Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the onset-offset and respond studies
Clinical Pharmacokinetics, 05/21/2012  Clinical Article

Husted SE et al. – Ticagrelor pharmacokinetics in stable coronary artery disease (CAD) patients were comparable to previous findings in stable atherosclerotic and acute coronary syndromes (ACS) patients, and were not affected by prior clopidogrel exposure or clopidogrel responsiveness. Ticagrelor effectively inhibited platelet aggregation, and trough plasma concentrations of ticagrelor and AR–C124910XX were sufficient to result in high IPA in stable CAD patients.

• Patients were treated with ticagrelor (180mg loading dose, 90mg twice daily maintenance dose) or clopidogrel (600mg loading dose, 75mg once daily maintenance dose) in addition to aspirin (acetylsalicylic acid) [75–100mg once daily].
• Ticagrelor administration was for 6 weeks in ONSET–OFFSET.
• In RESPOND, ticagrelor was given for 14 days before or after 2 weeks of clopidogrel in patients classified as clopidogrel responders or non–responders.
• Pharmacokinetics and IPA were evaluated following the loading and last maintenance doses.
• Exposure–IPA relationships were evaluated using a sigmoid maximum effect (Emax) model.
• The outcome measures were ticagrelor and AR–C124910XX (active metabolite) pharmacokinetics and exposure–IPA relationships in both trials, including the effect of prior clopidogrel exposure, and effects in clopidogrel responders and non–responders in RESPOND.

• In ONSET–OFFSET, maximum (peak) plasma concentration (Cmax), time to Cmax (tmax) and area under the plasma concentration–time curve from time 0 to 8 hours (AUC8) for ticagrelor were 733ng/mL, 2.0 hours and 4130ng•h/mL, respectively; and for AR–C124910XX were 210ng/mL, 2.1 hours and 1325ng•h/mL, respectively.
• Emax estimates were IPA >97%.
• Trough plasma ticagrelor (305ng/mL) and AR–C124910XX (121ng/mL) concentrations were 5.2 and 7.7 times higher than respective concentration producing 50% of maximum effect (EC50) estimates.
• In RESPOND, ticagrelor mean Cmax and AUC8 following 2–week dosing were comparable between clopidogrel responders (724ng/mL and 3983ng•h/mL, respectively) and non–responders (764ng/mL and 3986ng•h/mL, respectively).
• Pharmacokinetics of ticagrelor were unaffected by prior clopidogrel dosing.
• Emax estimates were IPA >96% for both responders and non–responders.
• Trough plasma concentrations were sufficient to achieve high IPA.