Predose Values Research Articles

Randomized trial of pharmacokinetic and pharmacodynamic effects of 13.2 mg intranasal epinephrine treatment in congestion

BackgroundNasal congestion could affect the absorption of an epinephrine nasal spray (ENS). ObjectiveTo compare the pharmacokinetics of 13.2 mg ENS with nasal congestion vs without congestion and vs intramuscular (IM) treatments. MethodsThis phase I, open-label, 4-period randomized crossover study enrolled 51 healthy adults with seasonal allergies into cohorts that received a single dose of 13.2 mg ENS (NDS1C; Bryn Pharma, Lebanon, New Jersey) administered as 2 consecutive sprays in either opposite nostrils (cohort 1) or the same nostril (cohort 2). Both cohorts received 13.2 mg ENS with and without nasal allergen challenge (NAC), 0.3 mg IM epinephrine by autoinjector, and 0.5 mg IM epinephrine by manual syringe (MS). ResultsThe ENS after NAC resulted in higher extent and peak exposures and more rapid time to maximum plasma concentration vs ENS without NAC and IM treatments. In cohort 1, the maximum observed baseline-adjusted epinephrine plasma concentration (pg/mL) of ENS with NAC, IM autoinjector, IM MS, or ENS without NAC was 458.0, 279.0, 364.2, and 270.1, respectively, and in cohort 2 was 436.3, 228.2, 322.3, and 250.8, respectively. The maximum observed baseline-adjusted epinephrine plasma concentration geometric mean ratio (90% CI) for ENS with NAC vs without NAC in cohort 1 was 170% (123%-234%), and in cohort 2 was 174% (115%-263%). In cohort 1, the time to maximum plasma concentration was 15, 21, 45, and 25 minutes, respectively, and in cohort 2 was 18, 20, 45, and 20 minutes, respectively (P < .01 for ENS with NAC vs IM MS). The postdose mean heart rate and blood pressure remained stable and relatively similar to predose values regardless of plasma epinephrine concentration. Mild nausea and headache were the most common adverse events with ENS. ConclusionThe 13.2 mg ENS with congestion exhibited enhanced absorption vs IM treatments and ENS without congestion and seemed to be well tolerated. There was no clinically impactful relationship between pharmacodynamic effects and plasma epinephrine concentration.

A Novel Mixture of δ-Tocotrienol, Vitamin D3, Resveratrol (NS-3) Significantly Decreases Diabetes Biomarkers Including Inflammatory in People with Type 2 Diabetes

Aims: Diabetes mellitus is a metabolic disorder identified by hyperglycemia due to insulin resistance. Impaired serum/plasma fasting glucose, HbA1c, hs-CRP are biomarkers, normally used to determine onset of diabetes. d-Tocotrienol, vitamin D3, and resveratrol (nutritional supplement-NS-3) are potent anticholesterolemic, anti-oxidative and anti-inflammatory agents. We hypothesized that a mixture of d-tocotrienol, vitamin D3, resveratrol (NS-3) will be more effective treatment for reducing diabetes biomarkers as compared to its individual components, in people with type 2 diabetes mellitus (T2DM). Methods: To test our hypothesis, evaluation of NS-3 mixture and its individual components was carried out on diabetes inflammatory biomarkers using peripheral blood mononuclear cells (PBMC) obtained from healthy, normal and people with T2DM. A randomized placebo controlled double-blinded prospective trial of individual components (n = 30/component), and NS-3 trial of people with T2DM (n = 52/group), were given two capsules/d of cellulose/olive oil as placebo, individual components, or NS-3 mixture for 24-weeks. Results: Significant down-regulation (15 - 74; P &lt; 0.002) of gene expression was observed with individual components and NS-3 on diabetes biomarkers (IRS-1, SOD-2, GCKR, ICAM-1, VCAM-1, IL-6, IL-8) in PBMCs of T2DM, and in serum values of fasting glucose (11%), HbA1c (10%), hs-CRP (23%), fasting insulin (9%), HOMA-IR (20%), MDA (20%) of NS-3 treated people with T2DM after 24-weeks. Treatment with individual components showed significant decrease but were less effective than the mixture. RT-PCR analysis of blood RNAs obtained from NS-3 treated people with T2DM for 24-weeks resulted in significant (P &lt; 0.01) down-regulation of gene expression in diabetes biomarkers (IRS-1, SOD-2, GCKR, IGFPB-2) compared to pre-dose values. Conclusions: Present results of in vitro and in vivo studies support our hypothesis that NS-3 mixture is more effective in lowering serum levels of several diabetes biomarkers including inflammatory gene expression markers compared to its individual components in people with T2DM.

