Peripheral blood mononuclear cell transcriptome profile in a clinical trial with subcutaneous, grass pollen allergoid immunotherapy.

INTRODUCTION: Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment in allergic airway diseases. Underlying immunological mechanisms and candidate biomarkers, which may be translated into predictive/surrogate measures of clinical efficacy, remain an active area of research. The aim of this study was to evaluate Pollinex Quattro (PQ) Grass AIT induced immunomodulatory mechanisms, based on transcriptome profiling of peripheral blood mononuclear cells. METHODS: 119 subjects with grass pollen induced seasonal allergic rhinitis (SAR) were randomized in a 2:2:1:1 ratio to receive a cumulative dose of PQ Grass as a conventional or extended pre-seasonal regimen, placebo, or placebo with MicroCrystalline Tyrosine. Gene expression analysis was an exploratory endpoint evaluated in a subgroup of 30 subjects randomly selected from the four treatment arms. Samples were collected at three time points: screening (baseline), before the start of the grass pollen season and at the end of the season. This study was funded by the manufacturer of PQ. RESULTS: Transcriptome analysis demonstrated that the most significant changes in gene expression, for both treatment regimens, were at the end of the grass pollen season, with the main Th1 candidate molecules (IL-12A, IFNγ) upregulated and Th2 signature cytokines downregulated (IL-4, IL-13, IL-9) (p < .05). Canonical pathways analysis demonstrated Th1, Th2, Th17 and IL-17 as the most significantly enriched pathways based on absolute value of activation z-score (IzI score ≥ 2, p < .05). Upstream regulator analysis showed pronounced inhibition of pro-inflammatory allergic molecules IgE, IL-17A, IL-17F, IL-25 (IL-17E) (IzI score ≥ 2, FDR < 0.05) and activation of pro-tolerogenic molecules IL-12A, IL-27, IL-35 (EBI3) at the end of the grass pollen season. CONCLUSION: Peripheral blood mononuclear cells transcriptome profile showed an inhibition of Th2, Th17 pro-inflammatory allergic responses and immune deviation towards Th1 responses. PQ Grass extended regimen exhibited a superior mechanistic efficacy profile in comparison with PQ conventional regimen.

Dogmas, challenges, and promises in phase III allergen immunotherapy studies.

The concept of treatment of an allergy with the offending allergen was introduced more than a century ago. Allergen immunotherapy (AIT) is the only disease modifying treatment of allergic diseases caused by inhalational allergens and insect venoms. Despite this, only few AIT products have reached licensure in the US or an official marketing authorization status in European countries. Moreover, most of these AIT products are provided on an individual patient basis as named patient products (NPP) in Europe, while individualized preparations of (mixed) allergenic extract vials for subcutaneous administration (compounding) is common practice in the US. AIT products are generally considered safe and well tolerated, but the major practical clinical development challenge is to define the optimal dose and prove the efficacy and safety of these products using state-of-the art Phase II and pivotal Phase III studies. In planning Phase II-III AIT studies, a thorough understanding of the study challenges is essential (e.g. variability and non-validated status of subjective primary endpoints, limitations of pollen season definitions) and dogmas of these products (e.g., for sublingual immunotherapy (SLIT) trials double-blinding conditions cannot be maintained, resulting in stronger placebo responses in the active treatment group and inflated treatment effects in Phase III). There is future promise for more objective biomarker endpoints (e.g. basophil activation (CD63 and CD203c), subsets of regulatory dendritic, T and B cells, IL-10-producing group 2 innate lymphoid cells; alone or in combination) to overcome several of these dogmas and challenges; innovation in AIT clinical trials can only progress with integral biomarker research to complement the traditional endpoints in Phase II-III clinical development. The aim of this paper is to provide an overview of these dogmas, challenges and recommendations based on published data, to facilitate the design of Phase III studies and improve the evidence basis of safe and effective AIT products.

Technical standards in allergen exposure chambers worldwide - an EAACI Task Force Report.

