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Pharmacology: Pharmacodynamics: Mechanism of action: Ticagrelor (BRILINTA) contains Ticagrelor, a member of the chemical class cyclopentyl-triazolo-pyrimidines (CPTP), which is an oral, direct acting, selective, and reversibly binding P2Y12 receptor antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y12 dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding, but when bound to the P2Y12 receptor prevents ADP-induced signal transduction. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of cardiovascular events such as CV death, MI, or stroke.
Ticagrelor has an additional mechanism of action, increasing local endogenous adenosine levels by inhibiting equilibrative nucleoside transporter-1 (ENT-1). Adenosine is formed locally at sites of hypoxia and tissue damage through degradation of released adenosine tri- and di-phosphate (ATP and ADP). As adenosine degradation is essentially restricted to the intracellular space, inhibition of ENT-1 by ticagrelor prolongs the half-life of adenosine and thereby increases its local extracellular concentration providing enhanced local adenosine responses. Ticagrelor has no clinically significant direct effect on adenosine receptors (A1, A2A, A2B, A3) and is not metabolised to adenosine. Adenosine has been documented to have a number of effects that include: vasodilation, cardioprotection, platelet inhibition, modulation of inflammation, and induction of dyspnoea, which may contribute to the clinical profile of ticagrelor.
Pharmacodynamic effects: Onset of action: 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 20μM ADP as the platelet aggregation agonist in patients with stable coronary artery disease (CAD) on ASA. The onset was evaluated following a loading dose of 180 mg ticagrelor or 600 mg clopidogrel.
Ticagrelor (BRILINTA) demonstrates a rapid onset of pharmacological effect as demonstrated by a mean IPA for Ticagrelor (BRILINTA) at 0.5 hours after 180 mg loading dose of about 41%, with the maximum IPA effect of 87.9% to 89.6% by 2-4 hours post dose. 90% of patients had final extent IPA >70% by 2 hours post dose. The high IPA effect of Ticagrelor (BRILINTA) between 87%-89% was maintained between 2-8 hours. (See Figure 1.)
Click on icon to see table/diagram/imageOffset of effect: The offset was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily, again in response to 20 μM ADP. After the Ticagrelor (BRILINTA) and the active metabolite concentrations decline to a level less than that required for receptor saturation, IPA gradually decreases with declining plasma concentrations. Since Ticagrelor (BRILINTA) binds reversibly, the recovery of platelet function does not depend on replacement of platelets. Ticagrelor (BRILINTA) has a faster rate of offset of IPA as compared to clopidogrel as determined by the slope of offset from 4-72 hours after last dose (see Precautions).
Median final extent IPA measured after the last dose of Ticagrelor (BRILINTA) is approximately 20-30% higher for Ticagrelor (BRILINTA) compared to clopidogrel. However, by 24 hours post-dose, %IPA is similar between Ticagrelor (BRILINTA) and clopidogrel, and is lower for Ticagrelor (BRILINTA) from 72 hours through 7 days compared with the clopidogrel. Mean %IPA for Ticagrelor (BRILINTA) at 72 hours (Day 3) post last dose was comparable to clopidogrel at Day 5, and %IPA for Ticagrelor (BRILINTA) at Day 5 was similar to clopidogrel at Day 7, which is not statistically different from placebo. (See Figure 2.)
Click on icon to see table/diagram/imageResponders to Ticagrelor (BRILINTA): IPA induced by Ticagrelor (BRILINTA) has less variability at peak plasma concentrations of Ticagrelor (BRILINTA) observed with the 90 mg twice daily dose compared to clopidogrel 75 mg once daily. Patients with stable CAD predetermined to have low IPA response to clopidogrel (non-responders), and given a concomitant dose of ASA, exhibited higher mean IPA response after administration of Ticagrelor (BRILINTA) as compared to clopidogrel. In non-responders to clopidogrel, the IPA response to Ticagrelor (BRILINTA) was observed to be higher and more consistent. Ticagrelor (BRILINTA) treatment resulted in consistently higher IPA compared with clopidogrel, and this was apparent post dose for both responders and non-responders.