Utility of Coproporphyrin-I Determination in First-in-Human Study for Early Evaluation of OATP1B Inhibitory Potential Based on Investigation of Ensitrelvir, an Oral SARS-CoV-2 3C-Like Protease Inhibitor

Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the OATP1B inhibitory potential because ensitrelvir had increased plasma concentrations of rosuvastatin in this study, raising concerns about breast cancer resistance protein and OATP1B inhibition. Furthermore, CP-I concentrations were compared between active and placebo groups in a first-in-human (FIH) study of ensitrelvir to verify whether the OATP1B inhibitory potential could be estimated at an early drug development stage. In the cocktail DDI study, CP-I did not differ between with/without administration of ensitrelvir, indicating that ensitrelvir has no OATP1B inhibitory effect. Although there were some individual variabilities in CP-I concentrations among the treatment groups in the FIH study, the normalization of CP-I concentrations with pre-dose values minimized these variabilities, suggesting that this normalized method would be helpful for comparing the CP-I from different participants. Finally, we concluded that CP-I concentrations were not affected by ensitrelvir in the FIH study. These results suggested that the CP-I determination in an FIH study and its normalized method can be useful for an early evaluation of the OATP1B-mediated DDI potential in humans.

Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3

ObjectiveThe objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. MethodsObservational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. ResultsTwenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre-dose and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) μg/mL and 747.4 (SD 444.3) μg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (p=0.002) and decreased serum creatinine at both higher pre- and post-dose concentrations (p=0.001 and p=0.017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 μg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% CV) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. ConclusionsThe present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Pharmacodynamic Evaluation of Acalabrutinib in Relapsed/Refractory and Treatment-Naive Patients with Chronic Lymphocytic Leukemia (CLL) in the Phase 1/2 ACE-CL-001 Study

Pharmacodynamic Evaluation of Acalabrutinib in Relapsed/Refractory and Treatment-Naive Patients with Chronic Lymphocytic Leukemia (CLL) in the Phase 1/2 ACE-CL-001 Study

A first‐in‐human study to evaluate the safety, tolerability and pharmacokinetics of RP3128, an oral calcium release‐activated calcium (CRAC) channel modulator in healthy volunteers

RP3128, a novel, orally available modulator of calcium released activated calcium (CRAC) channel, is being developed for the potential treatment of autoimmune and inflammatory diseases. RP3128 showed nano-molar potency and activity in a range of in vitro and in vivo models of inflammation. We report a first-in-human study investigating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RP3128 in healthy subjects. A randomized, double-blind, placebo-controlled trial of single (25, 50, 100, 200 and 400mg) and multiple (7days: 25, 100 and 400mg once daily) doses of RP3128 were performed. Thirty-two and 24 subjects were randomized in the single ascending dose (SAD) and multiple ascending dose (MAD) parts, respectively. RP3128 was well tolerated, with no dose-limiting toxicity at single and multiple doses. Incidence of treatment emergent adverse events (TEAEs) did not increase with ascending RP3128 doses. No changes were seen in cognitive function and ECG parameters. RP3128 was rapidly absorbed. Elimination was slow with a half-life of more than 80h. Exposures increased with increasing doses. Accumulation was seen on repeated dosing. PD response, as evidenced by lower plasma levels of tumour necrosis factor-alfa (TNFα) and interleukin-4 (IL-4), was seen when compared to pre-dose values or placebo. The safety, tolerability and PK/PD profile of RP3128 demonstrates its potential to be developed in inflammatory disorders and support further clinical development (ClinicalTrials.gov number: NCT02958982).

