Healthy Adult Male Volunteers Research Articles

Pharmacokinetic Study of Intranasal Dexamethasone and Methylprednisolone Compared with Intravenous Administration: Two Open-Label, Single-Dose, Two-Period, Two-Sequence, Cross-Over Study in Healthy Volunteers

Dexamethasone (DXM) and methylprednisolone (MEP) are potent glucocorticoids used to control several inflammatory conditions. Evidence of delayed DXM reaching the central nervous system (CNS) as well as tachyphylaxis and systemic, undesirable side effects are the main limitations of peripheral delivery. Intranasal administration offers direct access to the brain as it bypasses the blood-brain barrier. The Mucosal Atomization Device is an optimal tool that can achieve rapid absorption into the CNS and the bloodstream across mucosal membranes. This study was designed to evaluate and compare the bioavailability of DXM and MEP after intranasal versus intravenous administration. Two open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover studies were conducted, which involved healthy male and female adult volunteers. After intranasal administration, DXM and MEP were detected in plasma after the first sampling time. Mean peak concentrations of DXM and MEP were 86.61 ng/mL at 60 min and 843.2 ng/mL at 1.5 h post-administration, respectively. DXM and MEP showed high absolute bioavailability, with values of 80% and 95%, respectively. No adverse effects were observed. DXM and MEP systemic bioavailability by intranasal administration was comparable with the intravenous one, suggesting that the intranasal route can be used as a non-invasive and appropriate alternative for systemic drug delivery.

Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of Prasugrel in Healthy Male Volunteers.

This study evaluated the pharmacokinetics and pharmacodynamics of the antiplatelet agent prasugrel, and explored its optimal dose regimens via modeling and simulation using NONMEM. We measured platelet aggregation and the serial plasma concentrations of the inactive (R-95913) and active metabolites (R-138727) of prasugrel after a single oral dose of 10-60mg in 20 healthy adult male volunteers. A pharmacokinetic model for R-95913 and R-138727, and a pharmacodynamic model between the concentration of R-138727 and maximal platelet aggregation measured by light transmittance were constructed. The predictability of the model for platelet aggregation was evaluated by comparing the model prediction values with the observed ones not used in the construction of the model. Pharmacokinetic data were best described by a 3-compartment models for R-95913, a 1-compartment model for R-138727 with transit compartment model for absorption delay, and first-pass metabolic conversion of R-95913 into R-138727 during absorption. The association-dissociation model between R-138727 and its receptor in platelets was applied for the inhibitory effect of prasugrel on platelet aggregation. Prasugrel rapidly inhibited platelet aggregation after oral administration, with a prolonged duration of action; however, the concentration of the active metabolite decreased rapidly, which may have been due to the slow dissociation rate of R-138727 from its target receptor in platelets. The external validation suggests that our model could be used to individualize prasugrel treatment in various clinical situations. Simulation showed rapid onset of inhibitory effect with great magnitude and consistent inhibition after therapeutic dose of prasugrel.

Oxygen saturation measurements using novel diffused reflectance with hyperspectral imaging: Towards facile COVID-19 diagnosis

Oxygen saturation level plays a vital role in screening, diagnosis, and therapeutic assessment of disease’s assortment. There is an urgent need to design and implement early detection devices and applications for the COVID-19 pandemic; this study reports on the development of customized, highly sensitive, non-invasive, non-contact diffused reflectance system coupled with hyperspectral imaging for mapping subcutaneous blood circulation depending on its oxygen saturation level. The forearm of 15 healthy adult male volunteers with age range of (20–38 years) were illuminated via a polychromatic light source of a spectrum range 400–980 nm. Each patient had been scanned five times to calculate the mean spectroscopic reflectance images using hyperspectral camera. The customized signal processing algorithm includes normalization and moving average filter for noise removal. Afterward, employing K-means clustering for image segmentation to assess the accuracy of blood oxygen saturation (SpO2) levels. The reliability of the developed diffused reflectance system was verified with the ground truth technique, a standard pulse oximeter. Non-invasive, non-contact diffused reflectance spectrum demonstrated maximum signal variation at 610 nm according to SpO2 level. Statistical analysis (mean, standard deviation) of diffused reflectance hyperspectral images at 610 nm offered precise calibrated measurements to the standard pulse oximeter. Diffused reflectance associated with hyperspectral imaging is a prospective technique to assist with phlebotomy and vascular approach. Additionally, it could permit future surgical or pharmacological intercessions that titrate or limit ischemic injury continuously. Furthermore, this technique could offer a fast reliable indication of SpO2 levels for COVID-19 diagnosis.