Switching data: Switching from clopidogrel 75 mg once daily to Ticagrelor (BRILINTA) 90 mg results in an absolute IPA increase of 26.4% and switching from Ticagrelor (BRILINTA) to clopidogrel results in an absolute IPA decrease of 24.5%. Patients can be switched from clopidogrel to Ticagrelor (BRILINTA) without interruption of antiplatelet effect (see Dosage & Administration).
Adenosine mechanism (ENT-1): Ticagrelor increased plasma adenosine concentrations in ACS patients and has been shown to augment several physiological responses to adenosine. Adenosine is a vasodilator; ticagrelor has been shown to augment adenosine-induced coronary blood flow increases in healthy volunteers and ACS patients. Adenosine is an endogenous platelet inhibitor; ticagrelor has been shown to augment adenosine-mediated inhibition of platelet aggregation in addition to platelet inhibition due to its P2Y12 antagonism. Adenosine has been linked to the cardio-protective effect of preconditioning; ticagrelor has been shown to reduce infarct size via an adenosine-mediated mechanism in a rat model of reperfusion injury. Adenosine also induces dyspnoea; ticagrelor has been shown to augment adenosine-induced dyspnoea in healthy volunteers. Thus, the dyspnoea observed in some patients taking ticagrelor (see Adverse Reactions) may partly be mediated by adenosine.
Clinical efficacy: The clinical evidence for the efficacy of Ticagrelor (BRILINTA) is derived from four phase 3 trials: The PLATO [PLATelet Inhibition and Patient Outcomes] Study, a comparison of Ticagrelor (BRILINTA) to clopidogrel, both given in combination with ASA and other standard therapy.
The PEGASUS TIMI-54 [PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk AcUte Coronary Syndrome Patients] study, a comparison of Ticagrelor (BRILINTA) treatment combined with ASA to ASA therapy alone.
The THEMIS [Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study] Study, a comparison of Ticagrelor (BRILINTA) treatment combined with ASA to ASA therapy alone.
The THALES [Acute STroke or Transient IscHaemic Attack Treated with TicAgreLor and ASA for PrEvention of Stroke and Death] Study, a comparison of Ticagrelor (BRILINTA) treatment combined with ASA to ASA therapy alone.
PLATO study (Acute Coronary Syndromes): The PLATO Study was a 18,624 patient randomised, double-blind, parallel group, phase 3, efficacy and safety study of Ticagrelor (BRILINTA) compared with clopidogrel for prevention of thrombotic events (CV death, MI and stroke) in patients with ACS (unstable angina, non-ST elevation MI [NSTEMI] or ST elevation MI [STEMI]. The median treatment duration for Ticagrelor (BRILINTA) was 276 days.
The Study was comprised of patients who presented within 24 hours of onset of the most recent episode of chest pain or symptoms. Patients were randomised to receive clopidogrel (75 mg once daily, with an initial loading dose of 300 mg), or a loading dose of 180 mg of Ticagrelor (BRILINTA) followed by a maintenance dose of 90 mg of Ticagrelor (BRILINTA) twice daily. Patients could have been medically managed, treated with PCI or CABG. (See Figure 3.)
Click on icon to see table/diagram/imageTicagrelor (BRILINTA) reduced the occurrence of the primary composite endpoint compared to clopidogrel in both the UA/NSTEMI and STEMI population. (See Table 1.)
Click on icon to see table/diagram/imageTicagrelor (BRILINTA) is superior to clopidogrel in the prevention of thrombotic events (relative risk reduction [RRR] 16%, absolute risk reduction [ARR] 1.9%, NNT=54) of the composite efficacy endpoint CV death, MI, and stroke) over 12 months. The difference in treatments was driven by cardiovascular death and myocardial infarction with no difference on strokes. Ticagrelor (BRILINTA) demonstrated a statistically significant RRR of 16% (ARR 1.1%) for MI and a 21% relative risk reduction (ARR 1.1%) for CV death. Treating 91 patients with Ticagrelor (BRILINTA) instead of clopidogrel will prevent 1 CV death.
Ticagrelor (BRILINTA) showed superiority to clopidogrel in preventing the composite endpoint CV death, MI, or stroke). This result appeared early (ARR 0.6% and RRR of 12% at 30 days), with a constant treatment effect over the entire 12-month period, yielding ARR 1.9% per year with RRR of 16%. This suggests it is appropriate to treat for at least 12 months (see Dosage & Administration).
