Concentration-QTc modeling of sitravatinib in patients with advanced solid malignancies.

Sitravatinib (MGCD516) is an orally available, small molecule, tyrosine kinase inhibitor that has been evaluated in patients with advanced solid tumors. Concentration-corrected QT interval (QTc; C-QTc) modeling was undertaken, using 767 matched concentration-ECG observations from 187 patients across two clinical studies in patients with advanced solid malignancies, across a dose range of 10-200 mg, via a linear mixed-effects (LME) model. The effect on heart rate (HR)-corrected QT interval via Fridericia's correction method (QTcF) at the steady-state maximum concentration (Cmax,ss) for the sitravatinib proposed therapeutic dosing regimen (100 mg malate once daily [q.d.]) without and with relevant intrinsic and extrinsic factors were predicted. No significant changes in HR from baseline were observed. Hysteresis between sitravatinib plasma concentration and change in QTcF from baseline (ΔQTcF) was not observed. There was no significant relationship between sitravatinib plasma concentration and ΔQTcF. The final C-QTc model predicted a mean (90% confidence interval [CI]) ΔQTcF of 3.92 (1.95-5.89) ms and 2.94 (0.23-6.10) ms at the proposed therapeutic dosing regimen in patients with normal organ function (best case scenario) and patients with hepatic impairment (worst-case scenario), respectively. The upper bounds of the 90% CIs were below the regulatory threshold of concern of 10 ms. The results of the described C-QTc analysis, along with corroborating results from nonclinical safety pharmacology studies, indicate that sitravatinib has a low risk of QTc interval prolongation at the proposed therapeutic dose of 100 mg malate q.d.

Systematic Exposure in Revision Total Hip Arthroplasty: The Posterior Approach.

As indications for total hip arthroplasty (THA) continue to expand, and patients continue to live longer with more active lifestyles, the incidence of revision THA is expected to rise. General orthopaedic surgeons are now beginning to consider doing revision THA surgery because of the increased revision burden being experienced nationwide. While classical approaches to the hip can be used for simple revisions, extensile exposure techniques in conjunction with selective soft-tissue releases are often required for adequate visualization for more complex revision cases. This review provides a systematic approach to surgical exposure for revision THA using the posterior approach. The surgeon should follow a stepwise progression to obtain safe, adequate, and reproducible visualization of both the acetabulum and the proximal femur.

Developing Prediction Models Using Near-Infrared Spectroscopy to Quantify Cannabinoid Content in Cannabis Sativa.

Cannabis is commercially cultivated for both therapeutic and recreational purposes in a growing number of jurisdictions. The main cannabinoids of interest are cannabidiol (CBD) and delta-9 tetrahydrocannabidiol (THC), which have applications in different therapeutic treatments. The rapid, nondestructive determination of cannabinoid levels has been achieved using near-infrared (NIR) spectroscopy coupled to high-quality compound reference data provided by liquid chromatography. However, most of the literature describes prediction models for the decarboxylated cannabinoids, e.g., THC and CBD, rather than naturally occurring analogues, tetrahydrocannabidiolic acid (THCA) and cannabidiolic acid (CBDA). The accurate prediction of these acidic cannabinoids has important implications for quality control for cultivators, manufacturers and regulatory bodies. Using high-quality liquid chromatography-mass spectroscopy (LCMS) data and NIR spectra data, we developed statistical models including principal component analysis (PCA) for data quality control, partial least squares regression (PLS-R) models to predict cannabinoid concentrations for 14 different cannabinoids and partial least squares discriminant analysis (PLS-DA) models to characterise cannabis samples into high-CBDA, high-THCA and even-ratio classes. This analysis employed two spectrometers, a scientific grade benchtop instrument (Bruker MPA II-Multi-Purpose FT-NIR Analyzer) and a handheld instrument (VIAVI MicroNIR Onsite-W). While the models from the benchtop instrument were generally more robust (99.4-100% accuracy prediction), the handheld device also performed well (83.1-100% accuracy prediction) with the added benefits of portability and speed. In addition, two cannabis inflorescence preparation methods were evaluated: finely ground and coarsely ground. The models generated from coarsely ground cannabis provided comparable predictions to that of the finely ground but represent significant timesaving in terms of sample preparation. This study demonstrates that a portable NIR handheld device paired with LCMS quantitative data can provide accurate cannabinoid predictions and potentially be of use for the rapid, high-throughput, nondestructive screening of cannabis material.

