Journal Article

A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers

Butler, Kathleen, Teng, Renli

2013

Overview

Purpose Ticagrelor is a reversibly binding P2Y 12 receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between digoxin, a P-glycoprotein substrate, and ticagrelor by evaluating the pharmacokinetics, safety, and tolerability. Methods This was a randomized, double-blind, two-period crossover study in healthy volunteers ( n  = 20). Pharmacokinetic parameters of digoxin and ticagrelor were evaluated following co-administration of ticagrelor 400 mg qd or placebo on days 1–16, and digoxin (0.25 mg bid on day 6 and 0.25 mg qd on days 7–14). Results Co-administration of ticagrelor increased the digoxin maximum plasma concentration by 75 %, from 1.8 ng/ml to 3.0 ng/ml (Gmean ratio [GMR] 1.75 [95 % CI, 1.52–2.01]); minimum plasma concentration by 31 %, from 0.5 ng/ml to 0.7 ng/ml (GMR 1.31, 1.13–1.52); and mean area under the curve by 28 %, from 16.8 ng · h/ml to 21.0 ng · h/ml (GMR 1.28, 1.12–1.46), compared with placebo. Renal clearance of digoxin was unaffected by the presence of ticagrelor. Digoxin had no effect on the pharmacokinetics of ticagrelor or its active metabolite, AR-C124910XX. Co-administration of ticagrelor and digoxin was well tolerated. Conclusions Collectively, these results indicate that ticagrelor is a weak inhibitor of the P-glycoprotein transporter. Based on these findings, it is recommended that serum concentrations of drugs like digoxin (P-glycoprotein transporter substrates with a narrow therapeutic range) are monitored when initiating or changing ticagrelor therapy.

• Publisher: Springer Berlin Heidelberg,Springer,Springer Nature B.V
• Subject: Adenosine - analogs & derivatives / Adenosine - blood / Adenosine - pharmacokinetics / Adult / Antagonist drugs / Area Under Curve / ATP Binding Cassette Transporter, Sub-Family B / ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cross-Over Studies / Digoxin - blood / Digoxin - pharmacokinetics / Double-Blind Method / Drug Administration Schedule / Drug Interactions / Drug Therapy, Combination / Female / Glycoproteins / Humans / Male / Medical sciences / Metabolic Clearance Rate / Middle Aged / Nontherapeutic Human Experimentation / Pharmacokinetics and Disposition / Pharmacology / Pharmacology. Drug treatments / Pharmacology/Toxicology / Prescription drugs / Purinergic P2Y Receptor Antagonists - blood / Purinergic P2Y Receptor Antagonists - pharmacokinetics / Substrate Specificity / Young Adult