In PLATO, a large number of subgroup comparisons were conducted for the primary efficacy endpoint to assess the robustness and consistency of the overall benefit. The treatment effect of Ticagrelor (BRILINTA) vs. clopidogrel appears consistent across multiple patient subgroups by demographic characteristics including weight, gender, medical history, concomitant therapy, and by final index event diagnosis (STEMI, NSTEMI, and UA).
A weakly significant treatment interaction was observed with region whereby the hazard ration (HR) for the primary endpoint favours Ticagrelor (BRILINTA) in the rest of world but favours clopidogrel in North America, which represented approximately 10% of the overall population studied (interaction p-value=0.045).
This apparent treatment-by-region interaction observed in PLATO could plausibly be attributed to chance, at least in part. Additional analyses suggest that the efficacy of Ticagrelor (BRILINTA) relative to clopidogrel is associated with ASA dose during maintenance therapy. The data show greater efficacy of Ticagrelor compared to clopidogrel when used in conjunction with low maintenance dose ASA (75-150 mg). The relative efficacy of Ticagrelor versus clopidogrel when used with high doses of ASA (>300 mg) is less certain. Based on this observed relationship between maintenance ASA dose and relative efficacy of Ticagrelor compared to clopidogrel, it is recommended that Ticagrelor (BRILINTA) is used with a low maintenance dose of ASA 75-150 mg (see Dosage & Administration and Precautions).
The benefits associated with Ticagrelor (BRILINTA) were also independent of the use of other acute and long-term cardiovascular therapies, including heparin, low molecular weight heparin (LMWH), intravenous GpIIb/IIIa inhibitors, lipid-lowering drugs, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and proton pump inhibitors (see Interactions).
Ticagrelor (BRILINTA) demonstrated a statistically significant RRR in the composite endpoint of CV death, MI, and stroke in ACS patients planned for invasive management (RRR 16%, ARR 1.7%, p=0.0025). In an exploratory analysis, Ticagrelor (BRILINTA) demonstrated an RRR of the primary composite endpoint in ACS patients intended for medical management (RRR 15%, ARR 2.3%, nominal p=0.0444). Consistent with the primary endpoint of the study, the effect in these two groups was driven by CV death and MI with no effect on stroke. In patients receiving stents, there were numerically fewer definite stent thromboses among patients treated with Ticagrelor compared to clopidogrel (73 vs. 107, RRR 32%, ARR 0.6%, nominal p=0.0123).
Ticagrelor (BRILINTA) demonstrated a statistically significant RRR of 16% (ARR 2.1%) for the composite of all-cause mortality, MI, and stroke compared to clopidogrel.
The final secondary endpoint (all-cause mortality) was evaluated. Ticagrelor (BRILINTA) demonstrated a RRR of 22% for all-cause mortality compared to clopidogrel at a nominal significance level of p=0.0003 and an ARR of 1.4%.
Holter Substudy: To study the occurrence of ventricular pauses and other arrhythmic episodes during PLATO, investigators performed Holter monitoring in a subset of nearly 3,000 patients, of whom approximately 2,000 had recordings both in the acute phase of their ACS and after one month. The primary variable of interest was the occurrence of ventricular pauses ≥3 seconds. More patients had ventricular pauses with Ticagrelor (BRILINTA) (6.0%) than with clopidogrel (3.5%) in the acute phase; and 2.2% and 1.6%, respectively, after 1 month. More patients had ventricular pauses with Ticagrelor (BRILINTA) than with clopidogrel, however, there were no adverse clinical consequences associated with this imbalance (including pacemaker insertions) in this population of patients.
Genetic Substudy: In PLATO, 10,285 patients provided genetic samples for genotype determination of CYP2C19 and ABCB1 loci. An analysis provided these associations of genotype groupings on efficacy and safety outcomes in PLATO. The superiority of ticagrelor over clopidogrel in reducing major CV events was not significantly affected by patient CYP2C19 or ABCB1 genotype.