Allergen exposure chambers (AECs) can be used for controlled exposure to allergenic and non-allergenic airborne particles in an enclosed environment, in order to (i) characterize the pathological features of respiratory diseases and (ii) contribute to and accelerate the clinical development of pharmacological treatments and allergen immunotherapy for allergic disease of the respiratory tract (such as allergic rhinitis, allergic rhinoconjunctivitis, and allergic asthma). In the guidelines of the European Medicines Agency for the clinical development of products for allergen immunotherapy (AIT), the role of AECs in determining primary endpoints in dose-finding Phase II trials is emphasized. Although methodologically insulated from the variability of natural pollen exposure, chamber models remain confined to supporting secondary, rather than primary, endpoints in Phase III registration trials. The need for further validation in comparison with field exposure is clearly mandated. On this basis, the European Academy of Allergy and Clinical Immunology (EAACI) initiated a Task Force in 2015 charged to gain a better understanding of how AECs can generate knowledge about respiratory allergies and can contribute to the clinical development of treatments. Researchers working with AECs worldwide were asked to provide technical information in eight sections: (i) dimensions and structure of the AEC, (ii) AEC staff, (iii) airflow, air processing, and operating conditions, (iv) particle dispersal, (v) pollen/particle counting, (vi) safety and non-contamination measures, (vii) procedures for symptom assessments, (viii) tested allergens/substances and validation procedures. On this basis, a minimal set of technical requirements for AECs applied to the field of allergology is proposed.

The mode of action of sugammadex on coagulation.

OBJECTIVE: To explore the mode of action (MoA) by which sugammadex interferes with coagulation. MATERIALS AND METHODS: The effect of sugammadex on various steps in the coagulation cascade including thrombin generation, factor Xa activity, and factor Xa generation was explored in human plasma. RESULTS: Sugammadex did not affect a conventional thrombin generation test (TGT), while it prolongs activated partial thromboplastin time (APTT) and prothrombin time (PT). However, a customized TGT with PT reagent revealed sugammadex effects. In addition, sugammadex prolonged a one-step prothrombinase-induced clotting time (PiCT) using human factor Xa. Furthermore, sugammadex interfered with factor Xa generation induced by an intrinsic and not by an extrinsic activator, nor by Russell's viper venom factor X (RVV-X). CONCLUSION: Adapted, rather than standard, experiments show that sugammadex is likely to decrease factor Xa activity in the common pathway and activation of factor X specifically in the intrinsic pathway.

Shaping Modern Vaccines: Adjuvant Systems Using MicroCrystalline Tyrosine (MCT®).

The concept of adjuvants or adjuvant systems, used in vaccines, exploit evolutionary relationships associated with how the immune system may initially respond to a foreign antigen or pathogen, thus mimicking natural exposure. This is particularly relevant during the non-specific innate stage of the immune response; as such, the quality of this response may dictate specific adaptive responses and conferred memory/protection to that specific antigen or pathogen. Therefore, adjuvants may optimise this response in the most appropriate way for a specific disease. The most commonly used traditional adjuvants are aluminium salts; however, a biodegradable adjuvant, MCT®, was developed for application in the niche area of allergy immunotherapy (AIT), also in combination with a TLR-4 adjuvant-Monophosphoryl Lipid A (MPL®)-producing the first adjuvant system approach for AIT in the clinic. In the last decade, the use and effectiveness of MCT® across a variety of disease models in the preclinical setting highlight it as a promising platform for adjuvant systems, to help overcome the challenges of modern vaccines. A consequence of bringing together, for the first time, a unified view of MCT® mode-of-action from multiple experiments and adjuvant systems will help facilitate future rational design of vaccines while shaping their success.

Interactions of sugammadex with various anticoagulants
.

OBJECTIVE: To investigate in vitro the effect of sugammadex on activated partial thromboplastin time (APTT) and prothrombin time (PT) prolongations with various anticoagulants as well as the neutralizing effect of rocuronium and vecuronium on sugammadex effects on APTT and PT. MATERIALS AND METHODS: We investigated in vitro the effect of sugammadex on APTT and/or PT in plasma of patients on a vitamin K antagonist and with elevated international normalized ratios (INRs), in plasma of healthy subjects spiked with either a low or high concentration of enoxaparin, fondaparinux, rivaroxaban, and dabigatran, and in perioperatively collected patient plasma. In addition, we explored whether the effects of sugammadex persisted in the presence of rocuronium or vecuronium, or whether they were counteracted by these compounds. RESULTS: Sugammadex concentration-dependently increased APTT and PT(INR) in all anticoagulant conditions, mainly in a proportional manner, with no differences between perioperatively collected patient and control plasma. Rocuronium and vecuronium both neutralized the effects of sugammadex on APTT and PT. CONCLUSION: Sugammadex has a transient effect on coagulation and is unlikely to increase bleeding risk, this possibility cannot be excluded for scenarios not clinically studied.

