The Oral Bioavailability and Effect of Various Gastric Conditions on the Pharmacokinetics of Dersimelagon in Healthy Adult Volunteers.

Dersimelagon is a novel orally administered selective agonist for melanocortin receptor 1 being investigated for the treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis. In this open-label, multicenter, randomized, two-cohort, sequential crossover study, the relative oral bioavailability of two tablet formulations of dersimelagon was evaluated, and the effect of various gastric conditions (from a high-fat meal, a proton-pump inhibitor, and an acidic carbonated beverage) on the pharmacokinetics of dersimelagon were assessed in healthy participants (N = 50). Both tablet formulations demonstrated rapid absorption, and the 100-mg tablets showed a 97% relative oral bioavailability versus 50-mg tablets.

Pharmacokinetics and pharmacodynamics of ticagrelor in subjects on hemodialysis and subjects with normal renal function.

Purpose: This single-dose, randomized, open-label, parallel-group, and crossover study assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of ticagrelor in subjects on hemodialysis versus healthy subjects.

Methods: Hemodialysis subjects were randomized, receiving a single ticagrelor 90-mg dose 1 day post-hemodialysis or just before hemodialysis, with an intervening washout of ≥ 7 days. Healthy subjects (creatinine clearance ≥ 90 mL/min) received a single ticagrelor 90-mg dose.

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.

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.

Population pharmacokinetics of ticagrelor in patients with acute coronary syndromes.

Objective: Ticagrelor is an orally administered antiplatelet agent used to reduce thrombotic events in patients with acute coronary syndromes. Data from two studies in patients with acute coronary syndromes with large amounts of pharmacokinetic (PK) data (phase IIb DISPERSE-2 study (n = 609)); phase III PLATO PK substudy (n = 6,381)), along with non-linear mixed effects modeling software, were used to develop population PK models for ticagrelor and its metabolite, AR-C124910XX, and to evaluate the impact of demographic and clinical factors on the PK of ticagrelor and AR-C124910XX.

Methods: 32 covariates relating to disease history, biomarkers, clinical chemistry, and concomitant medications were assessed.

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).

Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Patients With Low-Risk ACS Undergoing Ad Hoc PCI.

Background: Many low-risk acute coronary syndrome (ACS) patients are not pre-treated with a P2Y12 receptor inhibitor, and percutaneous coronary interventions (PCIs) are often performed on an ad hoc basis in this population. Pharmacodynamic (PD) studies comparing ticagrelor versus clopidogrel in patients undergoing ad hoc PCI are lacking.

Objectives: This study sought to assess PD effects of ticagrelor versus clopidogrel loading dose (LD) in the peri-procedural period among troponin-negative ACS patients undergoing ad hoc PCI.

Platelet inhibition with ticagrelor versus clopidogrel in Hispanic patients with stable coronary artery disease with or without diabetes mellitus.

Background/purpose: Diabetes mellitus (DM) disproportionately affects Hispanic patients. DM patients have enhanced platelet reactivity and reduced sensitivity to clopidogrel. Ticagrelor demonstrated a more rapid onset and greater magnitude of platelet inhibition than clopidogrel in Hispanic patients with stable coronary artery disease (CAD).

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).

Ticagrelor: Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Profile: An Update.

Despite advancements in treatments for acute coronary syndromes over the last 10 years, they continue to be life-threatening disorders. Currently, the standard of treatment includes dual antiplatelet therapy consisting of aspirin plus a P2Y12 receptor antagonist. The thienopyridine class of P2Y12 receptor antagonists, clopidogrel and prasugrel, have demonstrated efficacy.

Effect of genetic variations on ticagrelor plasma levels and clinical outcomes.

Aims: Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial.

Methods And Results: A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941).

An open-label, randomized bioavailability study with alternative methods of administration of crushed ticagrelor tablets in healthy volunteers.

Objective: To compare the bioavailability and safety profile of crushed ticagrelor tablets suspended in water and administered orally or via nasogastric tube, with that of whole tablets administered orally.

Methods: In this single-center, open-label, randomized, three-treatment crossover study, 36 healthy volunteers were randomized to receive a single 90-mg dose of ticagrelor administered orally as a whole tablet or as crushed tablets suspended in water and given orally or via a nasogastric tube into the stomach, with a minimum 7-day wash-out between treatments. Plasma concentrations of ticagrelor and AR-C124910XX were assessed at 0, 0.

A randomised trial of the pharmacodynamic and pharmacokinetic effects of ticagrelor compared with clopidogrel in Hispanic patients with stable coronary artery disease.

The objective was to compare the pharmacodynamic (PD) and pharmacokinetic (PK) effects of ticagrelor with clopidogrel among subjects of Hispanic ethnicity, as the PD and PK effects of antiplatelet agents among Hispanics are not specifically known. This was a randomised, open-label, crossover PD/PK study of 40 Hispanic subjects with stable coronary artery disease (CAD). Subjects were allocated to either ticagrelor 180 mg loading dose (LD)/90 mg twice-daily maintenance dose (MD) followed by clopidogrel 600 mg LD/75 mg once-daily MD with an intervening washout period, or vice versa.

Evaluation of the pharmacokinetic interaction between ticagrelor and venlafaxine, a cytochrome P-450 2D6 substrate, in healthy subjects.