Similar to the overall PLATO Study, Total Major Bleeding did not differ between ticagrelor and clopidogrel regardless of CYP2C19 or ABCB1 genotype. Non-CABG PLATO Major bleeding was increased with ticagrelor compared to clopidogrel in patients with one or more CYP2C19 LOF allele, but was similar to clopidogrel in patients with no loss of function allele.
Combined Efficacy and Safety Composite: A combined efficacy and safety composite (CV death, MI, stroke, or PLATO-defined 'Total Major' bleeding) supports the clinical benefit of Ticagrelor compared to clopidogrel (RRR 8%, ARR 1.4%, HR 0.92; p=0.0257) over 12 months after ACS events.
PEGASUS Study (History of Myocardial Infarction): The PEGASUS TIMI-54 Study was a 21,162 patient, event-driven, randomised, double blind, placebo controlled, parallel group, international multicentre study to assess the prevention of thrombotic events with ticagrelor given at 2 doses (either 90 mg twice daily or 60 mg twice daily) combined with low dose ASA (75-150 mg) compared to ASA therapy alone in patients with history of MI and additional risk factors for atherothrombosis. The median treatment duration for Ticagrelor (BRILINTA) 60 mg was 29.4 months.
Patients were eligible to participate if they were aged 50 years or over, with a history of MI (1 to 3 years prior to randomisation), and had at least one of the following risk factors for atherothrombosis: age ≥65 years, diabetes mellitus requiring medication, a second prior MI, evidence of multivessel CAD, or chronic non-end-stage renal dysfunction. (See Figure 4 and Table 2.)
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Click on icon to see table/diagram/imageBoth 60 mg twice daily and 90 mg twice daily regimens of Ticagrelor (BRILINTA), in combination with ASA, were superior to ASA alone in the prevention of thrombotic events (composite endpoint: CV death, MI, and stroke), with a consistent treatment effect over the entire study period, yielding a 16% RRR and 1.27% ARR for ticagrelor 60 mg and a 15% RRR and 1.19% ARR for ticagrelor 90 mg.
Although the efficacy profile of ticagrelor 90 mg and 60 mg were similar, there is evidence that the lower dose has a better tolerability and safety profile in relation to risk of the bleeding and dyspnoea. Therefore, Ticagrelor (BRILINTA) 60 mg twice daily co-administered with ASA is recommended for the prevention of thrombotic events (CV death, MI and stroke) in patients with a history of myocardial infarction (MI occurred at least one year ago) and a high risk of developing a thrombotic event.
Relative to ASA alone, Ticagrelor (BRILINTA) 60 mg twice daily significantly reduced the primary composite endpoint of CV death, MI, and stroke. Each of the components contributed to the reduction in the primary composite endpoint (CV death 17% RRR, MI 16% RRR, and stroke 25% RRR).
Treating 79 patients for up to 36 months with Ticagrelor (BRILINTA) 60 mg twice daily in combination with ASA instead of ASA therapy alone will prevent one primary composite endpoint event.
The benefit of ticagrelor seen on the primary composite endpoint was also reflected across the two secondary endpoints, with a numerical decrease in both CV death and all-cause mortality for ticagrelor 60 mg combined with ASA compared to ASA therapy alone, but this did not reach statistical significance (see Table 2).
The RRR for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) was similar. This effect was consistent throughout the study, with duration up to 47 months (median 33 months). The consistency of RRR over time suggests that it is appropriate to continue treatment with ticagrelor as long as the patient remains at high risk of developing thrombotic events (see Dosage & Administration).
The treatment effect of Ticagrelor (BRILINTA) 60 mg twice daily vs. ASA was consistent across major subgroups, see Figure 5.
Click on icon to see table/diagram/imageThe treatment effect of Ticagrelor (BRILINTA) 60 mg twice daily vs. ASA therapy alone was consistent across multiple patient subgroups, based on demographic characteristics including weight, gender, medical history, and region.
The benefits associated with Ticagrelor (BRILINTA) were also independent of the use of other cardiovascular therapies including lipid-lowering drugs, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers, nitrates, and proton pump inhibitors (see Interactions).