Sublingual allergen immunotherapy with a liquid birch pollen product in patients with seasonal allergic rhinoconjunctivitis with or without asthma.

BACKGROUND: Sublingual allergen immunotherapy (SLIT) has been demonstrated to be both clinically efficacious and safe. However, in line with the current regulatory guidance from the European Medicines Agency, allergen immunotherapy (AIT) products must demonstrate their efficacy and safety in pivotal phase III trials for registration. OBJECTIVE: We sought to investigate the efficacy and safety of sublingual high-dose liquid birch pollen extract (40,000 allergy units native [AUN]/mL) in adults with birch pollen allergy. METHODS: A randomized, double-blind, placebo-controlled, parallel-group multicenter trial was conducted in 406 adult patients with moderate-to-severe birch pollen-induced allergic rhinoconjunctivitis with or without mild-to-moderate controlled asthma. Treatment was started 3 to 6 months before the birch pollen season and continued during the season in 40 clinical study centers in 5 European countries. For primary end point assessment, the recommended combined symptom and medication score of the European Academy of Allergy and Clinical Immunology was used. Secondary end points included quality-of-life assessments, immunologic parameters, and safety. RESULTS: Primary efficacy results demonstrated a significant (P < .0001) and clinically relevant (32%) reduction in the combined symptom and medication score compared with placebo after 3 to 6 months of SLIT. Significantly better rhinoconjunctivitis quality-of-life scores (P < .0001) and the patient's own overall assessment of his or her health status, including the visual analog scale score (Euro Quality of Life Visual Analogue Scale; P = .0025), were also demonstrated. In total, a good safety profile of SLIT was observed. CONCLUSION: This study confirmed both the clinical efficacy and safety of a sublingual liquid birch pollen extract in adults with birch pollen allergy in a pivotal phase III trial (EudraCT: 2013-005550-30; ClinicalTrials.gov: NCT02231307).

Discovery and Clinical Evaluation of MK-8150, A Novel Nitric Oxide Donor With a Unique Mechanism of Nitric Oxide Release.

BACKGROUND: Nitric oxide donors are widely used to treat cardiovascular disease, but their major limitation is the development of tolerance, a multifactorial process to which the in vivo release of nitric oxide is thought to contribute. Here we describe the preclinical and clinical results of a translational drug development effort to create a next-generation nitric oxide donor with improved pharmacokinetic properties and a unique mechanism of nitric oxide release through CYP3A4 metabolism that was designed to circumvent the development of tolerance. METHODS AND RESULTS: Single- and multiple-dose studies in telemetered dogs showed that MK-8150 induced robust blood-pressure lowering that was sustained over 14 days. The molecule was safe and well tolerated in humans, and single doses reduced systolic blood pressure by 5 to 20 mm Hg in hypertensive patients. Multiple-dose studies in hypertensive patients showed that the blood-pressure-lowering effect diminished after 10 days, and 28-day studies showed that the hemodynamic effects were completely lost by day 28, even when the dose of MK-8150 was increased during the dosing period. CONCLUSIONS: The novel nitric oxide donor MK-8150 induced significant blood-pressure lowering in dogs and humans for up to 14 days. However, despite a unique mechanism of nitric oxide release mediated by CYP3A4 metabolism, tolerance developed over 28 days, suggesting that tolerance to nitric oxide donors is multifactorial and cannot be overcome solely through altered in vivo release of nitric oxide. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01590810 and NCT01656408.

A PK-PD model-based assessment of sugammadex effects on coagulation parameters.