Method for evaluating the human bioequivalence of acarbose based on pharmacodynamic parameters.

ObjectiveTo explore a method for evaluating the bioequivalence of acarbose based on pharmacodynamic parameters using a single-dose, randomized-sequence, three-way crossover study of acarbose test (T) and reference (R) formulations.MethodsBaseline-adjusted, pre-dose value deduction, and direct comparison methods were used to evaluate the geometric T/R ratios and 90% confidence intervals (CIs) of the ln-transformed pharmacodynamic parameters to identify the most suitable evaluation system. Twelve participants were randomly divided into three groups to receive treatment in the following sequences: TRR, RTR, and RRT, each including a 7-day washout period between treatment periods. The serum glucose concentration (baseline) was determined. Pharmacodynamic parameters, including the maximum reduction in serum glucose concentrations (ΔCSG,max) and difference of the AUC of glucose between before and after acarbose exposure (ΔAUEC), were tested.ResultsUsing the direct comparison method, the geometric mean ratios of CSG,max, AUEC(0-2h), and AUEC(0-4h) were 94.13%, 97.82% and 99.76%, respectively. The 90% CIs of the geometric T/R ratios for CSG,max, AUEC(0-2h), and AUEC(0-4h) all fell between 80% and 125%. Conversely, ΔCSG,max and ΔAUEC(0-4h) were less reliable measures of acarbose bioequivalence.ConclusionsPre-dose value deduction and direct comparison methods can be initially considered suitable for assessing acarbose bioequivalence.

Effects of intravenous injection of indocyanine green on the oxygen reserve index (ORi™).

The oxygen reserve index (ORi™) is a parameter used for the noninvasive evaluation of arterial partial pressure of oxygen (PaO2), specifically in the 100-200mmHg range. We aimed to report on the impact of indocyanine green (ICG) on the ORi™. In this study, we retrospectively examined patients who underwent neurosurgery between April and July 2019 and assessed the impact of ICG on ORi™. We excluded patients who did not use ICG or who were not examined for ORi™. The dose and timing of ICG administration were determined by a neurosurgeon. The changes in ORi™ were measured for up to 30min. We analyzed ten patients and found that the ORi™ increased to 1.00 in all of them. The median time for ORi ™ to rise to 1.00 after ICG administration was 2min (range 1-4). After rising to 1.00, ORi ™ decreased and took 27min to return to the pre-dose value. It is important to consider the initial rapid increase and subsequent slow decrease in ORi™ when using ICG during surgery.

Effects of Caffeine on Splanchnic Oxygenation in Preterm Infants

The aim of this study is to assess the effects of administering 20 mg/kg loading dose of caffeine citrate intravenously on splanchnic oxygenation in preterm infants. The infants with a gestational age (GA) of <34 weeks who were administered with a 20 mg/kg intravenous loading dose of caffeine citrate within 48 hours after birth were investigated prospectively. Regional splanchnic oxygen saturation (rsSO2) and splanchnic fractional tissue oxygen extraction rate (sFTOE) were measured using near-infrared spectroscopy before caffeine infusion, immediately after caffeine infusion and 1, 2, 3, 4, and 6 hours (h) after dose completion; postdose values were compared with predose values. A total of 41 infants with a mean GA of 29.2 ± 1.6 weeks and birth weight of 1,315 ± 257 g as well as postnatal age of 32.2 ± 10.8 hours were included in the study. rsSO2 significantly reduced from 63.1 to 57.5% immediately after caffeine infusion, 55.1% after 1 hour, and 55.2% after 2 hours with partial recovery at 3-hour postdose. sFTOE increased correspondingly. Caffeine reduces splanchnic oxygenation and increases splanchnic oxygen extraction for at least 2 hours with partial recovery to predose levels at 3-hour postdose.

