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Mechanism Of Action
Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.
The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6 week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist.
The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 2, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours. The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP.
As shown in Figure 3, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 3 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel.
Figure 2 : Mean inhibition of platelet aggregation
(±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg
Figure 3 : Mean inhibition
of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mg
twice daily, or clopidogrel 75 mg daily
Transitioning from clopidogrel to BRILINTA resulted in an absolute IPA increase of 26.4% and from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to BRILINTA without interruption of antiplatelet effect [see DOSAGE AND ADMINISTRATION].
Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0–4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).
The mean absolute bioavailability of ticagrelor is about 36%, (range 30%-42%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax, but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC. BRILINTA can be taken with or without food.
BRILINTA as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80-125% for ticagrelor and ARC124910XX) with a median tmax of 1.0 hour (range 1.0 – 4.0) for ticagrelor and 2.0 hours (range 1.0 – 8.0) for AR-C124910XX.
The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins ( > 99%).
CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.
The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t½ is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.
The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 4. Effects are modest and do not require dose adjustment.
Figure 4 : Impact of intrinsic factors on the
pharmacokinetics of ticagrelor
Ticagrelor has not been evaluated in a pediatric population [see Use in Specific Populations].
No dose adjustment is necessary for ticagrelor based on weight.
Habitual smoking increased population mean clearance of ticagrelor by approximately 22% when compared to non-smokers. No dose adjustment is necessary for ticagrelor based on smoking status.
Effects of Other Drugs on BRILINTA
CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 5 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g. cyclosporine) increase ticagrelor exposure.
Figure 5 : Effect of
co-administered drugs on the pharmacokinetics of ticagrelor
Effects of BRILINTA on Other Drugs
In vitro metabolism studies demonstrate that ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and ARC124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 6.
Figure 6 : Impact of
BRILINTA on the pharmacokinetics of co-administered drugs
The clinical evidence for the effectiveness of BRILINTA is derived from PLATO, a randomized double-blind study comparing BRILINTA (N=9333) to clopidogrel (N=9291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS). Patients were treated for at least 6 months and for up to 12 months. Study endpoints were obtained until the study was complete, even if drug was discontinued.
Patients who presented within 24 hours of onset of the most recent episode of chest pain or symptoms were randomized to receive BRILINTA or clopidogrel. Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent. Subjects in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if previous clopidogrel therapy had not been given prior to randomization. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. All subjects randomized to BRILINTA received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Concomitant aspirin was recommended at a loading dose of 160-500 mg. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment.
Because of ticagrelor's metabolism by CYP3A enzymes, the protocol recommended limiting the maximum dosage of simvastatin and lovastatin to 40 mg in both study arms. Because of an increased bleeding risk, the study excluded patients with previous intracranial hemorrhage, a gastrointestinal bleed within the past 6 months, or other factors that predispose to bleeding.
PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were > 65 years and 15% were > 75 years.
The study's primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke. The components were assessed as secondary endpoints.
Median exposure to study drug was 277 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO.
Table 4 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality.
Table 4 : Patients with Outcome Events, in PLATO (KM%)
|Hazard Ratio (95% CI)||p-value|
|Composite of CV death, MI, or stroke||9.8||11.7||0.84
|1First occurrence of specified event at any
2Including patients who could have had other non-fatal events or died
The difference between treatments on the composite resulted from effects on CV death and MI; each was statistically significant when considered as a secondary endpoint and there was no beneficial effect on strokes. For all-cause mortality the benefit was also statistically significant (p = 0.0003) with a hazard ratio of 0.78.
Among 11289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50-0.91; p=0.0091). The results were similar for drug-eluting and bare metal stents.
The Kaplan-Meier curve (Figure 7) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke in the overall study.
Figure 7 : Time to First
Occurrence of CV death, MI, or Stroke in PLATO
The curves separate by 30 days (RRR 12%) and continue to diverge throughout the 12 month treatment period (RRR 16%).
A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Many of these are shown in Figure 8. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two marked exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further below.
Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e.g., final diagnosis, aspirin maintenance dose, use of PCI). Patients were not stratified by initial diagnosis, but the effect in the unstable angina subset (determined after randomization) appeared smaller than the effect in the NSTEMI and STEMI subsets. The results in the subsets based on final diagnosis (STEMI, NSTEMI and unstable angina) are also presented in Figure 8.
Figure 8 : Subgroup analyses
Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant (p=0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable.
A wide variety of baseline and procedural differences between the US and non-US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs. bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome.
The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were very different in the US and elsewhere, with about 8% of non-US investigators using aspirin doses above 100 mg, and about 2% using doses above 300 mg, in contrast with US practice, where 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored BRILINTA when used with low maintenance doses ( ≤ 100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 8 shows overall results by median aspirin dose. Table 5 shows results by region and dose.
Table 5 : PLATO: CV Death, MI, Stroke by maintenance
aspirin dose in the US and outside the US
Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI.
Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of BRILINTA.
In a genetic substudy of PLATO (n=10,285), the effects of BRILINTA compared to clopidogrel on thrombotic events and bleeding were not significantly affected by CYP2C19 genotype.
Last reviewed on RxList: 4/13/2015
This monograph has been modified to include the generic and brand name in many instances.
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