Exposure-response analyses of sugammadex on activated partial thromboplastin time (APTT) and prothrombin time international normalized ratio (PT(INR)) were performed using data from two clinical trials in which subjects were co-treated with anti-coagulants, providing a framework to predict these responses in surgical patients on thromboprophylactic doses of low molecular weight or unfractionated heparin. Sugammadex-mediated increases in APTT and PT(INR) were described with a direct effect model, and this relationship was similar in the presence or absence of anti-coagulant therapy in either healthy volunteers or surgical patients. In surgical patients on thromboprophylactic therapy, model-based predictions showed 13.1% and 22.3% increases in respectively APTT and PT(INR) within 30min after administration of 16mg/kg sugammadex. These increases remain below thresholds seen following treatment with standard anti-coagulant therapy and were predicted to be short-lived paralleling the rapid decline in sugammadex plasma concentrations.

Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers.

OBJECTIVE: Corifollitropin alfa (Elonva®) is the first hybrid follicle-stimulating hormone molecule with demonstrated sustained follicle-stimulating activity after a single subcutaneous injection. This trial evaluated if corifollitropin alfa is associated with QT/QTc prolongation and/ or proarrhythmic potential as compared to placebo in healthy post-menopausal women. MATERIALS: Participants were healthy, postmenopausal women. Study treatments were corifollitropin alfa 150 µg, corifollitropin alfa 240 µg, and moxifloxacin 400 mg with placebo. METHODS: This randomized, double blind, double-dummy, 4-period crossover trial compared single doses of corifollitropin alfa 150 µg (therapeutic dose), corifollitropin alfa 240 µg (supratherapeutic dose), and moxifloxacin 400 mg (positive control) with placebo. Corifollitropin alfa was administered on day 1 and moxifloxacin on day 2. RESULTS: The largest time-matched mean QTcF difference versus placebo for the therapeutic dose of corifollitropin alfa was 1.4 ms (upper limit of 1-sided 95% confidence interval (UL 95% CI) = 3.4 ms), and for the supratherapeutic dose was 1.2 ms (UL 95% CI = 3.6 ms). CONCLUSIONS: For both the therapeutic and the supratherapeutic dose of corifollitropin alfa and at all time points, the UL 95% CI for the time matched QTcF differences compared with placebo was below 10 ms, the threshold of relevance defined by the ICH E14 guideline. Single therapeutic and supratherapeutic doses of corifollitropin alfa are not associated with clinically relevant QT/QTc-interval prolongation in healthy post-menopausal women.

Pharmacokinetics of sugammadex 16 mg/kg in healthy Chinese volunteers.

OBJECTIVE: Elimination of sugammadex occurs predominantly via the kidneys, with the majority of the drug excreted unchanged in the urine. To date, most studies with sugammadex have been performed in non-Asian populations. The objectives of this open-label study were to determine the pharmacokinetics (PK) and safety of single-dose sugammadex (16 mg/kg) in healthy Chinese adult volunteers. METHODS: 12 Chinese subjects (6 male; 6 female) received intravenous sugammadex (16 mg/kg) as a 10-second bolus infusion. Blood samples were collected pre-sugammadex and at regular intervals up to 24 hours post-sugammadex for PK assessment. Safety was assessed via AEs, vital signs, electrocardiogram, and laboratory parameters. RESULTS: Following sugammadex 16 mg/kg infusion, peak sugammadex concentration was 197 µg/mL, clearance was 99.7 mL/min, and apparent volume of distribution at equilibrium was 10.5 L. Plasma sugammadex concentrations showed a polyexponential decline over time, with an overall geometric mean (CV%) terminal half-life of 145 minutes (17.9%) (139 minutes (17.7%) for males; 152 minutes (18.6%) for females). No influence of gender on the PK of sugammadex was observed. Three subjects experienced an adverse events (AE) (dysgeusia of mild intensity), which was considered possibly or probably related to sugammadex. There were no clinically significant changes in vital signs, electrocardiography or laboratory parameters. CONCLUSION: PK of sugammadex (16 mg/kg) was characterized in healthy Chinese subjects. Overall between-subject variability on clearance and apparent volume of distribution was ~ 10%. Sugammadex was generally well tolerated.

Effects of Extended-Release Niacin and Extended-Release Niacin/Laropiprant on the Pharmacokinetics of Simvastatin in Healthy Subjects.