The Absorption of Needle-Free Insulin Aspart Through Jet Injector in Different Body Parts of Healthy Individuals.

The absorption of needle-free fast-acting insulin injected into different body parts of healthy male subjects was studied in an attempt to provide clinical guidance for diabetic patients who take needle-free insulin injections in terms of providing reference in the clinical guidance regarding the correct use of needle-free insulin injections among diabetic patients. This randomized, open-label, cross-over trial was conducted on eight healthy adult male volunteers, in which the skin thickness at three injection sites (abdomen, upper arm, and thigh), the time to peak, peak rate, and area under the glucose infusion rate (GIR) curve of plasma insulin were measured through the hyperinsulin-normal glucose clamp test after the injection of insulin aspart with a needle-free syringe at three different sites to analyze the correlation between insulin absorption index at different injection sites and skin thickness. The values of the skin thickness of the abdomen, upper arm, and thigh measured by ultrasonic wave were 2.45 ± 0.34 mm, 2.18 ± 0.50 mm, and 1.93 ± 0.55 mm, respectively. There was a significant difference in the skin thickness of the abdomen and thigh (P = 0.014). The hyperinsulin-normal glucose clamp model was successfully established for each subject. Approximately 0–2 h after injection of insulin aspart with needle-free syringes, the area under the GIR-time curve of the abdomen, upper arm, and thigh was 29,400.75 ± 2,645.00 ml, 30,230.50 ± 4,937.87 ml, and 30,179.63 ± 6,188.57 ml, respectively. There was no significant difference in the area under the GIR curve between any two injection sites (P >0.05). The time to peak of GIR at different injection sites was 38.68 ± 13.57 min in the abdomen, 40.86 ± 12.70 min in the upper arm, and 37.03 ± 13.29 min in the thigh, respectively, in which no significant difference was found between each of them (P >0.05). The GIR curve after injection at the three different sites was consistent with each other. There was no significant difference in insulin absorption after the injection of insulin aspartate into the abdomen, upper arm, and thigh with a needleless syringe in healthy male adult volunteers, and there was no correlation between skin thickness at the injection site and insulin absorption. Injection sites did not affect the absorption of insulin in needle-free injections.

Atypical Macular Distortion After Chlorine Dioxide Administration Case Report

Chlorine dioxide, and its byproducts, chlorite, and chlorate, at daily dose of 5 ppm, administered to normal healthy adult male volunteers for 12 weeks, was accompanied by no clinically important physiological effects. An extensive battery of tests was used to evaluate the physiological impact of the ingested water disinfectants [1].

Association of Neck Circumference with Body Composition and Cardiovascular Parameters in Young Healthy Adult Males

Background and Aim: Increased Neck circumference is the marker of upper body obesity and identified as an indicator of future cardiovascular disease risk (CVD). Hence, in this study, we assessed the relationship of Neck circumference (NC) with basal cardiovascular and body composition (BC) parameter in young adult males. Methods: Sixty three healthy young adult male volunteers of age between 18 to 25 years were enrolled for this study and they were divided into two groups based on neck circumference (NC). Control group (n = 32) comprises of individuals with normal neck circumference of ≤ 35.5 cm and study group (n = 31) includes individuals with increased neck circumference of ≥ 35.5 cm. The, BC parameters was assessed by Bioimpedance Analysis (BIA) method using Quadscan 4000. And the basal cardiovascular parameters such as systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) was measured by automated sphygmomanometer and the pulse pressure (PP), mean arterial pressure (MAP) and the rate pressure product (RPP) were derived. Results: Data was expressed in Mean ± SD. The groups were compared using Independent Student’s t test. The association between NC and various study parameters were assessed by Pearson’s correlation analysis. Our study, revealed increased body fat and reduced muscle mass in individuals with increased NC. Further, we observed a positive correlation of NC with body fat (%) and negative correlation with Lean Body Mass. Cardiovascular parameters SBP, DBP, MAP and PP were elevated in subjects with increased NC. Further, positive correlation is seen with SBP, DBP, RPP and NC. Conclusion: Neck circumference is a readily measurable screening tool of upper-body adiposity and increased NC is associated with CVD risk.