THEMIS Study (Coronary Artery Disease and Type 2 Diabetes Mellitus): The THEMIS study was a 19,220 patient, event-driven, randomized, double-blind, placebo-controlled, parallel group, international multi-centre study to assess the prevention of thrombotic events with Ticagrelor (BRILINTA) combined with low dose ASA (75-150 mg) compared to ASA therapy alone in patients with Coronary Artery Disease and Type 2 Diabetes Mellitus. The median ticagrelor treatment duration was 33.2 months.
Patients were eligible to participate if they were aged 50 years or over, had Coronary Artery Disease defined as history of percutaneous coronary intervention (58% of study population) or coronary artery bypass graft (29%) or no history of coronary revascularisation but angiographic evidence of ≥50% lumen stenosis of at least 1 coronary artery (20%) and Type 2 Diabetes Mellitus treated with glucose-lowering medication for at least 6 months prior to study start. Patients with a history of MI or stroke were not eligible.
In the total THEMIS study population, Ticagrelor (BRILINTA) twice daily in combination with ASA, was superior to ASA alone in the prevention of thrombotic events (composite endpoint: CV death, MI and stroke), HR 0.90 (95% CI: 0.81, 0.99, p=0.0378), corresponding to a relative risk reduction (RRR) of 10% and an absolute risk reduction (ARR) of 0.73%. The effect was driven by the individual components MI (HR 0.84, 95% CI: 0.71, 0.98) and stroke (HR 0.82, 95% CI: 0.67, 0.99), with no difference in CV death (HR 1.02, 95% CI: 0.88, 1.18). Of the secondary endpoints not assessed as part of the primary composite endpoint, Ticagrelor (BRILINTA) reduced the number of ischemic stroke events (HR 0.80, 95% CI: 0.64, 0.99) with no difference in all-cause death (HR 0.98, 95% CI 0.87, 1.10).
In THEMIS patients who had undergone PCI, treatment with Ticagrelor (BRILINTA) in combination with ASA, compared to ASA alone, resulted in the prevention of thrombotic events (composite endpoint: CV death, MI and stroke), HR 0.85 [95% CI: 0.74, 0.97] (see Table 3) corresponding to a 15% RRR, a 1.19% ARR with a more favourable benefit-risk balance than the total THEMIS study population. Fewer events were reported on Ticagrelor (BRILINTA) in combination with ASA, compared to ASA alone, for each of the components of the composite endpoint. (See Table 3 and Figure 6.)
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Click on icon to see table/diagram/imageThe risk reduction in the primary composite endpoint seen over time up to 54 months with Ticagrelor (BRILINTA) (Figure 6) suggests that it is appropriate to continue treatment with Ticagrelor (BRILINTA) as long as the patient remains at risk of developing a thrombotic event (see Dosage & Administration).
The treatment effect of Ticagrelor (BRILINTA) was consistent across patient subgroups, based on patient characteristics including weight, gender, medical history, and geographic region (see Figure 7).
Click on icon to see table/diagram/imageTHALES Study (Acute Ischaemic Stroke or Transient Ischaemic Attack): The THALES study was a 11,016 patient, event-driven, randomised, double-blind, placebo-controlled, parallel group, international multi-centre phase 3 study to test the hypothesis that Ticagrelor (BRILINTA) 90 mg in combination with ASA is superior to ASA alone in preventing stroke and death in patients with acute ischaemic stroke or transient ischaemic attack (TIA).
Patients were eligible to participate if they were aged 40 years or over, with non-cardioembolic acute ischaemic stroke (NIHSS score ≤5) or high-risk TIA (defined as ABCD score ≥6 or ipsilateral atherosclerotic stenosis ≥50% in the internal carotid or an intracranial artery). Patients who received thrombolysis or thrombectomy within 24 hours prior to randomisation were not eligible.
The study was comprised of patients who were randomised within 24 hours of onset of an acute ischaemic stroke or TIA. Patients received ticagrelor (90 mg twice daily, with an initial loading dose of 180 mg) and ASA or ASA alone for 30 days. The recommended ASA dose was 75-100 mg once daily and an initial loading dose of 300-325 mg. The median treatment duration was 31 days. (See Figure 8 and Table 4.)