The use of multiple lipid-modifying agents with different mechanisms of action is often required to regulate lipid levels in patients with dyslipidemia. During combination therapy, alterations in the pharmacokinetics of any of the drugs used and their metabolites may occur. Three separate open-label, randomized, crossover studies evaluated the potential for pharmacokinetic interaction between extended-release niacin (with and without concomitant laropiprant) and simvastatin in healthy subjects. Study 1 used single doses of extended-release niacin and simvastatin; study 2 used multiple-dose coadministration of extended-release niacin/laropiprant and simvastatin in healthy subjects; and study 3 used single doses of both extended-release niacin and the coadministration of extended-release niacin/laropiprant and simvastatin in healthy Chinese subjects. During each treatment period, plasma samples were collected predose and at prespecified postdose time points for pharmacokinetic analyses. The safety and tolerability of simvastatin with and without coadministered extended-release niacin (or extended-release niacin/laropiprant) were assessed by clinical evaluation of adverse experiences. In 2 studies in healthy subjects, modest increases in exposure to simvastatin acid (by ∼60%) by extended-release niacin and extended-release niacin/laropiprant were observed. Based on the clinical experience with simvastatin, these effects are not believed to be clinically meaningful. In the third study on healthy Chinese subjects, no statistically meaningful increases in exposure to simvastatin by extended-release niacin and extended-release niacin/laropiprant were observed. In all populations examined in these studies, the coadministration of extended-release niacin and simvastatin was generally well tolerated.

Development of in vitro-in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers.

Development of in vitro-in vivo correlations (IVIVCs) for extended-release (ER) products is commonly pursued during pharmaceutical development to increase product understanding, set release specifications, and support biowaivers. This manuscript details the development of Level C and Level A IVIVCs for ER formulations of niacin, a highly variable and extensively metabolized compound. Three ER formulations were screened in a cross-over study against immediate-release niacin. A Multiple Level C IVIVC was established for both niacin and its primary metabolite nicotinuric acid (NUA) as well as total niacin metabolites urinary excretion. For NUA, but not for niacin, Level A IVIVC models with acceptable prediction errors were achievable via a modified IVIVC rather than a traditional deconvolution/convolution approach. Hence, this is in contradiction with current regulatory guidelines that suggest that when a Multiple Level C IVIVC is established, Level A models should also be readily achievable. We demonstrate that for a highly variable, highly metabolized compound such as niacin, development of a Level A IVIVC model fully validated according to agency guidelines may be challenging. However, Multiple Level C models are achievable and could be used to guide release specifications and formulation/manufacturing changes.

Lack of a clinically relevant effect of sugammadex on anti-Xa activity or activated partial thromboplastin time following pretreatment with either unfractionated or low-molecular-weight heparin in healthy subjects.

OBJECTIVE: To investigate the potential effect of sugammadex on anti-Xa anticoagulantactivity of enoxaparin and the activated partial thromboplastin time (APTT) of unfractionated heparin (UFH). METHODS: This two-part, randomized, double-blind, placebocontrolled, four-period cross-over study was performed in healthy males (18 - 45 years). In each period, subjects received 40 mg enoxaparin (in part 1), 5,000 units UFH (in part 2), or placebo followed by 4 or 16 mg/kg sugammadex, or placebo. Treatments were separated by ≥ 4 days. Primary endpoints were anti-Xa activity and APTT both time-averaged from 3 to 30 minutes post-dose. Geometric mean ratios (GMRs) and their two-sided 90% confidence limits were calculated for anticoagulant plus sugammadex (4 or 16 mg/kg) vs. anticoagulant plus placebo. The pre-specified threshold for a potential effect of clinical relevance was a 90% upper confidence limit (UCL) > 1.50. RESULTS: In part 1 (n = 13), the 90% UCLs were 1.07 and 1.08 for GMRs of anti-Xa activity after dosing with 4 and 16 mg/kg sugammadex, respectively. In part 2 (n = 43), the 90% UCLs for GMRs of APTT were 1.06 and 1.15. Neither sugammadex dose produced a treatment effect that met the pre-specified criterion for potential clinical relevance. Treatments were generally well tolerated. CONCLUSIONS: In healthy subjects, treatment with 4 mg/kg and 16 mg/kg sugammadex did not change either anti-Xa activity or APTT to a clinically meaningful extent following pretreatments with enoxaparin or UFH.

