Pharmacokinetic Profiles of Ticagrelor Orodispersible Tablets in Healthy Western and Japanese Subjects.

BACKGROUND AND OBJECTIVES: Ticagrelor is an antiplatelet agent for patients with acute coronary syndrome or a history of myocardial infarction. Two studies compared pharmacokinetic profiles of orodispersible (OD) ticagrelor tablets versus immediate-release (IR) tablets in Western and Japanese subjects. METHODS: Both studies were open-label, randomized, crossover, single-center trials. Thirty-six healthy subjects (94% white, 6% other race; Western study NCT02400333) and 42 Japanese healthy subjects (Japanese study NCT02436577) received a single 90-mg ticagrelor dose as an OD tablet [with/without water, and via a nasogastric tube (Western study only)], and an IR tablet; washout between treatments was ≥7 days. Assessments included ticagrelor and AR-C124910XX (active metabolite) plasma concentrations for pharmacokinetic analyses, and safety evaluations. RESULTS: In the Western study, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for ticagrelor and AR-C124910XX maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC) were within the acceptance interval (80%-125%) for OD tablets (with/without water, via a nasogastric tube) versus the IR tablet; except for an ~15% lowering of ticagrelor C max (90% CI: 76.77%-93.78%) for the OD tablet taken with water. In the Japanese study, 90% CIs of the GMRs for AUC and C max of both ticagrelor and AR-C124910XX were all within the acceptance intervals for the OD (with/without water) versus IR tablet. No new safety issues were identified. CONCLUSIONS: Ticagrelor administered as an OD tablet to Western (without water, and via a nasogastric tube) and Japanese (with/without water) subjects was bioequivalent to the IR tablet.

Impact of Diabetes Mellitus on the Pharmacodynamic Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Ad Hoc Percutaneous Coronary Intervention.

BACKGROUND: Diabetes mellitus (DM) is associated with enhanced platelet reactivity and impaired response to oral antiplatelet therapy, including clopidogrel. This post hoc analysis investigated the pharmacodynamic effects of ticagrelor versus clopidogrel loading dose (LD) in troponin-negative acute coronary syndrome patients with or without DM undergoing percutaneous coronary intervention in the Ad Hoc PCI study. METHODS AND RESULTS: Patients randomized (1:1) to receive ticagrelor 180 mg LD or clopidogrel 600 mg LD were assessed by diabetic status. Platelet reactivity (P2Y12 reaction units [PRU] on VerifyNow® assay) was measured pre-LD, at 0.5, 2, and 8 hours post-LD, and at the end of the percutaneous coronary intervention. The primary endpoint was PRU levels 2 hours post-LD; secondary endpoints included rates of high on-treatment platelet reactivity (PRU≥208). Of 100 randomized patients, 51 received ticagrelor (DM, n=20; non-DM, n=31) and 49 clopidogrel (DM, n=16; non-DM, n=33). At 2 hours post-LD, mean (SD) PRU levels in DM patients were 130.1 (111.7) with ticagrelor versus 287.6 (71.9) with clopidogrel (mean [95%CI] difference -157.5 [-225.3, -89.8]; P<0.001); in non-DM patients, they were 75.3 (75.7) versus 243.0 (72.4) (mean difference -167.7 [-207.1, -128.3]; P<0.001). High on-treatment platelet reactivity rates at 2 hours post-LD were also significantly (P<0.001) reduced with ticagrelor versus clopidogrel in DM and non-DM patients. Between-treatment differences for PRU and high on-treatment platelet reactivity were not significant at earlier time points but were at 8 hours post-LD (P<0.001). CONCLUSIONS: Compared with clopidogrel, ticagrelor achieved faster, enhanced platelet inhibition and reduced high on-treatment platelet reactivity rates, in DM and non-DM patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603082.

Pharmacodynamics, pharmacokinetics, and safety of ticagrelor in Chinese patients with stable coronary artery disease.