First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers

ApTOLL is an aptamer that antagonizes Toll-like receptor 4 and improves functional outcomes in models of ischemic stroke and myocardial infarction. The aim of this study was to characterize the safety and pharmacokinetics of ApTOLL in healthy volunteers. A first-in-human dose-ascending, randomized, placebo-controlled phase I clinical trial to assess safety and pharmacokinetics of ApTOLL (30-min infusion intravenously) was performed in 46 healthy adult male volunteers. The study was divided into two parts: part A included seven single ascending dose levels, and part B had one multiple dose cohort. Safety and pharmacokinetic parameters were evaluated. No serious adverse events or biochemistry alterations were detected at any dose nor at any administration pattern studied. Maximum concentration was detected at the end of the infusion and mean half-life was 9.3 h. Interestingly, exposure increased in the first four levels receiving doses from 0.7 mg to 14 mg (AUC of 2,441.26 h∗ng/mL to 23,371.11 h∗ng/mL) but remained stable thereafter (mean of 23,184.61 h∗ng/mL after 70 mg). Consequently, the multiple dose study did not show any accumulation of ApTOLL. These results show an excellent safety and adequate pharmacokinetic profile that, together with the efficacy demonstrated in nonclinical studies, provide the basis to start clinical trials in patients.

Biomechanics of extreme lateral interbody fusion with different internal fixation methods: a finite element analysis

BackgroundEstablishing a normal L3–5 model and using finite element analysis to explore the biomechanical characteristics of extreme lateral interbody fusion (XLIF) with different internal fixation methods.MethodThe L3–5 CT image data of a healthy adult male volunteer were selected to establish a normal lumbar finite element model (M0). The range of motion (ROM) of L3–4 and L4–5, under flexion, extension, left bending, right bending, left rotation, and right rotation, together with L3–4 disc pressure was analyzed. Then the L4–5 intervertebral disc was excised and implanted with a cage, supplemented by different types of internal fixation, including lateral two-hole plate model (M1), lateral four-hole plate model (M2), VerteBRIDGE plating model (M3), lateral pedicle model (M4), posterior unilateral pedicle screw model (M5) and posterior bilateral pedicle screw model (M6). The ROM,the maximum stress value of the cage, and the maximum stress value of the intervertebral disc of L3–4 were analyzed and studied .ResultsThe ROM of L3–4 and L4-L5 segments in the validation model under various motion states was basically consistent with previous reports. The lumbar finite element model was validated effectively. After XLIF-assisted internal fixation, the range of activity in L3–4 segments of each internal fixation model was greater than that of the normal model under various working conditions, among which the M5、M6 model had the larger range of activity in flexion and extension. After the internal fixation of L4–5 segments, the mobility in M1-M6 was significantly reduced under various motion patterns. In terms of flexion and extension, the posterior pedicle fixation model (M5、M6) showed a significant reduction,followed by M2. The maximal von mises cage stress of M1 was obviously greater than that of other models (except the left bending). Compared with M0, the intervertebral disc stress of M1-M6 at L3–4 segments was increased.ConclusionsIt is recommended that the posterior bilateral pedicle screw model is the first choice, followed by the lateral four-hole plate model for fixation during XLIF surgery. However, it is still necessary to be aware of the occurrence of adjacent segment degeneration (ASD) in the later stage.

Effects of Ramadan fasting on some biochemical parameters

Introduction: Holy month Ramadan lasts for about 29-30 days. It is mandatory for all adult individuals of the Islamic faith to fast during the holy month of Ramadan. During this period, healthy Muslims do not eat or drink (i.e., total abstinence from food and fluids) and refrain from tobacco, daily from pre‑dawn until dusk. Materials and Methods: The present study included healthy adult male and female Muslim volunteers from different towns in the Republic of North Macedonia. The number of subjects in the study was 195. Blood samples from all subjects were collected twice during the study - once 2-3 days prior to the beginning of Ramadan and then again, the last day of Ramadan fasting. The following biochemical parameters were taken into consideration: total cholesterol, triglycerides, HDL cholesterol, glucose, insulin, total proteins, albumin, total and direct bilirubin, urea, creatinine and uric acid. Results: It was observed that compared to pre‑fasting levels, total cholesterol (TC) and triglycerides (TG) were significantly decreased (P=0.000) and high‑density lipoprotein cholesterol (HDL‑C) level had significantly increased (P=0.000); total proteins were significantly increased (P=0.000); albumins were significantly increased (P=0.004); urea was significantly increased (P=0.004); total and direct bilirubin were significantly increased (P=0.000), glucose was significantly increased (P=0.000); there was no change in insulin levels (P<0.1) Conclusion: This study showed that Ramadan fasting has an effect on biochemical parameters. We can conclude that reduction in total cholesterol and triglycerides along with a rise in levels of HDL‑C have beneficial effects on lipid profile post-Ramadan fasting period.