The effect of therapeutic and supratherapeutic oral doses of nomegestrol acetate (NOMAC)/17ß-estradiol (E2) on QTcF intervals in healthy women: results from a randomized, double-blind, placebo- and positive-controlled trial.

BACKGROUND AND OBJECTIVE: Nomegestrol acetate (NOMAC)/17ß-estradiol (E2) is a monophasic oral contraceptive that contains a progesterone-derived progestogen (NOMAC), and E2, a bio-identical estrogen. The primary objective of this thorough QT/QTc study was to investigate whether once-daily administration of therapeutic (2.5/1.5 mg) and supratherapeutic (12.5/7.5 mg) doses of NOMAC/E2 were associated with prolongation of the mean Fridericia-corrected QT (QTcF) interval in electrocardiograms at steady-state concentrations of NOMAC/E2 versus placebo. The co-primary objective was to establish assay sensitivity after a single dose of moxifloxacin (positive control). METHODS: This was a randomized, double-blind, parallel-group trial comparing 2.5/1.5 mg of NOMAC/E2 (therapeutic dose), 12.5/7.5 mg of NOMAC/E2 (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Double-blind study medication was administered from day -1 to 14. Healthy women aged 18-50 years were randomized. RESULTS: The largest time-matched mean QTcF difference compared with placebo for the therapeutic dose of NOMAC/E2 was 1.6 ms, with an upper limit (UL) of a one-sided 95% confidence interval (CI) of 5.2 ms, and 3.1 ms with an UL 95% CI of 7.0 ms for the supratherapeutic dose. The UL for the time-matched QTcF differences compared with placebo were below the 10 ms threshold defined in the ICH E14 guideline for all time points, both for the therapeutic and the supratherapeutic dose. For moxifloxacin, assay sensitivity was demonstrated. CONCLUSIONS: This thorough QT/QTc study showed that therapeutic and supratherapeutic doses of NOMAC/E2 were not associated with clinically relevant QTc interval prolongation in healthy women after a 2-week period of dosing.

Effects of sugammadex on activated partial thromboplastin time and prothrombin time in healthy subjects.

OBJECTIVES: To assess the impact of sugammadex on activated partial thromboplastin time (APTT) and international normalized ratio for prothrombin time (PT(INR)) in healthy subjects and characterize the concentration-dependency of sugammadex effects on APTT and prothrombin time (PT) in normal human plasma in vitro. METHODS: Eight healthy subjects (18 - 45 years of age) were administered intravenous doses of 4 mg/kg sugammadex, 16 mg/kg sugammadex, or placebo in a randomized, placebo-controlled, three period cross-over trial. The primary endpoint was area under the curve from 2 to 60 minutes post-dose (AUC2-60min) for APTT and PT(INR). In vitro, the effects of sugammadex on APTT and PT were assessed in pooled normal human citrate plasma. RESULTS: In subjects dosed with 4 and 16 mg/kg sugammadex, geometric mean ratios (treated vs. placebo) for AUC2-60min were 1.085 (95% confidence interval, 0.888 - 1.325) and 1.019 (0.868 - 1.195), respectively, for APTT, and 1.047 (0.904 - 1.213) and 1.096 (0.953 - 1.261), respectively, for PT(INR). At individual timepoints, mean APTT and PT(INR) increased by up to 22% after 16 mg/kg sugammadex compared with placebo. All such increases occurred within 30 minutes post-dose. Sugammadex was generally well tolerated. In the in vitro experiments, addition of sugammadex to plasma resulted in limited, concentration dependent increases in both APTT and PT. At 200 µg/mL (the mean maximum concentration reached therapeutically), the relative increases were 29% and 19%, respectively. CONCLUSIONS: Administration of sugammadex is associated with a dose-related, limited and transient prolongation of APTT and PT(INR) that is unlikely to be of clinical relevance.

The effects of laropiprant on the antiplatelet activity of co-administered clopidogrel and aspirin.

