Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes.

AIMS: To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). METHODS AND RESULTS: In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4-11%). CONCLUSIONS: Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.

Information and communication on risks related to medications and proper use of medications for healthcare professionals and the general public: precautionary principle, risk management, communication during and in the absence of crisis situations.

Recent drug crises have highlighted the complexity, benefits and risks of medication communication. The difficulty of this communication is due to the diversity of the sources of information and the target audience, the credibility of spokespersons, the difficulty to communicate on scientific uncertainties and the precautionary principle, which is influenced by variable perceptions and tolerances of the risk. Globally, there is a lack of training in risk management with a tendency of modern society to refuse even the slightest risk. Communication on medications is subject to regulatory or legal requirements, often uses tools and messages that are not adapted to the target audience and is often based on a poor knowledge of communication techniques. In order to improve this situation, the available information must be coordinated by reinforcing the unique medication information website and by coordinating communication between authorities by means of a single spokesperson. A particular effort must be made in the field of training in the proper use and risk of medications for both the general population and patients but also for healthcare professionals, by setting up a unified academic on-line teaching platform for continuing medical education on medications and their proper use.

EPICOR (long-tErm follow-up of antithrombotic management Patterns In acute CORonary syndrome patients) study: rationale, design, and baseline characteristics.

BACKGROUND: There is limited information about patterns of use of newer antithrombotic drugs in patients with acute coronary syndromes (ACS) in a real-life setting. The effectiveness, safety and cost-effectiveness of potential combinations during hospitalization, the duration of therapies, interruptions, or discontinuations as well as their reasons and possible consequences are unknown. METHODS: EPICOR (NCT01171404) is a prospective, multinational, observational study on patients discharged after a hospitalization for an ACS with 2-year follow-up. The study is designed to describe the patterns of antithrombotic use and to evaluate potential differences in short- and long-term clinical outcomes (ischemic and bleeding events), quality of life and economic impact associated with initial combinations during hospitalization, and treatment duration, discontinuations, or interruptions and their reasons after discharge in different clinical environments. RESULTS: Between September 1, 2010, and March 31, 2011, 10,568 consecutive patients surviving an ACS (4943 with ST-segment elevation myocardial infarction, and 5625 with non-ST-segment elevation ACS) were enrolled from 555 hospitals in 20 countries from 4 pre-defined regions: Northern Europe (n = 3,782), Southern Europe (n = 2,337), Eastern Europe (n = 2,380), and Latin America (n = 2,069). Pre- and in-hospital management and outcomes were recorded, with a special focus on antithrombotic therapies and ischemic and bleeding events. Changes in antithrombotic treatments and outcomes are currently being registered during the planned 24-month follow-up. CONCLUSION: EPICOR will show current patterns of antithrombotic use during hospitalization and after discharge in 'real-world' patients with ACS, allowing exploration of potential differences in clinical outcomes, quality of life, and costs related to the different antithrombotic practice patterns.

Clinical pharmacology of selatogrel for self-administration by patients with suspected acute myocardial infarction.

INTRODUCTION: P2Y12 receptor antagonists (P2Y12 inhibitors) are well established for the treatment of coronary artery disease. The P2Y12 inhibitors currently commercially available present either pharmacokinetic limitations (due to delayed absorption, bioactivation requirement via CYP enzymes, or need of intravenous administration), pharmacodynamic (PD) limitations (limited % inhibition of platelet aggregation (IPA) or relevant PD interactions) or safety limitations (major bleeding in specific populations). AREAS COVERED: Selatogrel, a 2-phenylpyrimidine-4-carboxamide analog, is a potent, reversible, and selective P2Y12 inhibitor administered subcutaneously that is under development for the treatment of acute myocardial infarction (AMI) in patients with a recent history of AMI. In this review, the authors summarize the results from preclinical, phase 1, and phase 2 trials which showed that selatogrel provides rapid, pronounced, and reversible P2Y12 receptor inhibition with a favorable safety profile. EXPERT OPINION: These unique characteristics added to the limited potential to interact with co-medications and manageable PD interactions with other P2Y12 inhibitors provide a clear rationale for investigating the benefit of selatogrel as an emergency treatment to improve clinical outcomes in patients with AMI.

Mind the Gap: Model-Based Switching from Selatogrel to Maintenance Therapy with Oral P2Y12 Receptor Antagonists.