Effect of plinabulin, a novel late-clinical stage immunotherapeutic agent on the adaptive and innate immune system.

8 Background: Plinabulin (Plin) is a small molecule Dendritic Cell modulator, which in the presence of antigen, increases T-cell proliferation in an antigen-dependent manner marrow. The addition of Plin to Docetaxel (Doc) improved mOS with 4.6 months vs Docetaxel monotherapy, and prolonged DoR with more than 1 year (p &lt; 0.05), which is indicative of an immune-mediated mechanism of action (Mohanlal, ASCO-SITC 2017). Neutrophils are our first line of innate immune defense against foreign invaders. We previously reported that Plinabulin prevents chemotherapy (Chemo) Induced Neutropenia (CIN) in patients receiving Doc or TAC throughout the cycle (Doc, Doxorubicin, Cyclophosphamide) (Blayney ASH 2018, St Gallen 2019). Here we analyzed the onset time of neutrophil increase following Plin administration. In addition, we analyzed the impact of Plin on plasma haptoglobin, which is an acute phase protein with anti-inflammatory effects together with immune-enhancing effects and is an integral part of innate immunity (Kristiansen Nature 2001). Methods: Absolute neutrophil count (ANC) and haptoglobin data were analyzed from Phase 2 study BPI-2358-106 (NCT03294577) with 10 (n = 15), 20 (n = 15) and 30 mg/m2 (n = 12) Plin in Breast Cancer patients receiving TAC. Plin was administered on Day 1. ANC and Haptoglobin were analyzed by a Central Laboratory (Covance), from blood draws at predose, and post-dose Plin at Day 2,3,6,7,8,9,10,11,12,13 and 15, and changes relative to predose value were evaluated. Results: Plin dose-dependently increased ANC within 1 day (P &lt; 0.001) and Haptoglobin within 3 days (P &lt; 0.03) of dosing. Mean haptoglobin (P &lt; 0.0005) and ANC (P &lt; 0.001) levels increased with ~two-fold vs baseline levels. ANC levels remained increased for approximately 1 week and haptoglobin levels for &gt; 3 weeks. Conclusions: Based on Plinabulin’s ability to stimulate the innate system, together with its previously reported evidence as a potent activator of the adaptive immune system (Mohanlal, ASCO-SITC 2017), it is concluded that Plinabulin is a potent stimulator of the adaptive and innate immune system. Clinical trial information: NCT03294577.

Spasticity and Range of Motion Over Time in Stroke Patients Who Received Multiple-Dose Botulinum Toxin Therapy

ObjectiveThis study examined how the effects of botulinum toxin therapy changed over time by sequential evaluation of clinical improvements in spasticity and contracture in 24 chronic-stage stroke patients on repeated botulinum toxin therapy who were receiving fewer rehabilitation interventions. MethodsBotulinum toxin injection was administered into the spastic muscle of the paralyzed upper or lower limb 5 times with at least 3-month intervals. Modified Ashworth Scale and range of motion were measured before and 2 weeks after each dose in the extremities to compare the first measurement value with subsequent values. Each predose value was also compared with the first predose value. ResultsCompared with predose scores, Modified Ashworth Scale significantly improved in all flexors after 2 weeks from the first to fifth doses. Range of motion significantly improved in wrist dorsiflexion and ankle dorsiflexion. Comparison of values before each dose versus the first predose value showed significant improvement both in the Modified Ashworth Scale score of wrist flexors, finger flexors, and ankle planter flexors, and the range of motion of elbow extension, wrist dorsiflexion, and ankle dorsiflexion. ConclusionThe comparison of predose values versus 2-week postdose values indicated that the effect of botulinum toxin formulation would not lessen after repeated injections with continuous improvements of Modified Ashworth Scale and range of motion. The comparison of predose values versus the first predose value also suggested that multiple injections of botulinum toxin formulation could be more effective in reducing spasticity and increasing the range of motion than a single injection.