Purpose: Ticagrelor is a reversibly binding P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Ticagrelor has been shown in vitro to be a weak inhibitor of cytochrome P-450 (CYP) 2D6, a clinically important enzyme for the metabolism of many drugs. This study assessed the effects of coadministration of ticagrelor on the pharmacokinetics of the CYP2D6 substrate venlafaxine.

Pharmacokinetic interaction study of ticagrelor and cyclosporine in healthy volunteers.

Background And Objective: Patients with acute coronary syndrome and certain co-morbidities may receive ticagrelor, a reversibly binding P2Y(12) receptor antagonist, and cyclosporine, a commonly used immunosuppressant drug. This study assessed the potential pharmacokinetic drug-drug interaction between ticagrelor and cyclosporine.

Methods: In this single-centre, open-label, three-treatment, three-period crossover study (NCT01504906), healthy volunteers (n = 26) randomly received each of three treatments: cyclosporine (600 mg single oral dose) plus ticagrelor (180 mg single oral dose); cyclosporine alone; ticagrelor alone.

Pharmacokinetics, pharmacodynamics, and tolerability of single and multiple doses of ticagrelor in Japanese and Caucasian volunteers.

Objectives: Two studies assessing ticagrelor pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and Caucasian volunteers.

Materials And Methods: Single-ascending dose (SAD) study: Japanese (n = 20) and Caucasians (n = 20) received single doses of ticagrelor (50, 100, 200, 300, 400, and 600 mg) or placebo. Multiple-ascending dose (MAD) study: Japanese (n = 36) and Caucasians (n = 36) received single doses of 100 mg or 300 mg ticagrelor (day 1), twice-daily 100 mg or 300 mg ticagrelor, or placebo (days 4 – 9), and single doses of 100 mg or 300 mg ticagrelor (day 10).

Absolute bioavailability and regional absorption of ticagrelor in healthy volunteers.

Objective: Ticagrelor is a direct-acting, reversibly-binding, oral P2Y12 receptor antagonist. It demonstrates predictable, linear pharmacokinetics. Two studies were undertaken to further elucidate the absolute bioavailability of ticagrelor and its regional absorption in the gastrointestinal (GI) tract.

Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers.

Objective: Previous studies have indicated that ticagrelor is well tolerated and exhibits linear pharmacokinetics up to doses of 600 mg/day. The safety, tolerability, pharmacokinetics and pharmacodynamics (bleeding times and pulmonary function tests) of high single-ascending doses of ticagrelor were assessed to determine the maximum tolerated dose of ticagrelor.

Materials And Methods: This was a randomized, double-blind, placebo-controlled study.

The effect of ticagrelor on the metabolism of midazolam in healthy volunteers.

Background: In vitro studies have demonstrated that ticagrelor, an oral antiplatelet agent, is a substrate, activator, and inhibitor of cytochrome P450 (CYP) 3A. Thus, potential CYP3A-mediated drug-drug interactions may occur.

Objectives: The goal of this article was to report study results on the effect of ticagrelor on the pharmacokinetics of oral midazolam (oral midazolam study) and oral versus intravenous (IV) midazolam (oral/IV midazolam study).

A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers.

Purpose: Ticagrelor is a reversibly binding P2Y12 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.

Effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease patients.

Background: Ticagrelor is a direct-acting, reversibly binding, oral P2Y12 platelet inhibitor that reduces thrombotic cardiovascular events in patients with acute coronary syndrome. Dyspnea is one of the most commonly reported adverse events associated with ticagrelor.

Objective: To determine the effect of ticagrelor on pulmonary function in healthy elderly volunteers and asthma or chronic obstructive pulmonary disease (COPD) patients.

Evaluation of the pharmacokinetic interaction between ticagrelor and tolbutamide, a cytochrome P450 2C9 substrate, in healthy volunteers.

Objectives: To assess the effect of ticagrelor on the pharmacokinetics of tolbutamide (a CYP2C9 substrate), and the effect of tolbutamide on ticagrelor pharmacokinetics.

Methods: In this randomized, double-blind, two-period, crossover study, 23 healthy volunteers received either placebo or ticagrelor 180 mg twice daily (b.i.

Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers.

Objectives: Two open-label, two-period, crossover studies in healthy volunteers were designed to determine the pharmacokinetic interactions between ticagrelor, a P2Y12 receptor antagonist, and a moderate (diltiazem) and a strong (ketoconazole) cytochrome P450 (CYP) 3A inhibitor.

Methods: Seventeen volunteers received diltiazem (240 mg once daily) for 14 days. In the second study, ketoconazole (n = 14) 200 mg twice daily was given for 10 days.

Evaluation of the pharmacokinetics and pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers.

The results of two independent, randomized, two-period crossover, single-center studies, conducted to assess the pharmacokinetics of ticagrelor ± aspirin, inhibition of platelet aggregation (IPA) with ticagrelor/aspirin vs. clopidogrel/aspirin, and safety, tolerability, and bleeding times are reported here. In Study A (open-label), 16 volunteers received ticagrelor (50 mg bid Days 1-5; 200 mg bid Days 6-9; one 200 mg dose on Day 10) ± 300 mg qd aspirin (Days 1-10).