The Cannabis Plant as a Complex System: Interrelationships between Cannabinoid Compositions, Morphological, Physiological and Phenological Traits.

Maintaining specific and reproducible cannabinoid compositions (type and quantity) is essential for the production of cannabis-based remedies that are therapeutically effective. The current study investigates factors that determine the plant's cannabinoid profile and examines interrelationships between plant features (growth rate, phenology and biomass), inflorescence morphology (size, shape and distribution) and cannabinoid content. An examination of differences in cannabinoid profile within genotypes revealed that across the cultivation facility, cannabinoids' qualitative traits (ratios between cannabinoid quantities) remain fairly stable, while quantitative traits (the absolute amount of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabichromene (CBC), cannabigerol (CBG), Δ9-tetrahydrocannabivarin (THCV) and cannabidivarin (CBDV)) can significantly vary. The calculated broad-sense heritability values imply that cannabinoid composition will have a strong response to selection in comparison to the morphological and phenological traits of the plant and its inflorescences. Moreover, it is proposed that selection in favour of a vigorous growth rate, high-stature plants and wide inflorescences is expected to increase overall cannabinoid production. Finally, a range of physiological and phenological features was utilised for generating a successful model for the prediction of cannabinoid production. The holistic approach presented in the current study provides a better understanding of the interaction between the key features of the cannabis plant and facilitates the production of advanced plant-based medicinal substances.

A Systematic Approach to Revision Total Knee Arthroplasty.

With the recent increase in primary total knee arthroplasties and the associated rise in failures of the index operation, there has been growing demand for orthopaedic surgeons to perform revision procedures. The orthopaedic surgeon performing revision total knee arthroplasty should be knowledgeable about the various etiologies of primary total knee arthroplasty failure, the steps for proper patient evaluation, and important factors in the preoperative planning process. A systematic methodology for obtaining surgical exposure, strategies for reconstruction, fundamentals of soft-tissue closure, and postoperative care also should be reviewed.

Assessing Technology Platforms for Global Health Engagement to Support Integration of Efforts Across Geographic Combatant Commands.

Global health engagement (GHE) is an integral part of the cooperation efforts of the U.S. Department of Defense (DoD) and the geographic combatant commands (GCCs) with partner nations and provides support in training and preparing their military and civilian health systems. These activities encompass a wide spectrum of engagements-military-to-military, military-to-civilian, and multilateral-and support joint missions of humanitarian aid and disaster response, deterrence, access and presence, counterterrorism, and homeland defense. Global health engagements and activities require extensive planning, funding, and resource allocation within the GCCs and component commands. For a continuously growing breadth of GHE and the need to support joint exercises with partner military and civilian medical professionals for partner capacity-building, GHE also requires a robust information technology infrastructure. In this study, the authors assess the technology and process requirements to support the life cycle of GHE activities and assessments-from planning to evaluation-and the information- and knowledge-sharing needs of the GHE community. To do so, they conducted a literature review related to GHE activities, funding sources, and stakeholders; the evolution of technology solutions to support GHE; systems in use by GHE practitioners; and technology solutions in the market, focusing particularly on cloud infrastructure and services and cloud service providers. They held discussions with GHE subject-matter experts to document and analyze GHE technology platform requirements. And they assessed the available and planned platforms according to their features, enhancements, support and maintenance, data integration, interoperability, and future road maps.

The Workplace and Psychosocial Experiences of Australian Senior Doctors during the COVID-19 Pandemic: A Qualitative Study.