Effects of a short-term cold exposure on circulating microRNAs and metabolic parameters in healthy adult subjects.

This discovery study investigated in healthy subjects whether a short‐term cold exposure may alter circulating microRNAs and metabolic parameters and if co‐expression networks between these factors could be identified. This open randomized crossover (cold vs no cold exposure) study with blind end‐ point evaluation was conducted at 1 center with 10 healthy adult male volunteers. Wearing a cooling vest perfused at 14°C for 2 h reduced the local skin temperature without triggering shivering, increased norepinephrine and blood pressure while decreasing copeptin, C‐peptide and heart rate. Circulating microRNAs measured before and after wearing the cooling vest twice (4 time points) identified 196 mature microRNAs with excellent reproducibility over 72 h. Significant correlations of microRNA expression with copeptin, norepinephrine and C‐peptide were found. A co‐expression‐based microRNA‐microRNA network, as well as microRNA pairs displaying differential correlation as a function of temperature were also detected. This study demonstrates that circulating miRNAs are differentially expressed and coregulated upon cold exposure in humans, supporting their use as predictive and dynamic biomarkers of cardio‐metabolic disorders.

Randomized, double‐blind, placebo‐controlled phase 1 study to evaluate the safety and pharmacokinetics of high doses of ubiquinol in healthy adults

AbstractBackgroundMultiple system atrophy (MSA) is an intractable neurodegenerative disease. Higher frequencies of carriers of the V393A variant in COQ2 and lower levels of coenzyme Q10 (CoQ10) in body tissues have been reported in patients with MSA than in healthy controls. On the basis of the hypothesis that CoQ10 supplementation may slow the progression of MSA, we have been developing CoQ10 as an investigational drug for MSA.MethodsA single‐center, randomized, double‐blind, placebo‐controlled phase 1 study of ubiquinol in healthy adult male volunteers was conducted. Participants were randomly assigned to groups that orally receive 900, 1200, and 1500 mg of ubiquinol or placebo daily for 14 days. Safety was assessed by examining the frequency and severity of adverse events. The levels of ubiquinol in plasma and total CoQ10 in peripheral blood mononuclear cells and cerebrospinal fluid were investigated.ResultsThirty‐two participants provided informed consent to participate in this study. No clinically relevant changes in standard laboratory tests, physical examination, vital signs, or electrocardiogram attributable to ubiquinol administration were observed in any groups. The trough of plasma ubiquinol levels after repeated administration for 14 days reached a steady state, and the plasma ubiquinol levels in the 1500 mg/day‐administered group tended to be the highest.ConclusionsHigh‐dose ubiquinol supplementation was shown to be safe and tolerated when administered orally to healthy adult males at a maximum dosage of 1500 mg/day for 14 days (UMIN Clinical Trials Registry number, UMIN000016695).

Finite analysis of stability between modified articular fusion technique, posterior lumbar interbody fusion and posteriorlateral lumbar fusion

BackgroundIt is not clear whether modified facet fusion (MFF) is biomechanically different from traditional fusion techniques such as posterior lateral lumbar fusion (PLF) and posterior lumbar interbody fusion (PLIF).MethodsIn this study, a healthy adult Chinese male volunteer was selected to perform 3D reconstruction of CT image data and simulate the successful fusion of L4–5 MFF, PLF and PLIF, respectively. The motion range of L4–5 segments of the model was simulated under 6 working conditions, including forward flexion, extension, lateral flexion and rotation under normal physiological conditions, and the stability of the three fusion procedures in the pathological segments of the lumbar spine was compared.ResultsThere was no difference in range of motion between MFF model and PLF or PLIF model (P < 0.05). Also, the stiffness of the PLFand the MFF model were comparable (P > 0.05), but were smaller than the PLIF model (P < 0.05).ConclusionsMFF provides reliable stability at the lumbar fixation fusion level and does not differ significantly from PLF and PLIF in terms of range of motion.