Laropiprant is an antagonist of the prostaglandin PGD2 receptor DP1. Laropiprant has a weak affinity for the thromboxane A2 receptor TP. Two double-blinded, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose laropiprant at steady state on the antiplatelet effects of multiple-dose aspirin and clopidogrel. Study 1 had two treatment periods, in which each healthy subject received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 80 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 80 mg (Treatment B) once daily for 7 days. Study 2 consisted of three treatment periods. In the first two, each patient with hypercholesterolemia or mixed dyslipidemia received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 81 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 81 mg (Treatment B) once daily for 7 days. In period 3, patients received a single dose of two tablets of extended release nicotinic acid 1 g/laropiprant 20 mg (Treatment C). In both studies, pharmacodynamic endpoints included bleeding time at 24 (primary) and 4 hours (secondary) post-dose following 7 days of once-daily laropiprant in combination with clopidogrel and aspirin, and platelet aggregation in platelet-rich plasma at 4 and 24 hours post-dose on day 7 (secondary). After 7 days, increased bleeding time of 27% (Study 1) and 23% (Study 2) at 24 hours post-dose was observed with laropiprant compared to placebo (both combined with clopidogrel and aspirin), with corresponding upper bounds of the 90% CI marginally exceeding the prespecified upper comparability bound of 1.50 in both studies. The GMR and 90% CI for bleeding time of laropiprant compared to placebo (both combined with clopidogrel and aspirin) at 4 hours post-dose on day 7 was 0.92 (0.70, 1.21) in Study 1, and 1.46 (1.20, 1.78) in Study 2. Compared with placebo, laropiprant (both combined with clopidogrel and aspirin) increased the inhibition of collagen- and ADP-induced platelet aggregation, respectively, by ∼2.4% and ∼8.1% in Study 1 and by ∼4% and ∼5.4% in Study 2, at 24 hours post-dose on day 7. The inhibition of collagen- and ADP-induced platelet aggregation, respectively, was increased by ∼0.1% and ∼5.0% in Study 1, and by ∼5% and ∼12% in Study 2, at 4 hours post-dose on day 7. In conclusion, co-administration of multiple doses of laropiprant with aspirin and clopidogrel induced a prolongation of bleeding time and an inhibitory effect on platelet aggregation ex vivo in healthy subjects and patients with dyslipidemia.

No clinically relevant interaction between sugammadex and aspirin on platelet aggregation and coagulation parameters.

OBJECTIVES: This study evaluated interaction potential between sugammadex and aspirin on platelet aggregation. METHODS: This was a randomized, double-blind, placebo-controlled, four-period crossover study in 26 healthy adult males. Treatments were i.v. placebo, i.v. sugammadex 4 mg/kg, and i.v. placebo/sugammadex with oncedaily oral aspirin 75 mg. Primary objective was to assess interaction between sugammadex and aspirin on platelet aggregation using collagen-induced whole-blood aggregometry. Effects on activated partial thromboplastin time (APTT) and cutaneous bleeding time were also evaluated. Platelet aggregation and APTT were evaluated by geometric mean ratios, using area-under-effect curves 3 - 30 minutes after sugammadex/placebo dosing. Bleeding time ratio was evaluated at 5 minutes post-dosing. Non-inferiority margins were pre-specified via literature review. Type I error was controlled using a hierarchical strategy. RESULTS: Ratio for platelet aggregation for aspirin with sugammadex vs. aspirin alone was 1.01, with lower limit of two-sided 90% CI of 0.91(above non-inferiority margin of 0.75). Ratio for statistical interaction between sugammadex and aspirin on APTT was 1.01, with upper 90% CI of 1.04 (below non-inferiority margin of 1.50), and for sugammadex vs. placebo alone was 1.06, with an upper 90% CI of 1.07 (below non-inferiority margin of 1.50). Ratio for bleeding time for aspirin with sugammadex vs. aspirin plus placebo was 1.20, with upper 90% CI of 1.45 (below non-inferiority margin of 1.50). Sugammadex was generally well tolerated. CONCLUSION: There was no clinically relevant reduction in platelet aggregation with addition of sugammadex 4 mg/kg to aspirin. Pre-determined non-inferiority margins were not exceeded for bleeding time and APTT.