AIM: The aim of the study was to assess ticagrelor's effects on inhibition of platelet aggregation (IPA), P2Y12 reaction units (PRU, measure of platelet P2Y12 receptor blockade), pharmacokinetic (PK) parameters and safety in Chinese patients with stable coronary artery disease (CAD). METHODS: This was an open label, single centre, randomized study. Thirty-six patients on low dose aspirin (75-100 mg day(-1) ) received ticagrelor 45, 60 or 90 mg (single dose, days 1 and 7; twice daily, days 3-6). IPA (final extent), PRU and ticagrelor and AR-C124910XX plasma concentrations were determined. RESULTS: On day 1, peak IPA >80% occurred 2-6 h post-dose (all doses). PRU was markedly reduced at 1 h vs. baseline (all doses). With ticagrelor 45 and 90 mg twice daily, maximum IPA (mean, SD) was 91% (13%), and 99% (3%), and maximum PRU reduction from baseline (mean, SD) was 82% (17%) and 92% (9%), respectively. Approximate dose-proportional increases (mean [%CV]; 45 vs. 90 mg twice daily) in ticagrelor Cmax (616 [37] vs. 1273 [43] ng ml(-1) ) and AUC (3882 [42] vs. 8206 [51] ng ml(-1) h) and AR-C124910XX parameters were seen. Pharmacodynamic and PK differences between 45 and 60 mg were small. No safety issues were identified. CONCLUSIONS: In Chinese patients with CAD, ticagrelor (45, 60 and 90 mg) markedly reduced platelet aggregation. The IPA and PRU magnitude increased generally with increasing doses. However, the mean pharmacodynamic differences between 45 and 60 mg doses were small. Following single and multiple doses, the mean Cmax and AUC values of ticagrelor and AR-C124910XX increased approximately dose proportionally between 45 and 90 mg doses.

Ticagrelor Versus Clopidogrel in Black Patients With Stable Coronary Artery Disease: Prospective, Randomized, Open-Label, Multiple-Dose, Crossover Pilot Study.

BACKGROUND: The burden of coronary artery disease (CAD) is high in blacks, highlighting the need for clinical research of antiplatelet agents in this population. We sought to evaluate platelet reactivity during loading and maintenance dosing of ticagrelor versus clopidogrel, and the pharmacokinetic profile of ticagrelor and its metabolite AR-C124910XX, in black patients with stable CAD taking low-dose aspirin (acetylsalicylic acid). METHODS AND RESULTS: In a multicenter, randomized, open-label, crossover study, 34 blacks with stable CAD receiving acetylsalicylic acid 75 to 100 mg/d were randomized to clopidogrel (600 mg, then 75 mg QD for 7-9 days) or ticagrelor (180 mg, then 90 mg BID for 7-9 days). After washout 10 to 14 days, patients switched regimens. The primary end point was platelet reactivity 2 hours post loading dose (P2Y12 reactivity units [PRU] measured by the VerifyNow assay). Least-squares mean PRU at 2 hours post loading dose was lower with ticagrelor (27.6) versus clopidogrel (211.2); least-squares mean difference was -183.6 (95% confidence interval, -213.9 to -153.3; P<0.001). At all time points, the least-squares mean PRU was significantly lower, and the percent reduction in PRU from baseline was statistically greater, with ticagrelor versus clopidogrel. At 2 hours post dose, the prevalence of high on-treatment platelet reactivity (≥208 PRU) was lower with ticagrelor (0%) than with clopidogrel (57.1%). Pharmacokinetic profiles of ticagrelor and AR-C124910XX were consistent with previous reports in stable CAD populations. CONCLUSIONS: In black patients with stable CAD receiving low-dose acetylsalicylic acid, ticagrelor provided a faster onset and greater degree of platelet inhibition than clopidogrel. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01523392.

The evaluation and management of drug effects on cardiac conduction (PR and QRS intervals) in clinical development.