Abstract 615: The Cardiac Myosin Inhibitor, CK-3773274, Reduces Contractility in the R403q Mouse Model of Hypertrophic Cardiomyopathy

Cardiac sarcomere hypercontractility appears to underlie pathological hypertrophy and fibrosis in select genetic hypertrophic cardiomyopathies. The small molecule, CK-3773274, is a novel cardiac myosin inhibitor that decreases contractility in vitro and in healthy animals in vivo . The objective of this study was to evaluate the effect of CK-3773274 in the genetic R403Q mouse model of hypertrophic cardiomyopathy. At approximately 40 weeks of age, left ventricular wall dimensions were determined by echocardiography in male wild type (WT) and heterozygous R403Q mice. As an indicator of cardiac hypertrophy, R403Q mice had significantly greater septal and posterior wall thickness than WT mice (septal wall WT: 0.93 ± 0.03 mm vs. R403Q: 1.22 ± 0.08 mm; posterior wall WT: 0.84 ± 0.04 mm vs. R403Q: 1.09 ± 0.04 mm; mean ± SEM, p&lt; 0.05). R403Q mice were treated with single oral doses of CK-3773274 ranging from 0.25 to 1.5 mg/kg and fractional shortening (FS) and heart rate were assessed at select time points over a 24-hour period. One hour after dose administration, CK-3773274 significantly reduced FS in a dose-related fashion relative to pre-dose baseline values (FS % R403Q baseline: 55.5 ± 2%; 0.25 mg/kg: 43.9 ± 2%; 1 mg/kg: : 27.3 ± 2%; 1.5 mg/kg: 13.7 ± 1%; mean ±SEM, p&lt;0.05 vs. baseline at all doses) without any changes to heart rate. At all dose levels, fractional shortening returned to baseline values by 24 hours. The plasma concentration at 10% and 50% reduction of FS relative to baseline (IC 10 and IC 50 ) was 0.11 and 0.78 μM, respectively. In summary, single oral dose administration of CK-3773274 reduced fractional shortening in a dose and concentration-dependent manner in the genetic R403Q mouse model of hypertrophic cardiomyopathy. Cardiac myosin inhibition may be a viable approach to reduce underlying hypercontractility of the cardiac sarcomere in hypertrophic cardiomyopathies.

Influence of cytochrome P450 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke previously treated with clopidogrel

This randomized double-blind crossover study aimed to investigate the influence of cytochrome P450 (CYP) 2C19 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke treated with clopidogrel. Patients received clopidogrel 75 mg/day for > 4 weeks. Subsequently, patients received prasugrel 3.75 mg/day (group A; n = 64) or 2.5 mg/day (group B; n = 65) for 4 weeks followed by a 4 week switched-dose regimen. To assess the influence of CYP2C19 polymorphisms, patients were classified as extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs). The primary endpoint was P2Y12 reaction units (PRU) at the end of each 4 week treatment. A significant reduction in PRU was noted after treatment with prasugrel 3.75 mg/day compared with the pre-dose value (after treatment with clopidogrel) (p < 0.0001). By CYP2C19 phenotypes, a significant reduction in PRU was noted in IMs and PMs after treatment with prasugrel 3.75 mg/day and in PMs after treatment with prasugrel 2.5 mg/day, as compared with the pre-dose value (p < 0.0001). The plasma concentration of the active metabolite of clopidogrel was relatively low in PMs compared to EMs and IMs; prasugrel was similar across all CYP2C19 phenotypes. No major or clinically significant hemorrhagic adverse events occurred. By CYP2C19 phenotype, the antiplatelet effects of prasugrel were greater with 3.75 mg/day in IMs and PMs, and with 2.5 mg/day in PMs compared with clopidogrel 75 mg/day, without safety concerns. CYP2C19 polymorphisms did not affect the plasma concentration of the active metabolite of prasugrel or its antiplatelet effects. (JapicCTI-101044).

