Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor represents the standard of care treatment for the management of patients with acute coronary syndrome. |
Ticagrelor is the first of a new class of P2Y12 receptor inhibitors, which is distinct from clopidogrel and prasugrel with respect to its unique mode of action. |
This article provides a comprehensive overview of the pharmacokinetic, pharmacodynamic and pharmacogenetic profiles of ticagrelor in different study populations—updating a previous review on this topic. |
1 Introduction
2 Ticagrelor Pharmacokinetic Profile
2.1 Absorption, Distribution, Metabolism and Excretion
End point | Prasugrel [31] | ||
---|---|---|---|
Metabolic activation required | No Major metabolite (AR-C124910XX) is equipotent to the parent compound | Yes | Yes |
Reversibility of binding to ADP receptor | Reversible | Irreversible | Irreversible |
Single-dose pharmacokinetic parameters | |||
t
max
| Ticagrelor: 1.3–2 h AR-C124910X: 1.3–3 h | 30–60 mina
| 30 mina
|
t
½
| Ticagrelor: 7.7–13.1 h AR-C124910X: 7.5–12.4 h | 30 mina
| 7 (2–15) ha
|
Onset of IPA | |||
40–50 % IPA | 30 min | 2–4 h | 1 h |
Maximum IPA | 2 h | 8 h | 3 h |
Duration of IPA | 3–5 days | 7–10 days | 5–10 days |
2.2 Ticagrelor Pharmacokinetics in Special Populations
2.3 Drug Interactions
2.3.1 Effects of Ticagrelor on the Pharmacokinetics of Other Products
2.3.2 Effects of Other Products on the Pharmacokinetics of Ticagrelor
Effect of ticagrelor on the pharmacokinetics of other compounds | |||
---|---|---|---|
Compound | Observation following co-administration of ticagrelor | Author recommendation | References |
CYP3A substrates, e.g. midazolam, ergot alkaloids, cisapride | Ticagrelor is a weak inhibitor or activator of midazolam affecting both hepatic and intestinal CYP3A activity | Co-administration of ticagrelor with CYP3A substrates that have a narrow therapeutic profile such as ergot alkaloids and cisapride should be avoided | Zhou et al. [28] Teng et al. [20] Teng and Butler [46] Brilinta PI [29] |
Statins, i.e. atorvastatin, simvastatin |
C
max of atorvastatin increased by 23 %; AUC increased by 36 %
C
max of simvastatin increased by 81 %; AUC increased by 56 % | Concomitant use of simvastatin or lovastatin at doses greater than 40 mg should be avoided with ticagrelor | Teng et al. [47] Brilinta PI [29] |
Oral contraceptives, e.g. ethinyl oestradiol, levonorgestrel | No effects on pharmacokinetics of ethinyl oestradiol and levonorgestrel | No clinically relevant effect of ticagrelor on oral contraceptive efficacy or safety is expected | Butler and Teng [48] |
CYP2C9-mediated drugs, e.g. proton pump inhibitors | No interactions observed | Proton pump inhibitors (metabolized by CYP2C enzymes) are unlikely to have any significant pharmacokinetic interaction with ticagrelor | Agewall et al. [50] |
CYP2D6-mediated drugs, e.g. venlafaxine |
C
max of venlafaxine increased by 22 % | Ticagrelor is not expected to affect CYP2D6-mediated drug metabolism to a clinically relevant extent on the basis of these data | Teng et al. [51] |
P-gp-dependent drugs, e.g. digoxin |
C
max of digoxin increased by 75 %; AUC increased by 28 % | Appropriate monitoring is recommended when administering ticagrelor with P-gp-dependent drugs possessing a narrow therapeutic profile (e.g. digoxin) | Teng and Butler [52] |
Effect of other compounds on the pharmacokinetics of ticagrelor | |||
---|---|---|---|
Compound | Observation following co-administration of ticagrelor | Study conclusions | References |
CYP3A inducers, e.g. rifampicin | Rifampicin reduced ticagrelor pharmacokinetic parameters: C
max by 73 %, AUC by 86 % and plasma half-life by 67 % | Co-administration of strong CYP3A/P-gp inducers with ticagrelor should be discouraged | Teng et al. [53] |
Moderate CYP3A4 inhibitors, e.g. grapefruit juice | Grapefruit juice increased ticagrelor pharmacokinetic parameters: C
max by 165 % and AUC by 221 % | Care is needed if grapefruit juice is taken with ticagrelor | Holmberg et al. [54] |
Strong CYP3A4 inhibitors, e.g. ketoconazole | Ketoconazole increased ticagrelor pharmacokinetic parameters: C
max by 135 % and AUC by 632 % | The use of ticagrelor with strong CYP3A4 inhibitors is contraindicated | Teng and Butler [55] Brilinta PI [29] |
Immunosuppressants, e.g. cyclosporine | Cyclosporine increased ticagrelor pharmacokinetic parameters: AUC by 283 % and C
max by 230 % | The magnitude of effect on ticagrelor pharmacokinetics is not considered sufficient to warrant dose adjustment of ticagrelor | Teng et al. [56] |
Anticoagulants, e.g. heparin and enoxaparin | No noticeable influence on ticagrelor pharmacokinetics | No dose adjustment with ticagrelor is required | Teng and Butler [57] |