Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
BRILINTA can be taken with or without food. 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 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 AR-C124910XX) 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 t1/2 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 6. Effects are modest and do not require dose adjustment.
Patients with End-Stage Renal Disease on Hemodialysis
In patients with end stage renal disease on hemodialysis AUC and Cmax of BRILINTA 90 mg administered on a day without dialysis were 38% and 51% higher respectively, compared to subjects with normal renal function. A similar increase in exposure was observed when BRILINTA was administered immediately prior to dialysis showing that BRILINTA is not dialyzable. Exposure of the active metabolite increased to a lesser extent. The IPA effect of BRILINTA was independent of dialysis in patients with end stage renal disease and similar to healthy adults with normal renal function.
Figure 6 — Impact of intrinsic factors on the pharmacokinetics of ticagrelor
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 7 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.
Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure by up to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. Tmax was delayed by 1-2 hours. Exposure of the active metabolite decreased to a similar extent. Morphine co-administration did not delay or decrease platelet inhibition in healthy adults. Mean platelet aggregation was higher up to 3 hours post loading dose in ACS patients co-administered with morphine.
Co-administration of intravenous fentanyl with 180 mg loading dose of ticagrelor in ACS patients undergoing PCI resulted in similar effects on ticagrelor exposure and platelet inhibition.
Figure 7 — 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 AR-C124910XX 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 8.
Figure 8 — Impact of BRILINTA on the pharmacokinetics of co-administered drugs
In a genetic substudy cohort of PLATO, the rate of thrombotic CV events in the BRILINTA arm did not depend on CYP2C19 loss of function status.
Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MRHD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29‑fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8‑fold the MRHD based on AUC) was not carcinogenic in female rats.
Ticagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay.
Impairment of Fertility
Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (>15‑fold the MRHD on the basis of AUC). Doses of ≥10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5‑fold the MRHD based on AUC).
PLATO (NCT00391872) was 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), who presented within 24 hours of onset of the most recent episode of chest pain or symptoms. The study’s primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke.
Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients with previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent.
All patients randomized to BRILINTA received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Patients in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if clopidogrel therapy had not already been given. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment. Patients were treated for at least 6 months and for up to 12 months.
PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years. Median exposure to study drug was 276 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 7 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.
Events / 1000 patient years
Events / 1000 patient years
Composite of CV death, MI, or stroke
0.84 (0.77, 0.92)
Secondary endpoints †
0.79 (0.69, 0.91)
0.84 (0.75, 0.95)
1.17 (0.91, 1.52)
0.78 (0.69, 0.89)
The Kaplan-Meier curve (Figure 9) 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 9 - Time to first occurrence of CV death, MI, or stroke (PLATO)
The curves separate by 30 days [relative risk reduction (RRR) 12%] and continue to diverge throughout the 12‑month treatment period (RRR 16%).
Among 11,289 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=0.009). The results were similar for drug-eluting and bare metal stents.
A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Some of these are shown in Figure 10. 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 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., aspirin maintenance dose, use of PCI).
Figure 10 - Subgroup analyses of (PLATO)
Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified. 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.
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 different in US sites from sites outside of the US. About 8% of non-US investigators administered aspirin doses above 100 mg, and about 2% administered doses above 300 mg. In the US, 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 10 shows overall results by median aspirin dose. Figure 11 shows results by region and dose.
Figure 11 — CV death, MI, stroke by maintenance aspirin dose in the US and outside the US (PLATO)
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.
The PEGASUS TIMI-54 study (NCT01225562) was a 21,162-patient, randomized, double-blind, placebo-controlled, parallel-group study. Two doses of ticagrelor, either 90 mg twice daily or 60 mg twice daily, co-administered with 75-150 mg of aspirin, were compared to aspirin therapy alone in patients with history of MI. The primary endpoint was the composite of first occurrence of CV death, non-fatal MI and non-fatal stroke. CV death and all-cause mortality were assessed as secondary endpoints.
Patients were eligible to participate if they were ≥50 years old, with a history of MI 1 to 3 years prior to randomization, and had at least one of the following risk factors for thrombotic cardiovascular events: age ≥65 years, diabetes mellitus requiring medication, at least one other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance <60 mL/min. Patients could be randomized regardless of their prior ADP receptor blocker therapy or a lapse in therapy. Patients requiring or who were expected to require renal dialysis during the study were excluded. Patients with any previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. A small number of patients with a history of stroke were included. Based on information external to PEGASUS, 102 patients with a history of stroke (90 of whom received study drug) were terminated early and no further such patients were enrolled.
Patients were treated for at least 12 months and up to 48 months with a median follow up time of 33 months.
Patients were predominantly male (76%) Caucasian (87%) with a mean age of 65 years, and 99.8% of patients received prior aspirin therapy. See Table 8 for key baseline features.
History of >1 MI
Chronic non-end stage renal disease
Prior P2Y12 platelet inhibitor therapy
Lipid lowering therapy
The Kaplan-Meier curve (Figure 12) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke.
Figure 12 - Time to First Occurrence of CV death, MI or Stroke (PEGASUS)
Ti = Ticagrelor BID, CI = Confidence interval; HR = Hazard ratio; KM = Kaplan-Meier; N = Number of patients.
Both the 60 mg and 90 mg regimens of BRILINTA in combination with aspirin were superior to aspirin alone in reducing the incidence of CV death, MI or stroke. The absolute risk reductions for BRILINTA plus aspirin vs. aspirin alone were 1.27% and 1.19% for the 60 and 90 mg regimens, respectively. Although the efficacy profiles of the two regimens were similar, the lower dose had lower risks of bleeding and dyspnea.
Table 9 shows the results for the 60 mg plus aspirin regimen vs. aspirin alone.
HR (95% CI)
Events / 1000 patient years
Events / 1000 patient years
Time to first CV death, MI, or stroke †
0.84 (0.74, 0.95)
0.83 (0.68, 1.01)
Myocardial infarction §
0.84 (0.72, 0.98)
0.75 (0.57, 0.98)
All-cause mortality ‡
0.89 (0.76, 1.04)
CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; MI = Myocardial infarction; N = Number of patients.
In PEGASUS, the relative risk reduction (RRR) for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) were similar.
The treatment effect of BRILINTA 60 mg over aspirin appeared similar across most pre-defined subgroups, see Figure 13.
Figure 13 — Subgroup analyses of ticagrelor 60 mg (PEGASUS)
Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. 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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