelor is independent of organ function and does not interfere with other drugs metabolised by hepatic enzymes.
The half-life of cangrelor is three to six minutes, independent of dose. Following the intravenous administration of a 2 micrograms/kg/min infusion of [3H] cangrelor to healthy male volunteers, 93% of total radioactivity was recovered. Of the recovered material, 58% was found in urine and the remaining 35% was found in faeces, presumably following biliary excretion. Initial excretion was rapid, such that approximately 50% of the administered radioactivity was recovered in the first 24 hours, and 75% was recovered by 48 hours. Mean clearance was approximately 43.2 L/kg.
The pharmacokinetic properties of cangrelor have been evaluated and found to be linear in patients and healthy volunteers.
The pharmacokinetics of cangrelor are not affected by gender, age, or renal or hepatic status. No dose adjustment is needed for these populations.
Cangrelor has not been evaluated in a paediatric population.
Non-clinical data reveal no special safety risk for humans based on studies of safety pharmacology, mutagenicity and clastogenic potential.
Carcinogenicity studies have not been performed.
The primary adverse effects of cangrelor in rats and dogs occurred in the upper urinary tract and consisted of injury to renal tubules, renal pelvis, and ureter. Anatomical changes correlated with increased plasma creatinine and urea, and increased albumin and blood cells in urine. Injury to the urinary tract was reversible following cessation of dosing in an investigative study in rats.
Cangrelor produced dose-related foetal growth retardation characterised by increased incidences of incomplete ossification and unossified hind limb metatarsals in rats. In rabbits, cangrelor was associated with increased incidences of abortion and intrauterine losses, as well as foetal growth retardation at higher doses which may have been secondary to maternal toxicity. Cangrelor did not produce malformations in either the rat or rabbit reproductive studies.
Effects on fertility, ability to produce a pregnancy with female partner(s), sperm morphology and sperm motility were observed in the male rat fertility study when cangrelor was administered at human equivalent doses equal to 1.8 fold the recommended PCI dose. These effects were not apparent at lower doses and were reversible following cessation of dosing. In this study, semen analysis was conducted after 8 weeks of continuous treatment.
Female fertility was not affected at any dose.
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