Generalized ROC methods for immunogenicity data analysis of vaccine phase I studies in a seropositive population

ABSTRACTImmunogenicity data from phase 1 vaccine studies can be difficult to interpret, especially in seropositive populations and when multiple assays are used. We developed 3 statistical methods (Youden index [YI] threshold, receiver-operating characteristic relative to baseline [ROC-B], and ROC of postdose levels [ROC-P]) to characterize complex immunogenicity data by assessing the proportion of a study population that achieved values above thresholds. The YI method calculates a single threshold per assay. Both ROC methods construct ROC curves for individual assays and surfaces for assay combinations to assess degree of separation of postdose values from a reference distribution; the ROC-B method uses overall predose values as the reference distribution and the ROC-P method uses pooled postdose values. All methods are applicable to a seropositive population with overlapping distributions of baseline and postdose measurements and can evaluate results of multiple assays jointly. The ROC-P method is also applicable when postdose levels are fully separated from baseline levels, as is common in a seronegative population. These methods were demonstrated using data from a phase 1a study of respiratory syncytial virus vaccines formulated with and without an adjuvant in a seropositive population of adults aged ≥60 years. All 3 methods provided a comprehensive assessment of vaccine immunogenicity effects with results presented in easily interpretable formats. In the example data, the methods demonstrated antigen dose response trend and contribution of adjuvant to response in multiple assays individually and jointly where optimal responses in assay combinations (humoral and cellular) are important.

Sustained plasma hepcidin suppression and iron elevation by Anticalin-derived hepcidin antagonist in cynomolgus monkey.

Anaemia of chronic disease (ACD) has been linked to iron-restricted erythropoiesis imposed by high circulating levels of hepcidin, a 25 amino acid hepatocyte-derived peptide that controls systemic iron homeostasis. Here, we report the engineering of the human lipocalin-derived, small protein-based anticalin PRS-080 hepcidin antagonist with high affinity and selectivity. Anticalin- and hepcidin-specific pharmacokinetic (PK)/pharmacodynamic modelling (PD) was used to design and select the suitable drug candidate based on t1/2 extension and duration of hepcidin suppression. The development of a novel free hepcidin assay enabled accurate analysis of bioactive hepcidin suppression and elucidation of the observed plasma iron levels after PRS-080-PEG30 administration in vivo. PRS-080 had a hepcidin-binding affinity of 0.07nM and, after coupling to 30kD PEG (PRS-080-PEG30), a t1/2 of 43h in cynomolgus monkeys. Dose-dependent iron mobilization and hepcidin suppression were observed after a single i.v. dose of PRS-080-PEG30 in cynomolgus monkeys. Importantly, in these animals, suppression of free hepcidin and subsequent plasma iron elevation were sustained during repeated s.c. dosing. After repeated dosing and followed by a treatment-free interval, all iron parameters returned to pre-dose values. In conclusion, we developed a dose-dependent and safe approach for the direct suppression of hepcidin, resulting in prolonged iron mobilization to alleviate iron-restricted erythropoiesis that can address the root cause of ACD. PRS-080-PEG30 is currently in early clinical development.

Comparison of fluticasone/formoterol with budesonide/formoterol pMDI in adults with moderate to severe persistent asthma: Results from a 12-week randomized controlled trial

