Population pharmacokinetic–pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter

Vernakalant hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were initially given a 10-min intravenous (IV) infusion of vernakalant 3 mg/kg or placebo. If SR was not evident after a 15-min observation, then a second 10-min IV infusion of vernakalant 2 mg/kg or placebo was given. Population pharmacokinetic/pharmacodynamic (PK/PD) models were constructed for QT interval prolongation corrected for heart rate by Fridericia’s formula (QTcF) and for changes in systolic blood pressure (SBP). The exposure–response relationships for QTcF and SBP were best described by sigmoidal maximum-effect (E _max) models. For QTcF, the model was characterized by a typical E _max of 20.3 ms, and by a vernakalant median effective concentration dependent (EC ₅₀) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by E _max of 3.05 mmHg and EC ₅₀ of 1,141 ng/ml. Risk of hypotension (SBP <90 mmHg) was primarily associated with low baseline SBP and to a smaller extent with a history of congestive heart failure (CHF); plasma vernakalant concentrations showed a small contribution to the risk of hypotension (relative risk = 1.4 at 4,000 ng/ml), which may be significant with a baseline SBP of <105 mmHg. These results show that vernakalant had a smaller effect on QTcF in patients who demonstrated conversion to SR than those remaining in AF or AFL, and it had a relatively small effect on SBP.     

More light at the end of the tunnel – apixaban in atrial fibrillation

Introduction: Subjects with atrial fibrillation are at risk of thromboembolic events. The vitamin K antagonists (e.g., warfarin) are useful at preventing coagulation in atrial fibrillation, but are difficult to use. One of the FXa inhibitors, oral apixaban, has been tested as an anticoagulant in atrial fibrillation.

Areas covered: In ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) apixaban was compared to warfarin in subjects with atrial fibrillation, and shown to cause a lower rate of stroke or systemic embolism and of major bleeding, than warfarin. In the AVERROES (Apixaban versus acetylsalicylic acid [ASA] to prevent stroke in atrial fibrillations patients who have failed or are unsuitable for vitamin K antagonist treatment) trial, stroke or systemic embolism occurred less often with apixaban than aspirin, whereas the occurrence of major bleeding was similar in the groups.

Expert opinion: Apixaban is much easier for subjects with atrial fibrillation to use than warfarin, as it does not require regular monitoring by a health professional, with dosage adjustment. In addition to replacing warfarin in subjects with atrial fibrillation who are unable or not prepared to use warfarin, apixaban has the potential to replace warfarin more widely in the prevention of thromboembolism in subjects with atrial fibrillation.     

Leukotriene receptor antagonists – risks and benefits for use in paediatric asthma

Leukotrienes (LTs) are important mediators of the pathophysiology of asthma, specifically, bronchoconstriction, airway inflammation and oedema and mucus hypersecretion. The LT receptor antagonists (LTRAs) inhibit these potent effects by selectively blocking the cysteinyl LT₁ receptor. These are the first novel therapies for asthma since the introduction of inhaled corticosteroids (ICS) in 1972. Unlike generalised inhibition of airway inflammation by ICS, the LTRAs target inhibition of specific mediators. In general, paediatric data concerning these agents remain quite limited. However, they have demonstrated efficacy against allergen- and exercise-induced bronchospasm in both adults and children. Recently, their potential role for the treatment of viral-induced wheeze in young children has been explored. In multiple, placebo-controlled trials, the LTRAs have demonstrated efficacy for the treatment of mild persistent asthma, additive benefit in the management of symptomatic moderate asthmatics on maintenance ICS and evidence of significant steroid-sparing. Findings from these clinical trials and real-world experience support the use of the LTRAs as controller agents for persistent asthma. Based on their excellent safety profiles, tolerance and ease of administration (including once daily dosing with montelukast), this drug class may offer several important features for use as controller therapy, particularly in asthmatic children as young as 1 year of age, however, this must continue to be reviewed as new paediatric data become available.     