Background: The P2Y12 receptor antagonist selatogrel is being developed for subcutaneous self-administration with a ready-to-use autoinjector at the onset of acute myocardial infarction (AMI) symptoms. The unique pharmacological profile of selatogrel (fast, potent, and short-acting) can bridge the time gap between the onset of AMI and first medical care. A clinical Phase 1 study showed a time-dependent pharmacodynamic interaction between selatogrel and loading doses of clopidogrel and prasugrel. As treatment switching is a common clinical practice, the assessment of subsequent switching from a clopidogrel loading dose to the first maintenance dose of oral P2Y12 receptor antagonists is highly relevant. Objectives: Model-based predictions of inhibition of platelet aggregation (IPA) for the drugs triggering pharmacodynamic interactions were to be derived to support clinical guidance on the transition from selatogrel to oral P2Y12 receptor antagonists. Methods: Scenarios with selatogrel 16 mg administration or placebo followed by a clopidogrel loading dose and, in turn, prasugrel or ticagrelor maintenance doses at different times of administration were studied. Population pharmacokinetic/pharmacodynamic modeling and simulations of different treatment scenarios were used to derive quantitative estimates for IPA over time. Results: Following selatogrel/placebo and a clopidogrel loading dose, maintenance treatment with ticagrelor or a prasugrel loading dose followed by maintenance treatment quickly achieved sustained IPA levels above 80%. Prior to maintenance treatment, a short time span from 18 to 24 h was identified where IPA levels were predicted to be lower with selatogrel than with placebo if clopidogrel was administered 12 h after selatogrel or placebo. Predicted IPA levels reached with placebo alone and a clopidogrel loading dose at 4 h were consistently lower than with selatogrel administration, followed by a clopidogrel loading dose at 12 h. If a clopidogrel loading dose is administered at 12 h, selatogrel maintains higher IPA levels up to 16 h. IPA levels are subsequently lower than on the placebo until the administration of the first maintenance dose. Conclusions: Model-based predictions informed the transition from selatogrel subcutaneous administration to oral P2Y12 therapy. The application of modeling techniques illustrates the value of employing pharmacokinetic and pharmacodynamic modeling for the simulation of various clinical scenarios of switching therapies.

Subcutaneous Selatogrel Inhibits Platelet Aggregation in Patients With Acute Myocardial Infarction.

BACKGROUND: Oral P2Y12 receptor antagonists exhibit delayed onset of platelet inhibition in patients with acute myocardial infarction (AMI). Selatogrel is a potent, highly selective, and reversible P2Y12 receptor antagonist with a rapid onset and short duration of action. OBJECTIVES: This study sought to assess inhibition of platelet aggregation following subcutaneous administration of selatogrel in patients with AMI. METHODS: Patients with AMI were randomized to a single subcutaneous dose of selatogrel of 8 or 16 mg. The primary endpoint was response to treatment (P2Y12 reaction units <100; measured by VerifyNow) at 30 min post-dose. Safety was assessed up to 48 h post-injection. RESULTS: Forty-seven patients received selatogrel 8 mg (n = 24) or 16 mg (n = 23) followed by ticagrelor (n = 43) or clopidogrel (n = 1). The proportion of responders 30 min post-dose was 91% (one-sided 97.5% confidence interval [CI]: 80% to 100%) and 96% (97.5% CI: 87% to 100%) with 8 and 16 mg, respectively (p values for responders >85% target; p = 0.142 and p = 0.009, respectively). Response rates were independent from type of AMI presentation, age, or sex. A similar response rate was observed at 15 min (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 91% [97.5% CI: 80% to 100%]), which was sustained at 60 min post-dose (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 96% [97.5% CI: 87% to 100%]). At 15 min, median P2Y12 reaction units was 51 (range: 4 to 208) for 8 mg and 9 (range: 2 to 175) for 16 mg. Selatogrel was well tolerated, without major bleeding complications. CONCLUSIONS: Single-dose subcutaneous administration of selatogrel in patients with AMI was safe and induced a profound, rapid, and dose-related antiplatelet response. (A Medical Research Study to Evaluate the Effects of ACT-246475 in Adults With Heart Attack; NCT03487445, 2018-000765-36 [EudraCT]).

Differential time effect profiles of amlodipine, as compared to valsartan, revealed by ambulatory blood pressure monitoring, self blood pressure measurements and dose omission protocol.

Amlodipine and valsartan are once-daily antihypertensive agents. To date, no comparison between these agents given as monotherapies was reported. This study was aimed to evaluate the therapeutic coverage and safety of amlodipine and valsartan in mild-to-moderate hypertensive patients. Multicenter, double-blind, randomized, comparative study. After a 4-week placebo wash-out period, 246 outpatients with office diastolic blood pressure 95 < or = DBP < or =110 mmHg and systolic blood pressure (SBP) < 180 mmHg, in addition to a mean daytime SBP and/or DBP > 135/85 mmHg on 24-h ambulatory blood pressure monitoring (ABPM), were randomly allocated to once-daily amlodipine 5-10 mg or valsartan 40-80 mg, for 12 weeks. In a subgroup of patients, 48-h ABPM were performed at the end of the treatment period. Dose omission was simulated by a single-blind placebo dosing. The primary efficacy end-point was the 24-h trough office BP after 12 weeks of active therapy. The reductions in 24-h trough BP were more pronounced in amlodipine compared with valsartan group as well in office [SBP: -17.8 +/- 10.9 vs. -14.6 +/- 11.2, P = 0.025, DBP: -12.7 +/- 7.2 vs. -10.9 +/- 7.8 mmHg, P = 0.06) as in ambulatory BP (SBP/DBP: -13.0 +/- 13.7/-10.8 +/- 9.1 vs. -7.2 +/- 19.4/-4.9 +/- 13.4 mmHg, P < 0.05). Forty-eight hours after the last active dose, the slope of the morning BP surge (4-9 h) was less steep with amlodipine vs. valsartan [DBP (P < 0.04), SBP (n.s.)]. Ankle edema were more often reported in amlodipine group. These results suggest a superior BP lowering and a longer duration of action with amlodipine compared with valsartan.