Recent advances in electrocardiographic monitoring and waveform analysis have significantly improved the ability to detect drug-induced changes in cardiac repolarization manifested as changes in the QT/corrected QT interval. These advances have also improved the ability to detect drug-induced changes in cardiac conduction. This White Paper summarizes current opinion, reached by consensus among experts at the Cardiac Safety Research Consortium, on the assessment of electrocardiogram-based safety measurements of the PR and QRS intervals, representing atrioventricular and ventricular conduction, respectively, during drug development.

Evaluation of the effect of dapagliflozin on cardiac repolarization: a thorough QT/QTc study.

INTRODUCTION: Dapagliflozin is a first-in-class sodium-glucose transporter 2 (SGLT2) inhibitor under investigation for the treatment of type 2 diabetes mellitus. A thorough QTc study was conducted, according to International Conference on Harmonization E14 guidelines, to characterize the effect of dapagliflozin on cardiac repolarization. METHODS: The present study was a double-blind, four-period, placebo-controlled crossover study at a single-center inpatient clinical pharmacology unit. The study enrolled 50 healthy men who were randomized to receive sequences of single doses of dapagliflozin 150 mg, dapagliflozin 20 mg, moxifloxacin 400 mg, and placebo. The sequences were randomized based on the Williams design for a cross-over study to reduce the "carryover" effects from drug-to-drug even with sufficient washout periods. Digital 12-lead electrocardiograms were recorded at nine time points over 24 hours in each period. QT intervals were corrected for heart rate using a study-specific correction factor (QTcX) and Fridericia's formula. RESULTS: For dapagliflozin, the upper bound of the one-sided 95% confidence interval (CI) for time-matched, placebo-subtracted, baseline adjusted QTc intervals (ΔΔQTc) was <10 ms. ΔΔQTc was independent of dapagliflozin concentrations. No QTc thresholds >450 ms or QTc increases >30 ms were observed. Moxifloxacin increased the mean QTcX interval by 7.7 ms (lower bound 90% CI, 6.2 ms) over 1-4 hours after dosing, confirming assay sensitivity. CONCLUSION: Dapagliflozin, at supratherapeutic doses, does not have a clinically significant effect on the QT interval in healthy subjects.

A pharmacokinetic study of the combined administration of amiodarone and ximelagatran, an oral direct thrombin inhibitor.

The oral direct thrombin inhibitor ximelagatran is being developed for the prevention and treatment of thromboembolism. This single-blind, randomized, placebo-controlled, parallel-group study investigated the potential for the interaction of ximelagatran (36 mg every 12 hours for 8 days, measured as its active form melagatran in blood) and amiodarone (single 600-mg oral dose on day 4) in healthy male subjects (n = 26). For amiodarone + ximelagatran versus amiodarone + placebo, geometric mean ratios (90% confidence intervals for amiodarone AUC(0-120) and C(max) were 0.87 (0.69-1.08) and 0.86 (0.66-1.11), respectively. For desethylamiodarone, the principal metabolite of amiodarone, the corresponding ratios were 1.00 (0.89-1.12) for AUC(0-120) and 0.92 (0.77-1.09) for C(max). The geometric mean ratios (90% confidence intervals) for ximelagatran + amiodarone versus ximelagatran were 1.21 (1.17-1.25) for melagatran AUC(0-12) and 1.23 (1.18-1.28) for melagatran C(max). These confidence intervals were within or only slightly outside the interval, suggesting no interaction (0.8-1.25 for the effect of amiodarone on melagatran and 0.7-1.43 for the effect of melagatran on amiodarone or desethylamiodarone). Amiodarone did not affect the concentration-effect relationship of melagatran on activated partial thromboplastin time. Ximelagatran was well tolerated when coadministered with a single dose of amiodarone. Evaluation of the safety of the combination is needed to confirm that the relatively small pharmacokinetic changes in this study are of no clinical significance.