Anabolic–androgenic steroid abuse and testicular function in men; recent insights

The use of illegal androgens by young men is not uncommon. The majority of users take multiple courses of androgens during their lifetime, leading to a high cumulative exposure. An inseparable side effect is suppression of gonadal function. Although this usually recovers, recovery can take a long time and is not without symptoms.This review focusses on recent studies that have greatly increased our knowledge of the disruption and recovery of testicular function during and after androgen abuse. For the guidance and treatment of (potential) users, in-depth knowledge of this is indispensable.     

Edoxaban population pharmacokinetics and exposure–response analysis in patients with non-valvular atrial fibrillation

Purpose

The aim of this study was to evaluate the population pharmacokinetics (PK) and exposure–response relationship of edoxaban in patients with non-valvular atrial fibrillation (AF).

Methods

Concentration data from 1,134 subjects in 11 clinical studies (eight phase I, one phase II, and two phase III) were used to perform a population PK analysis, including estimation of the bioavailability and quantification of the effects of P-glycoprotein (P-gp) inhibitors as well as renal impairment on edoxaban PK. The potential relationship between edoxaban PK exposure and incidence of bleeding events was explored based on data from 893 AF patients.

Results

Absolute bioavailability of edoxaban was estimated as 58.3 %. With oral dosing of edoxaban, co-administration of various P-gp inhibitors significantly increased edoxaban bioavailability and decreased volume of distribution (V ₂), resulting in a predicted increase of 33–77 % in area under the curve (AUC) and 65–104 % in C _max. A much smaller increase was seen in edoxaban concentration at 24 h post-dose (C ₂₄, ?24 to 38 %), due to decreased V ₂ and shortened elimination half-life. With IV dosing of edoxaban, co-administration of the P-gp inhibitor quinidine decreased both edoxaban clearance (CL) and V ₂, resulting in an increase of 32 % in AUC and 66 % in C ₂₄. Creatinine clearance was a significant covariate on renal clearance, whereas age and body weight significantly affected nonrenal clearance. Model-predicted steady state C _min was slightly higher, but AUC was comparable for patients who had severe renal impairment and received edoxaban 15 mg once daily (QD) versus patients who had normal renal function or mild renal impairment and received edoxaban 30 mg QD. Exposure–response analysis suggested that edoxaban C _min and country/region are significantly associated with the incidence of bleeds.

Conclusions

The model provided reasonable estimation with regard to the absolute bioavailability of edoxaban, the magnitude of change in edoxaban exposure upon co-administration of P-gp inhibitors, and the impact of renal impairment on edoxaban clearance. Analysis results supported a 50 % dose reduction scheme for subjects with severe renal impairment. Further confirmation will be sought by incorporating clinical safety and efficacy information from larger phase III trials.     

PALLAS: limiting indications for dronedarone treatment of atrial fibrillation?

Atrial fibrillation increases the risk of stroke. Dronedarone has been shown to reduce the composite of hospitalizations due to cardiovascular events or death, in subjects with intermittent atrial fibrillation or flutter. Recently, dronedarone has been tested in subjects with permanent atrial fibrillation in the PALLAS (permanent atrial fibrillation outcome study using dronedarone on top of standard therapy) trial, and this clinical trial is evaluated in this paper. PALLAS was stopped early as there was an increased incidence of cardiovascular events in the dronedarone group. Dronedarone also increased the rate of hospitalizations in PALLAS. As a result of PALLAS, dronedarone has been contraindicated in permanent atrial fibrillation. The outcomes of PALLAS highlight a discontinuity between dronedarone actions in permanent and intermittent atrial fibrillation. The mechanism(s) underlying the detrimental effects of dronedarone in permanent atrial fibrillation are unknown at present and need to be investigated.     

PALLAS: limiting indications for dronedarone treatment of atrial fibrillation?