BackgroundCombination therapy of inhaled corticosteroid/long acting β2-agonist (ICS/LABA) is the cornerstone of managing asthmatics who are uncontrolled with low-medium dose of ICS. The novel ICS/LABA combination of fluticasone propionate and formoterol (flu/form) provides potent anti-inflammatory and rapid bronchodilatory effect.This randomized, multi-centre, double-blind study compared the efficacy and safety of flu/form (125/6 mcg BD; Maxiflo®) with the well-established budesonide/formoterol combination (bud/form 200/6 mcg BD), both delivered through a pressurized metered dose inhaler (pMDI) in patients with moderate to severe persistent asthma over 12 weeks. MethodsThis study enrolled patients between 18 and 65 years. The primary end-point was to demonstrate non-inferiority for the mean change in the pre-dose morning peak expiratory flow values (PEF). The secondary end-points included lung function assessments, number of symptom-free days and nights, rescue medication use, day-and night-time symptom scores and safety evaluation. ResultsTwo hundred and thirty-two patients were randomized to either flu/form (n = 117) or bud/form (n = 115). At the end of 12 weeks, flu/form was non-inferior to bud/form with regards to the primary end-point of morning PEF (48.07 L/min vs. 49.03 L/min, p > 0.05). These improvements were statistically significant (p < 0.0001) vs baseline. Similar improvements were observed between the two groups for secondary efficacy end-points including FEV1, symptom-free nights, rescue medication use, day-and night-time symptom scores (p > 0.05). Flu/form exhibited a safety profile comparable to that of bud/form. ConclusionFluticasone/formoterol combination administered through a pMDI is as efficacious and well-tolerated as budesonide/formoterol and offers a new therapeutic option for patients with moderate to severe persistent asthma.

Mitigation of Initial Cardiodynamic Effects of the S1P1 Receptor Modulator Ponesimod Using a Novel Up‐Titration Regimen

Ponesimod, a potent selective sphingosine-1-phosphate receptor 1 modulator, leads to a reduction in circulating total lymphocyte count and transient decreases in heart rate (HR). Based on a modeling and simulation approach, this study was conducted to investigate whether a gradual up-titration regimen may mitigate these cardiodynamic effects. In this double-blind, placebo-controlled, randomized, 2-way crossover study, 32 healthy participants (15 males) received placebo on day 1 followed by multiple-dose administration of either ponesimod or placebo (ratio 3:1). Ponesimod was administered alternately using regimen A (incremental dose increase from 2 to 20 mg in 9 steps) or B (10 mg for 7 days followed by a single-dose administration of 20 mg). Cardiodynamic (Holter and 12-lead ECG), pharmacokinetic, pharmacodynamic (total lymphocyte count), and safety variables were assessed. After first-dose ponesimod administration (day 2), a transient decrease in HR was observed (nadir 2-3 hours postdose, back to predose values within 4-5 hours) of approximately 6 and 12 beats/min (bpm) (mean) following regimens A and B, respectively. On day 2, occurrence of HR <45 bpm, HR decrease from baseline of over 20 bpm, PR interval ≥200 milliseconds, or PR interval increase from baseline >20 ms, was lower following regimen A than B (14 vs 43 events). During the course of the study, incidence of HR <45 bpm was lower following regimen A than B (20 vs 58 events). Fewer participants reported adverse events following regimen A than B. Pharmacokinetics and pharmacodynamics were similar between the regimens. The novel gradual up-titration with ponesimod markedly mitigated initial cardiodynamic effects.

Platelet Inhibition With Ticagrelor 60 mg Versus 90 mg Twice Daily in the PEGASUS-TIMI 54 Trial

BackgroundThe PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial studied 2 doses of ticagrelor, 90 mg twice a day (bid) and 60 mg bid, for long-term prevention of ischemic events in patients with prior myocardial infarction. Both doses similarly reduced the rate of ischemic events versus placebo. The pharmacokinetics and pharmacodynamics of ticagrelor 60 mg bid have not been studied. ObjectivesIn this study, the authors sought to study the pharmacokinetics and pharmacodynamics for ticagrelor 60 mg compared with 90 mg bid. MethodsA total of 180 patients who received >4 weeks of study medication had blood sampling in the morning pre-maintenance dose and again 2 h post-dose. All patients received aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were determined. P2Y12 inhibition was assessed by the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) (P2Y12 reaction units [PRU]), light transmittance aggregometry (adenosine diphosphate 5 and 20 μmol/l and arachidonic acid), and vasodilator-stimulated phosphoprotein phosphorylation assays. VerifyNow Aspirin assays and serum thromboxane B2 measurements were performed. ResultsMean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose PRU values were 59 ± 63 and 47 ± 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose. ConclusionsTicagrelor 60 mg bid achieved high levels of peak and trough platelet inhibition in nearly all patients, similar to that with 90 mg bid, helping to explain the efficacy of the lower ticagrelor dose in PEGASUS-TIMI 54.