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Click on icon to see table/diagram/imageTicagrelor (BRILINTA) 90 mg twice daily, in combination with ASA, was superior to ASA alone in prevention of the composite endpoint of stroke and death, which corresponded to a relative risk reduction (RRR) of 17% and an absolute risk reduction (ARR) of 1.1% (Table 4). The effect was driven by a reduction in the stroke component of the primary endpoint (19% RRR, 1.1% ARR).
There was a statistically significant reduction in the rate of ischaemic stroke for Ticagrelor (BRILINTA) in combination with ASA compared to ASA alone (21% RRR, 1.2% ARR).
In a pre-defined exploratory analysis, there were fewer subsequent disabling stroke events (defined by patients with a subsequent stroke and having an mRS score >2) in patients treated with Ticagrelor (BRILINTA) 90 mg with ASA compared to ASA alone (150 (2.7%) vs. 188 (3.5%), respectively).
A pre-defined exploratory analysis was performed in patients with ipsilateral atherosclerotic stenosis >30%, in whom there were numerically fewer primary endpoint events (composite of stroke and death) for patients treated with Ticagrelor (BRILINTA) 90 mg with ASA compared to ASA alone (92 (8.1%) vs 132 (10.9%), respectively).
The treatment effect of Ticagrelor (BRILINTA) in combination with ASA vs. ASA alone was consistent across pre-defined subgroups, see Figure 9.
Click on icon to see table/diagram/imagePaediatric population: In a randomised, double-blind, placebo-controlled, phase 3 trial, the primary objective of reducing the rate of vaso-occlusive crises in paediatric patients aged 2 to less than 18 years with sickle cell disease, was not met.
Pharmacokinetics: General: Ticagrelor demonstrates linear pharmacokinetics and exposure to Ticagrelor (BRILINTA) and the active metabolite (AR-C124910XX) are approximately dose proportional.
Absorption: Absorption of Ticagrelor (BRILINTA) is rapid with a median tmax of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) from Ticagrelor (BRILINTA) is rapid with a median tmax of approximately 2.5 hours. The Cmax and AUC of Ticagrelor (BRILINTA) and the active metabolite increased in an approximately proportional manner with dose over the dose range studied (30-1260 mg).
The mean absolute bioavailability of Ticagrelor (BRILINTA) was estimated to be 36% (range 25.4% to 64.0%). Ingestion of a high-fat meal had no effect on Ticagrelor (BRILINTA) Cmax or the AUC of the active metabolite, but resulted in a 21% increase in Ticagrelor (BRILINTA) AUC and 22% decrease in the active metabolite Cmax. These small changes are considered of minimal clinical significance; therefore, Ticagrelor (BRILINTA) can be given with or without food.
Ticagrelor 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 the active metabolite). Initial exposure (0.5 and 1 hour post-dose) from crushed ticagrelor tablets mixed in water was higher compared to whole tablets, with a generally identical concentration profile thereafter (2 to 48 hours).
Distribution: The steady state volume of distribution of Ticagrelor (BRILINTA) is 87.5 L. Ticagrelor (BRILINTA) and the active metabolite is extensively bound to human plasma protein (>99.0%).
Metabolism: CYP3A is the major enzyme responsible for Ticagrelor (BRILINTA) metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. Ticagrelor (BRILINTA) and the active metabolite are weak P-glycoprotein inhibitors.
The major metabolite of Ticagrelor (BRILINTA) is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for Ticagrelor (BRILINTA).
Excretion: The primary route of Ticagrelor (BRILINTA) elimination is via hepatic metabolism. When radiolabeled Ticagrelor (BRILINTA) is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 26.5% in urine). Recoveries of Ticagrelor (BRILINTA) and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the active metabolite is mostly via biliary secretion. The mean t½ was approximately 6.9 hours (range 4.5-12.8 hours) for Ticagrelor (BRILINTA) and 8.6 hours (range 6.5-12.8 hours) for the active metabolite.
Special populations: Elderly: Higher exposures to Ticagrelor (BRILINTA) (approximately 60% for both Cmax and AUC) and the active metabolite (approximately 50% for both Cmax and AUC) were observed in elderly (≥65 years) subjects compared to younger subjects. These differences are not considered clinically significant (see Dosage & Administration).