Pharmacokinetics And Bioavailability Of Ibuprofen Tablets Produced by AKRKHIN Company (Russia) In Comparison With Ibuprofen Tablets Produced by BOOTS Company (Brufen Tablets, England).

Ten healthy male adult volunteers aged 20-40 years and of weight 55-75 kgm administered in empty stomach and in two occasions under same conditions 200 mg of ibuprofen tablets produced by AKRKHIN company (Russia) and 200 mg of ibuprofen tablets produced by BOOTS company (England). Statistical comparison of the pharmacokinetic parameters including the absorption half-life, the elimination half-life, the time to reach maximum concentration of the drug in serum and the maximum concentration of the drug in serum between the above companies indicated insignificant differences. Moreover it appeared that ibuprofen tablets produced by AKRKHIN company (Russia) is bioequivalent to the ibuprofen tablets produced by BOOTS company (England).

Quercetin LipoMicel—A Novel Delivery System to Enhance Bioavailability of Quercetin

Background: Quercetin, a flavonoid found in plant-based foods, has a range of biological activities that may be beneficial for human health. The pharmacokinetic profile of quercetin remains, however, a limiting factor for its use as a nutritional supplement. Quercetin LipoMicel®—a novel delivery system encapsulating quercetin into a liquid micelle matrix—has been designed to address the low bioavailability issue associated with non-conjugated forms by improving the absorption of quercetin. Objective: The purpose of this study was to evaluate the solubility and gastrointestinal absorption of quercetin in a novel Quercetin LipoMicel delivery system in healthy adult volunteers by comparing it with free quercetin and another commercial quercetin product. Several pharmacokinetic parameters were compared between these three formulations. Methods: Twelve healthy adult male and female volunteers aged between 21 and 65, with BMIs under 30, participated in a non-blinded, crossover bioavailability study conducted with three quercetin products. Each treatment contained a total dose of 500 mg quercetin. Capillary whole blood samples from participants were collected serially at intervals from 0–24 hours. Quercetin concentrations were detected and measured by ultra-performance liquid chromatography (UHPLC) coupled to a Thermo QExactive Orbitrap Mass Spectrometer. Solubility of quercetin in water and simulated gastrointestinal media was determined by UHPLC. Results: Oral absorption of quercetin was significantly enhanced with the LipoMicel delivery system compared to free quercetin. Improvements in in vitro gastric stability and intestinal solubility were observed with LipoMicel, leading to significantly higher blood concentration and enhanced duration of a stable concentration of quercetin in the body. Compared to free quercetin, 8- and 9-fold increases in AUC and Cmax were attained with the LipoMicel delivery system, and 10-fold higher quercetin plasma concentrations detected at 12 hours after administration. Conclusions: Quercetin LipoMicel represents an efficient delivery system for augmenting the bioavailability of quercetin in vivo. Significantly higher blood concentrations and a sustained release of quercetin over the study period was achieved following the administration of quercetin via the LipoMicel technology. Optimization in the in vivo bioavailability of quercetin may promote its salutary effects.

A Lipid Mixture Enriched by Ceramide NP with Fatty Acids of Diverse Chain Lengths Contributes to Restore the Skin Barrier Function Impaired by Topical Corticosteroid