Bronchodilator response in adults with bronchiectasis: correlation with clinical parameters and prognostic implications.

Bronchial dilation testing is an important tool to assess airway reversibility in adults with bronchiectasis. This study aims to investigate the association of bronchodilator response (BDR) and clinical parameters in bronchiectasis, and the utility of BDR to indicate lung function decline and risks of bronchiectasis exacerbations (BEs). We recruited 129 patients with clinically stable bronchiectasis. Baseline measurements included assessment of sputum inflammation and matrix metalloproteinase-8 and -9, sputum bacterial culture, spirometry, bronchial dilation test (for baseline FEV1 less than 80% predicted only) and chest high-resolution computed tomography (HRCT). Bronchiectasis patients were followed-up for 1 year to determine the incidence of BEs and lung function trajectories. Significant BDR was defined as FEV1 improvement from pre-dose value by at least 200 mL and 12%. Clinical trial registry No.: NCT01761214; URL: www.clinicaltrials.gov. BDR was negatively correlated with baseline FEV1 percentage predicted, but not blood or sputum eosinophil count. Significant BDR was not associated with greater proportion of never-smokers, poorer past history, greater HRCT scores, poorer diffusing capacity or increased sputum matrix metalloproteinases (all P>0.05). There was a trend towards higher bronchiectasis severity index (BSI) and greater proportion of patients with Pseudomonas aeruginosa isolation or infection. Significant BDR at baseline was linked to poorer spirometry, but not more rapid lung function decline, throughout follow-up. Patients with significant BDR demonstrated non-significantly lower risks of experiencing the first BEs than those without (P=0.09 for log-rank test). Significant BDR is associated with poorer lung function compared with non-significant BDR. Whether BDR predicts future risks of BEs needs to be tested in a larger cohort.

Salmeterol/fluticasone through breath-actuated inhaler versus pMDI: a randomized, double-blind, 12 weeks study

Objective: Salmeterol/fluticasone combination (SFC) formulated in a breath-actuated inhaler (BAI) overcomes the co-ordination problem associated with the pressurized-metered dose inhaler (pMDIs). Our aim was to compare the efficacy and the safety of SFC given through the BAI versus the conventional pMDI in moderate-to-severe asthmatics. Methods: In this randomized, double-blind, double-dummy, prospective, active-controlled, parallel group, multicenter, 12 weeks study, 150 asthmatics were randomized to receive SFC (25/125 mcg) through either BAI or pMDI. The primary efficacy endpoint was mean change in pre-dose morning PEFR value at 12 weeks and the secondary efficacy endpoints included, mean change in FEV1, pre-bronchodilator FVC, pre-dose morning and evening PEFR, symptom scores at 2, 4, 8, and 12 weeks. Patient preferences for device and safety were also assessed. Results: At 12 weeks, the mean change in pre-dose morning PEFR in BAI and pMDI groups was 50.72 L/min and 48.82 L/min, respectively (p < 0.0001; both groups) and the difference between the two groups was not significant. Both the treatment groups showed a statistically significant improvement in secondary endpoints at all-time points compared with baseline. The usability questionnaire assessment results showed that the BAI device was preferred by 75% of patients as compared with 25% preferring pMDI. SFC in both BAI and pMDI devices was found to be safe and well tolerated. Conclusion: This is the first study to demonstrate that SFC given through the BAI produces comparable efficacy and safety endpoints as pMDI. Additionally, BAI was the preferred inhaler by patients compared to conventional pMDI.