|
|
| (2 intermediate revisions by one other user not shown) |
| Line 1: |
Line 1: |
| __NOTOC__
| | #REDIRECT [[Ticagrelor#Pharmacology]] |
| {{Ticagrelor}}
| |
| {{CMG}}; {{AE}} {{JH}}
| |
| | |
| ==Clinical Pharmacology==
| |
| | |
| Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature.
| |
| | |
| BRILINTA tablets for oral administration contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow.
| |
| | |
| ===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.
| |
| | |
| ===Pharmacodynamics===
| |
| | |
| 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 clopidogrel
| |
| | |
| {|
| |
| |[[File:Ticagrelor_06.png|thumb|800px]]
| |
| |}
| |
| | |
| {|
| |
| |[[File:Ticagrelor_07.png|thumb|800px]]
| |
| |}
| |
| | |
| 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 (2)].
| |
| | |
| ===Pharmacokinetics===
| |
| | |
| Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
| |
| | |
| ====<u>Absorption</u>====
| |
| | |
| 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.
| |
| | |
| ====<u>Distribution</u>====
| |
| | |
| The steady state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).
| |
| | |
| ====<u>Metabolism</u>====
| |
| | |
| [[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.
| |
| | |
| ====<u>Excretion</u>====
| |
| | |
| 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.
| |
| | |
| ====<u>Special Populations</u>====
| |
| | |
| 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
| |
| | |
| {|
| |
| |[[File:Ticagrelor_08.png|thumb|800px]]
| |
| |}
| |
| | |
| * BRILINTA has not been studied in patients with moderate or severe hepatic impairment.
| |
| | |
| '''Pediatric'''
| |
| | |
| Ticagrelor has not been evaluated in a pediatric population [see Use in Specific Populations (8.4)].
| |
| | |
| '''Body Weight'''
| |
| | |
| No dose adjustment is necessary for ticagrelor based on weight.
| |
| | |
| '''Smoking'''
| |
| | |
| 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.
| |
| | |
| {|
| |
| |[[File:Ticagrelor_09.png|thumb|800px]]
| |
| |}
| |
| | |
| ===<u>Effects of Other Drugs on BRILINTA</u>===
| |
| | |
| [[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
| |
| | |
| ==References==
| |
| | |
| <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = BRILINTA (TICAGRELOR) TABLET [ASTRAZENECA LP] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f7b3f443-e83d-4bf2-0e96-023448fed9a8 | publisher = |date = | accessdate = 26 February 2014 }}</ref>
| |
| {{Reflist|2}}
| |
| | |
| {{Antithrombotics}}
| |
| | |
| [[Category:ADP receptor inhibitors]]
| |
| [[Category:Triazolopyrimidines]]
| |
| [[Category:Organofluorides]]
| |
| [[Category:Alcohols]]
| |
| [[Category:AstraZeneca]]
| |
| [[Category:Cardiovascular Drugs]]
| |
| [[Category:Drugs]]
| |