Randomized, comparative, double-blind study of amlodipine vs. nicardipine as a treatment of isolated systolic hypertension in the elderly.

A 90-day, multicenter, randomized, double-blind, parallel-group study was conducted to compare the efficacy of amlodipine (once a day) with nicardipine (two to three times a day), in the treatment of isolated systolic hypertension (ISH) in the elderly. Patients (n = 133) aged > or = 60 years, with ISH were randomized to receive either amlodipine 5 mg/day, or nicardipine 60 mg/day (titrated if necessary to 10 mg/day and 100 mg/day, respectively) for 90 days. Efficacy was assessed by measuring office blood pressure (BP), and 24-h ambulatory blood pressure monitoring (ABPM). The two treatments substantially and comparably reduced office systolic blood pressure (SBP) and pulse pressure (PP), and also produced a slight decrease in diastolic blood pressure (DBP). Amlodipine reduced SBP, as assessed by ABPM, to a significantly greater extent than nicardipine. Both treatments were well-tolerated. The sustained effect of amlodipine, compared with nicardipine, was reflected in its significantly greater antihypertensive activity, particularly during the nocturnal period, as assessed by ABPM. The study demonstrates that once a day dose of amlodipine is an effective antihypertensive treatment for elderly ISH patients.

Rationale, design and methods of the CASHMERE study.

Carotid intima-media thickness (IMT) measurement is a noninvasive method used for quantification of early stage of atherosclerosis. Data suggest that the combination of statin and hormone replacement therapy (HRT) might be useful in reducing the early progression of atherosclerosis in postmenopausal women. The main aim of the study is to compare the effects of 12-month therapy with atorvastatin (80 mg/day), HRT (oral 17beta-estradiol 1 or 2 mg/day, plus cyclic dydrogesterone 10 mg) alone and their combination vs. placebo on the progression of carotid IMT by using a high-definition echotracking device. The secondary objectives are to assess the effects of the treatments vs. placebo on arterial stiffness, lipid profile and C-reactive protein. The CASHMERE trial is an European randomized study with a 2 x 2-factorial design, double blinded for atorvastatin and prospective randomized, open blinded endpoint evaluation (PROBE) method applied to HRT. The investigators can adjust the dose of estradiol at any time during follow-up if necessary. A total of 800 postmenopausal women with mild hypercholesterolemia and with no previous history of cardiovascular disease will be included and followed up by their physicians [general practitioners (GPs) or gynecologists] for 1 year. The CASHMERE trial is the first randomized clinical trial to examine the effects of a statin alone or combined with HRT on the structure and the function of carotid artery as early markers of atherosclerosis in postmenopausal women with mild hypercholesterolemia. The results are expected for 2007.

Surrogate endpoints in randomized cardiovascular clinical trials.

Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints.

Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients.

BACKGROUND: Hypertension and hyperuricaemia are common side-effects of cyclosporin A (CsA) treatment in renal transplant recipients. While it is well established that the calcium channel blocker amlodipine can control CsA-induced hypertension effectively in this patient population, recent evidence suggests amlodipine might also reduce hyperuricaemia. The present study was designed to compare the effects of the calcium channel blocker amlodipine (5-10 mg/day) and the beta-adrenoceptor antagonist tertatolol (5-10 mg/day) on CsA-induced hyperuricaemia in post-renal transplant recipients with hypertension. METHODS: Forty-eight hypertensive renal transplant recipients on a stable dose of CsA were randomized in a double-blind, parallel-group manner to receive either amlodipine (n = 24) or tertatolol (n = 24) for 60 days. The primary outcome measure was the change from baseline in serum uric acid concentration. Secondary analyses of efficacy were based on changes in renal function and blood pressure. RESULTS: Amlodipine significantly decreased serum uric acid levels from 483 +/- 99 to 431 +/- 110 microM/l (P < 0.001), while tertatolol significantly increased uric acid from 450 +/- 98 to 476 +/-84 microM/l (P = 0.006). Amlodipine also significantly increased glomerular filtration rate (P = 0.0048) and the clearance rate of uric acid (P = 0.023) and it reduced the fractional proximal tubular reabsorption of sodium (P < 0.001), compared with tertatolol. Renal plasma flow and filtered fraction were unaffected by both treatments, as was trough CsA blood concentration. Amlodipine lowered systolic blood pressure to a significantly greater extent than did tertatolol (P = 0.007). The time-dependent profile of diastolic blood pressure did not differ significantly between treatment groups. Both drugs were well tolerated. CONCLUSIONS: Amlodipine could be more appropriate than tertatolol for CsA-induced hypertension and hyperuricaemia in renal transplant recipients.