Introduction: The stratum corneum (SC) is a skin barrier that consists of corneocytes, intercellular lipids, and corneodesmosomes. Ceramides are composed of sphingoid bases linked with various types of fatty acids (FAs), and they are an essential constituent of SC intercellular lipids. Among their subtypes, ceramide NP with a phytosphingosine base is especially important. Most of the previous studies on barrier recovery have focused on a specific ceramide with a single chain FA, not with diverse chain lengths. Skin barrier function is impaired by various factors, including topical corticosteroid. Objective: We evaluated whether a lipid mixture enriched by ceramide NP with FAs of diverse chain lengths (CER [NP]*) can restore the skin barrier function impaired by topical corticosteroid. Methods: Twenty-seven healthy adult male volunteers were recruited. Topical corticosteroid was applied on both volar forearms of volunteers. Then, the test cream containing a lipid mixture with CER (NP)* was applied on the left forearm, and a vehicle cream without a lipid mixture was applied on the right forearm of each subject. The functional parameters of the skin barrier were compared before and after the treatment. Epidermal differentiation markers, hyaluronic acid synthase 3 (HAS3), cytokine levels, and the lipid profiles in the SC were analyzed. Results: The functional parameters of the skin barrier, such as barrier recovery rate, SC integrity, and SC hydration were significantly improved in the test cream-applied site compared to the vehicle cream-applied sites. Filaggrin and HAS3 levels were significantly higher in the sites applied with the test cream. Interleukin (IL)-1α levels were also significantly increased in these sites. IL-2, IL-6, IL-10, and IL-13 levels were significantly decreased in the test cream-applied sites. Lipid analyses showed that C18, C20, and total ceramide NP levels significantly increased in the sites where the test cream was applied. Also, C16, C18, C20, C24, and total ceramide NP levels were significantly elevated in the test cream-applied sites after acute barrier disruption. Conclusion: Our results demonstrate that a lipid mixture enriched by CER (NP)* could recover the barrier function impaired by topical corticosteroid.

3D-Encoded DENSE MRI with Zonal Excitation for Quantifying Biventricular Myocardial Strain During a Breath-Hold.

Right ventricular (RV) function is increasingly recognized for its prognostic value in many disease states. As with the left ventricle (LV), strain-based measurements may have better prognostic value than typical chamber volumes or ejection fraction. Complete functional characterization of the RV requires high-resolution, 3D displacement tracking methods, which have been prohibitively challenging to implement. Zonal excitation during Displacement ENcoding with Stimulated Echoes (DENSE) magnetic resonance imaging (MRI) has helped reduce scan time for 2D LV strain quantification. We hypothesized that zonal excitation could alternatively be used to reproducibly acquire higher resolution, 3D-encoded DENSE images for quantification of bi-ventricular strain within a single breath-hold. We modified sequence parameters for a 3D zonal excitation DENSE sequence to achieve in-plane resolution < 2 mm and acquired two sets of images in eight healthy adult male volunteers with median (IQR) age 32.5 (32.0-33.8) years. We assessed the inter-test reproducibility of this technique, and compared computed strains and torsion with previously published data. Data for one subject was excluded based on image artifacts. Reproducibility for LV (CoV: 6.1-9.0%) and RV normal strains (CoV: 6.3-8.2%) and LV torsion (CoV = 7.1%) were all very good. Reproducibility of RV torsion was lower (CoV = 16.7%), but still within acceptable limits. Computed global strains and torsion were within reasonable agreement with published data, but further studies in larger cohorts are needed to confirm. Reproducible acquisition of 3D-encoded biventricular myocardial strain data in a breath-hold is feasible using DENSE with zonal excitation.

Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A.

AimsDysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine‐specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK‐418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK‐418 (ClinicalTrials.gov: NCT03228433, NCT03501069).MethodsTwo randomized, double‐blind, placebo‐controlled, phase 1 studies of oral TAK‐418 were performed, a first‐in‐human single‐rising‐dose (SRD) study (5–60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK‐418, n = 30), and an SRD (120–160 mg) and multiple‐rising‐dose (MRD) study (20–160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK‐418, n = 6 [SRD] and n = 18 [MRD]).ResultsTAK‐418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK‐418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half‐life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK‐418 rapidly crossed the blood–brain barrier and generally showed a dose‐dependent response in the peripheral pharmacodynamic biomarker formyl‐flavin adenine dinucleotide.ConclusionThe brain‐penetrant LSD1 inhibitor TAK‐418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation.