Paediatric: Ticagrelor (BRILINTA) is not indicated in a pediatric population (see Dosage & Administration and Pharmacology: Pharmacodynamics as previously mentioned).
Gender: Higher exposures to Ticagrelor (BRILINTA) (approximately 52% and 37% for Cmax and AUC, respectively) and the active metabolite (approximately 50% for both Cmax and AUC) were observed in women compared to men. These differences are not considered clinically significant.
Renal impairment: Exposure to Ticagrelor (BRILINTA) was approximately 20% lower and exposure to the active metabolite was approximately 17% higher in patients with severe renal impairment compared to subjects with normal renal function. The IPA effect of Ticagrelor (BRILINTA) was similar between the two groups, however there was more variability observed in individual response in patients with severe renal impairment.
In patients with end stage renal disease on haemodialysis AUC and Cmax of Ticagrelor (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 Ticagrelor (BRILINTA) was administered immediately prior to dialysis showing that Ticagrelor (BRILINTA) is not dialysable. Exposure of the active metabolite increased to a lesser extent. The IPA effect of Ticagrelor (BRILINTA) was independent of dialysis in patients with end stage renal disease and similar to subjects with normal renal function.
No dosing adjustment is needed in patients with renal impairment.
Hepatic impairment: Cmax and AUC for Ticagrelor (BRILINTA) were 12% and 23% higher in patients with mild hepatic impairment compared to matched healthy subjects, respectively, however the IPA effect of Ticagrelor (BRILINTA) was similar between the two groups. No dose adjustment is needed for patients with mild hepatic impairment. Ticagrelor (BRILINTA) has not been studied in patients with severe hepatic impairment and there is no pharmacokinetic information in patients with moderate hepatic impairment. (See Dosage & Administration, Contraindications, and Precautions.)
Ethnicity: Patients of Asian descent have a 39% higher mean bioavailability compared to Caucasian patients. Patients self-identified as Black had an 18% lower bioavailability of Ticagrelor (BRILINTA) compared to Caucasian patients. In clinical pharmacology studies, the exposure (Cmax and AUC) to Ticagrelor (BRILINTA) in Japanese subjects was approximately 40% (20% after adjusting for body weight) higher compared to that in Caucasians. The exposure in patients self-identified as Hispanic or Latino was similar to that in Caucasians.
Toxicology: Preclinical safety data: Preclinical data for Ticagrelor and major metabolite have not demonstrated unacceptable risk for adverse effects for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, and genotoxic potential.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar or above to clinical exposure levels and with possible relevance to clinical use were as follows: GI toxicity and gastrointestinal irritation.
No compound-related tumours were observed in a 2-year mouse study at oral doses up to 250 mg/kg/day (>18-fold the maximum human therapeutic exposure). There was no increase in tumours in male rats at oral doses up to 120 mg/kg/day (>15-fold the maximum human therapeutic exposure). There was an increase in uterine adenocarcinomas and hepatocellular adenomas plus adenocarcinomas and a decrease in pituitary adenomas and mammary fibroadenomas in female rats only exposed to high doses (>25-fold the maximum human therapeutic exposures). No change in tumour incidence was observed at 60 mg/kg/day (8-fold difference to the maximum human therapeutic exposure). The uterine tumours seen only in rats were found to be the result of a non-genotoxic endocrine effect of hormonal imbalance present in rats given high doses of Ticagrelor. The benign liver tumours are considered secondary to the response by the liver to the metabolic load placed on the liver from the high doses of Ticagrelor.
Ticagrelor has been tested in a range of in vitro and in vivo tests, and was not shown to be genotoxic.
Ticagrelor was found to have no effect on fertility of female rats at oral doses up to 200 mg/kg/day (approximately 20 times the maximum human therapeutic exposure) and had no effect on fertility of male rats at doses up to 180 mg/kg/day (15.7 times the maximum human therapeutic exposure).
Ticagrelor had no effect on foetal development at oral doses up to 100 mg/kg/day in rats (5.1 times the maximum human therapeutic exposure) and up to 42 mg/kg/day in rabbits (equivalent to the maximum human therapeutic exposure). Ticagrelor had no effects on parturition or postnatal development in rats at doses up to 60 mg/kg/day (4.6 times the maximum human therapeutic exposure).