Atrial fibrillation increases the risk of stroke. Dronedarone has been shown to reduce the composite of hospitalizations due to cardiovascular events or death, in subjects with intermittent atrial fibrillation or flutter. Recently, dronedarone has been tested in subjects with permanent atrial fibrillation in the PALLAS (permanent atrial fibrillation outcome study using dronedarone on top of standard therapy) trial, and this clinical trial is evaluated in this paper. PALLAS was stopped early as there was an increased incidence of cardiovascular events in the dronedarone group. Dronedarone also increased the rate of hospitalizations in PALLAS. As a result of PALLAS, dronedarone has been contraindicated in permanent atrial fibrillation. The outcomes of PALLAS highlight a discontinuity between dronedarone actions in permanent and intermittent atrial fibrillation. The mechanism(s) underlying the detrimental effects of dronedarone in permanent atrial fibrillation are unknown at present and need to be investigated.     

Decision-making around antithrombotics for stroke prevention in atrial fibrillation: the health professionals’ views

International Journal of Clinical Pharmacy - Background For stroke prevention in patients with atrial fibrillation (AF), the decision-making around antithrombotic therapy has been complicated by...     

Pharmacotherapies for the treatment of glioblastoma – current evidence and perspectives

Introduction: Glioblastoma, the most common malignant brain tumor, exhibits a poor prognosis with little therapeutic progress in the last decade. Novel treatment strategies beyond the established standard of care with temozolomide-based radiotherapy are urgently needed.

Areas covered: We reviewed the literature on glioblastoma with a focus on phase III trials for pharmacotherapies and/or innovative concepts until December 2015.

Expert opinion: In the last decade, phase III trials on novel compounds largely failed to introduce efficacious pharmacotherapies beyond temozolomide in glioblastoma. So far, inhibition of angiogenesis by compounds such as bevacizumab, cediranib, enzastaurin or cilengitide as well as alternative dosing schedules of temozolomide did not prolong survival, neither at primary diagnosis nor at recurrent disease.

Promising strategies of pharmacotherapy currently under evaluation represent targeting epidermal growth factor receptor (EGFR) with biomarker-stratified patient populations and immunotherapeutic concepts including checkpoint inhibition and vaccination. The clinical role of the medical device delivering ‘tumor-treating fields’ in newly diagnosed glioblastoma which prolonged overall survival in a phase III study has remained controversial. After failure of several phase III trials with previously promising agents, improvement of concepts and novel compounds are urgently needed to expand the still limited therapeutic options for the treatment of glioblastoma.     

Perspective: does ranolazine have potential for the treatment of atrial fibrillation?

Atrial fibrillation is the most common arrhythmia seen in clinical practice, and novel pharmacological approaches for treatment are sought. Ranolazine (Ranexa; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-[2-methoxyphenoxy]propyl)piperazin-1-yl]acetamide) is used clinically for the treatment of angina pectoris. Evidence is reviewed from both pre-clinical and clinical studies, which suggests that ranolazine also exhibits antiarrhythmic activity with growing evidence for atrio-selectivity. Further work is required in order to explore more fully the potential of ranolazine in the treatment of atrial fibrillation. In particular, investigation of ranolazine actions against atrial fibrillation in animal models that incorporate atrial fibrillation-related remodeling and data from carefully controlled trials in human atrial fibrillation would be of value.     

Drug therapy for atrial fibrillation: where do we go from here?

Atrial fibrillation, the most common cardiac arrhythmia requiring medical attention, has effects that range from mild symptoms to devastating stroke. Although treatments have evolved since the foxglove plant (later identified as containing digitalis) was first administered to slow the heart rate, satisfactory drug therapy has not been developed. In this review we describe present-day medical options and developments of future therapies to treat atrial fibrillation and maintain normal sinus rhythm.     

Why is warfarin underused for stroke prevention in atrial fibrillation? A detailed review of electronic medical records

Abstract

Objective:

Automated electronic queries of structured data fields in electronic medical records (EMR) found no barriers to warfarin in 42% of patients with atrial fibrillation or atrial flutter (AF) with moderate or high risk of stroke and no warfarin. A thorough manual review of records (including text reports) from the same EMR may better identify physicians’ reasons for not using warfarin.