MO283IMPACT OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, ON TETANUS- AND DIPHTHERIA-TOXOID VACCINATION-ELICITED IMMUNE RESPONSES IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

Abstract Background and Aims VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of a proliferation-inducing ligand (APRIL), is in clinical development as a potential treatment for immunoglobulin A (IgA) nephropathy (IgAN). In a Phase 1 study, VIS649 was associated with dose-dependent reductions in serum IgA, IgG and IgM, which were reversible and showed a dose-response effect with respect to time-to-recovery. The aim of the present analysis was to determine if VIS649 suppression of APRIL influences antibody responses to tetanus and diphtheria toxoid vaccination. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). In one cohort within the study, participants were randomized in a 2:1 ratio to receive intravenous administration of VIS649 6.0 mg/kg or placebo, followed by a vaccine composed of tetanus and diphtheria toxoids (TENIVAC®, Sanofi Pasteur Limited), in order to evaluate the effect of VIS649 on recipients’ ability to generate a vaccine booster response (exploratory endpoint). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, received a single intramuscular dose of vaccine at the Week 4 visit, and were followed for 16 weeks in total on an outpatient basis. Blood samples were taken at regular intervals, and anti-tetanus toxoid and anti-diphtheria toxoid IgG, IgM and IgA quantitative ELISA assays were performed. Tetanus and diphtheria anti-toxoid IgG titers ≥0.1 IU/mL are generally considered to be protective. Results In the vaccination cohort, 15 participants were randomized and dosed with study drug or placebo, of whom 14 completed the study, and one participant who received VIS649 was lost to follow-up prior to receiving the vaccine. Both groups (placebo and VIS649) demonstrated increased tetanus anti-toxoid IgG titers following immunization, with a mean 7.9-fold increase in IU/mL at Week 6 for placebo recipients and a mean 6.4-fold increase in IU/mL for VIS649 recipients (Figure). At visits after Week 6, tetanus anti-toxoid IgG titers declined faster in the VIS649 group than in the placebo group (consistent with the reduction in total IgG associated with VIS649 administration) but remained above the protective threshold of 0.1 IU/mL for all participants throughout the study. Similar trends were observed for diphtheria anti-toxoid IgG titers, with a mean 5.5-fold increase in IU/mL at the Week 6 visit for placebo recipients and a mean 5.1-fold increase for VIS649 recipients (Figure). There was no evidence of tetanus- or diphtheria-toxoid elicited IgM responses in either the placebo or VIS649 groups, consistent with the recall nature of the vaccination. In a post hoc analysis, pre-existing serum tetanus/diphtheria anti-toxoid IgA titers fell between Day 1 and Week 4 in the VIS649 group, consistent with the overall suppression of total serum IgA, were boosted after vaccination in both groups, and declined faster in the VIS649 recipients thereafter. Conclusion VIS649 treatment did not interfere with participants’ ability to mount an antigen-specific serum IgG or IgA boost response to tetanus and diphtheria toxoid vaccination. There was no evidence of tetanus- or diphtheria-specific IgM responses in either the placebo or VIS649 groups, consistent with recall vaccination exposure. These data indicate that qualitative antibody responses are preserved during APRIL suppression.

MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

Randomized, single-dose, two-period, two-sequence crossover bioequivalence study evaluating two oral formulations of lamotrigine in healthy volunteers

Background: Lamotrigine is an anti-epileptic medicine used to treat epilepsy and bipolar disorder. The mechanism of action is to block voltage activated sodium channels. The aim of this study was to evaluate the bioequivalence of 2 oral formulations of lamotrigine 25 mg in healthy volunteers.Methods: A single-dose, two-period, randomized crossover study design in - healthy Indian adult volunteers was conducted at Amaris Clinical, a division of Caplin Point Laboratories Ltd., Chennai. A validated high performance liquid chromatography in conjunction with mass spectrometry was used. Lamotrigine concentration in plasma. Adverse events were determined by measuring vital functions after dosing. A total of 24 subjects were included.Results: The mean and 90% confidence intervals of the test / reference ratios for these parameters were as follows: The mean Cmax and Tmax of the test were 758.606 (157.453) ng / ml and 1.17 (0.50-5.00) hours, respectively. The mean Cmax and Tmax of the reference were 775.993 (151.654) ng / ml or 0.88 (0.25-4.00) hours. The mean AUC0-72 was 24142. 031±3641.691 (ng.hr/mL) for the test formulation and 24202.099±3742.957 (ng. h / ml) for the reference formulation. The mean test / reference ratios for Cmax and AUC0-72 were 97.92 and 99.82 respectively. The 90% parametric CIs for Cmax and AUC0-72 were 90.17-105.68% or 97.87-101.81%.Conclusions: The 90% confidence intervals ranged from 80-125% and it was concluded that the test product was bioequivalent to the reference product in these healthy adult male volunteers.