Effect of sugammadex on QT/QTc interval prolongation when combined with QTc-prolonging sevoflurane or propofol anaesthesia.

BACKGROUND: We evaluated the potential for QT/corrected QT (QTc) interval prolongation after sugammadex given with propofol or sevoflurane anaesthesia. METHODS: This was a two-factorial, randomized, parallel-group study in 132 healthy subjects. Anaesthesia was maintained with sevoflurane or propofol. At ~20 min following sevoflurane/propofol initiation, sugammadex 4 mg/kg or placebo was administered. Neuromuscular blocking agents were not administered. Electrocardiograms were recorded regularly. The primary variable was the time-matched mean difference in the Fridericia-corrected QT interval (QTcF) change from baseline for sugammadex versus placebo when combined with propofol or sevoflurane. No relevant QTcF prolongation was concluded if the upper one-sided 95 % confidence interval (CI) was below the 10 ms margin of regulatory non-inferiority, up to 30 min post-study drug. Blood samples were taken for pharmacokinetic analysis. An exploratory analysis evaluated potential QT/QTc effects of neostigmine 50 µg/kg/glycopyrrolate 10 µg/kg in combination with propofol. RESULTS: The estimated mean QTcF differences between sugammadex and placebo ranged from -2.4 to 0.6 ms when combined with either anaesthetic. The largest upper one-sided 95 % CI for the mean QTcF difference between sugammadex and placebo was 2 ms, occurring 2 min post-dosing. Propofol and sevoflurane resulted in mean QTcF increases exceeding 10 and 30 ms, respectively. On top of these prolongations, the effect of sugammadex was negligible at all timepoints. The mean peak sugammadex concentration was 66.5 µg/mL, with exposure similar in the sevoflurane/propofol groups. The mean QTcF changes from baseline following neostigmine/glycopyrrolate in 10 healthy subjects ranged between -1.4 and 3.6 ms. CONCLUSION: Sugammadex 4 mg/kg does not cause clinically relevant QTc interval prolongation versus placebo when combined with propofol or sevoflurane.

Sugammadex is not associated with QT/QTc prolongation: methodology aspects of an intravenous moxifloxacin-controlled thorough QT study.

OBJECTIVE: Sugammadex is a novel γ-cyclodextrin and the first selective relaxant binding agent to be developed for the reversal of rocuronium and vecuroniuminduced neuromuscular blockade. According to International Conference on Harmonization (ICH) E14, a thorough QT/QTc study is required for most new compounds to assess the potential to cause QT prolongation, because a delay in cardiac repolarization may create an electrophysiological environment that favors the development of cardiac arrhythmias, most notably Torsade de Pointes. Therefore a thorough QTc study was conducted to evaluate the effect of sugammadex on the individually corrected QTc interval (QTcI). METHODS: Following two baseline electrocardiogram (ECG) days (Day -2 and Day -1), in this randomized, double-blind, cross-over study, healthy volunteers received a sequence of four treatments comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control, open label), sugammadex 4 mg/kg and sugammadex 32 mg/kg. ECGs were recorded in triplicate at 12 time points up to ~ 24 h after study drug administration, and the QT intervals were evaluated manually under blinded conditions. The pre-specified primary endpoint was the largest time-matched mean QTcI difference compared with placebo across all time points. RESULTS: A total of 62 subjects received treatment, of which 58 completed the study. After intravenous moxifloxacin, QTcI prolongations compared with placebo exceeded the ICH E14 safety margin of 10 msec and the one-sided 95% lower confidence limit exceeded 5 msec, confirming assay sensitivity. For both sugammadex doses, the one-sided 95% upper confidence limits for the largest time-matched mean QTcI differences compared with placebo were ≤ 5.3 msec at each timepoint and thus considerably below the 10 msec safety margin. Unexpectedly, the two full-day baseline ECGs indicated systematically prolonged QTc values when comparing the first baseline with the second baseline day, reaching a maximum mean difference of 3.8 msec. CONCLUSION: Single therapeutic (4 mg/kg) and supra-therapeutic (32 mg/kg) intravenous doses of sugammadex are not associated with clinically important QTc prolongation.