The coronavirus disease 2019 (COVID-19) pandemic has had significant mental health impacts among healthcare workers (HCWs), related to resource scarcity, risky work environments, and poor supports. Understanding the unique challenges experienced by senior doctors and identifying strategies for support will assist doctors facing such crises into the future. A cross-sectional, national, online survey was conducted during the second wave of the Australian COVID-19 pandemic. Inductive content analysis was used to examine data reporting workplace and psychosocial impacts of the pandemic. Of 9518 responses, 1083 senior doctors responded to one or more free-text questions. Of the senior doctors, 752 were women and 973 resided in Victoria. Four themes were identified: (1) work-life challenges; (2) poor workplace safety, support, and culture; (3) poor political leadership, planning and support; and (4) media and community responses. Key issues impacting mental health included supporting staff wellbeing, moral injury related to poorer quality patient care, feeling unheard and undervalued within the workplace, and pandemic ill-preparedness. Senior doctors desired better crisis preparedness, HCW representation, greater leadership, and accessible, authentic psychological wellbeing support services from workplace organisations and government. The pandemic has had significant impacts on senior doctors. The sustainability of the healthcare system requires interventions designed to protect workforce wellbeing.

High-Throughput Quantitation of Cannabinoids by Liquid Chromatography Triple-Quadrupole Mass Spectrometry.

The high-throughput quantitation of cannabinoids is important for the cannabis industry. As medicinal products increase, and research into compounds that have pharmacological benefits increase, and the need to quantitate more than just the main cannabinoids becomes more important. This study aims to provide a rapid, high-throughput method for cannabinoid quantitation using a liquid chromatography triple-quadrupole mass spectrometer (LC-QQQ-MS) with an ultraviolet diode array detector (UV-DAD) for 16 cannabinoids: CBDVA, CBDV, CBDA, CBGA, CBG, CBD, THCV, THCVA, CBN, CBNA, THC, Δ8-THC, CBL, CBC, THCA-A and CBCA. Linearity, limit of detection (LOD), limit of quantitation (LOQ), accuracy, precision, recovery and matrix effect were all evaluated. The validated method was used to determine the cannabinoid concentration of four different Cannabis sativa strains and a low THC strain, all of which have different cannabinoid profiles. All cannabinoids eluted within five minutes with a total analysis time of eight minutes, including column re-equilibration. This was twice as fast as published LC-QQQ-MS methods mentioned in the literature, whilst also covering a wide range of cannabinoid compounds.

Ct Values Do Not Predict Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmissibility in College Students.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious and has caused significant medical/socioeconomic impacts. Other than vaccination, effective public health measures, including contact tracing, isolation, and quarantine, is critical for deterring viral transmission, preventing infection progression and resuming normal activities. Viral transmission is affected by many factors, but the viral load and vitality could be among the most important ones. Although in vitro studies have indicated that the amount of virus isolated from infected individuals affects the successful rate of virus isolation, whether the viral load carried at the individual level would determine the transmissibility was unknown. We examined whether the cycle threshold (Ct) value, a measurement of viral load by RT-PCR assay, could differentiate the spreaders from the non-spreaders in a population of college students. Our results indicate that while at the population level the Ct value is lower, suggesting a higher viral load, in the symptomatic spreaders than that in the asymptomatic non-spreaders, there is a significant overlap in the Ct values between the two groups. Thus, Ct value, or the viral load, at the individual level could not predict the transmissibility. Instead, a sensitive method to detect the presence of virus is needed to identify asymptomatic individuals who may carry a low viral load but can still be infectious.

Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator.

Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism, and excretion of ozanimod were investigated after a single oral dose of 1.0 mg [14C]ozanimod hydrochloride to six healthy subjects. In vitro experiments were conducted to understand the metabolic pathways and enzymes involved in the metabolism of ozanimod and its active metabolites. The total mean recovery of the administered radioactivity was ∼63%, with ∼26% and ∼37% recovered from urine and feces, respectively. Based on exposure, the major circulating components were active metabolite CC112273 and inactive metabolite RP101124, which together accounted for 50% of the circulating total radioactivity exposure, whereas ozanimod accounted for 6.7% of the total radioactive exposure. Ozanimod was extensively metabolized, with 14 metabolites identified, including two major active metabolites (CC112273 and CC1084037) and one major inactive metabolite (RP101124) in circulation. Ozanimod is metabolized by three primary pathways, including aldehyde dehydrogenase and alcohol dehydrogenase, cytochrome P450 isoforms 3A4 and 1A1, and reductive metabolism by gut microflora. The primary metabolite RP101075 is further metabolized to form major active metabolite CC112273 by monoamine oxidase B, which further undergoes reduction by carbonyl reductases to form CC1084037 or CYP2C8-mediated oxidation to form RP101509. CC1084037 is oxidized rapidly to form CC112273 by aldo-keto reductase 1C1/1C2 and/or 3ß- and 11ß-hydroxysteroid dehydrogenase, and this reversible oxidoreduction between two active metabolites favors CC112273. The ozanimod example illustrates the need for conducting timely radiolabeled human absorption, distribution, metabolism, and excretion studies for characterization of disproportionate metabolites and assessment of exposure coverage during drug development. SIGNIFICANCE STATEMENT: Absorption, metabolism, and excretion of ozanimod were characterized in humans, and the enzymes involved in complex metabolism were elucidated. Disproportionate metabolites were identified, and the activity of these metabolites was determined.

Concentration-QTc Modeling of Ozanimod's Major Active Metabolites in Adult Healthy Subjects.

Ozanimod, approved by regulatory agencies in multiple countries for the treatment of adults with relapsing multiple sclerosis, is a sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. The relationships between plasma concentrations of ozanimod and its major active metabolites, CC112273 and CC1084037, and the QTc interval (C-QTc) from a phase I multiple-dose study in healthy subjects were analyzed using nonlinear mixed effects modeling. QTc was modeled linearly as the sum of a sex-related fixed effect, baseline, and concentration-related random effects that incorporated interindividual and residual variability. Common linear, power, and maximum effect (Emax ) functions were assessed for characterizing the relationship of QTc with concentrations. Model goodness-of-fit and performance were evaluated by standard diagnostic tools, including a visual predictive check. The placebo-corrected change from baseline in QTc (ΔΔQTc) was estimated based on the developed C-QTc model using a nonparametric bootstrapping approach. QTc was better derived using a study-specific population formula (QTcP). Among the investigated functions, an Emax function most adequately described the relationship of QTcP with concentrations. Separate models for individual analytes characterized the C-QTcP relationship better than combined analytes models. Attributing QT prolongation independently to CC1084037 or CC112273, the upper bound of the 95% confidence interval of the predicted ΔΔQTcP was ~ 4 msec at the plateau of the Emax curves. Therefore, ΔΔQTcP is predicted to remain below 10 msec at the supratherapeutic concentrations of the major active metabolites.

Multiple-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites and the Pharmacodynamic and Pharmacokinetic Interactions with Pseudoephedrine, a Sympathomimetic Agent, in Healthy Subjects.

INTRODUCTION: The aims of this study were to characterize the multiple-dose pharmacokinetics (PK) of ozanimod's major active metabolites (CC112273 and CC1084037) and to evaluate the pharmacodynamic and PK interactions with pseudoephedrine (PSE). METHODS: In this phase 1, single-center, randomized, double-blind, placebo-controlled study, 56 healthy adult subjects were randomized to receive either placebo or ozanimod once daily for 30 days (0.23 mg on days 1-4, 0.46 mg on days 5-7, 0.92 mg on days 8-10, and 1.84 mg on days 11-30). On day 30, a single oral dose of PSE 60 mg was co-administered with placebo or ozanimod. Maximum time-matched change in systolic blood pressure (SBP) from baseline (day 29) following PSE administration on day 30 was calculated. Plasma PK parameters for ozanimod, CC112273, CC1084037, and PSE were estimated using noncompartmental methods. RESULTS: Fifty-two subjects (92.9%) completed the study. Following multiple dosing, approximately 94% of circulating total active drug exposure was represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%). Exposures of CC112273 and CC1084037 were highly correlated. Mean maximum time-matched change from baseline for SBP was not significantly different between ozanimod + PSE and placebo + PSE. Ozanimod also had no effect on the PK of PSE. Co-administration of ozanimod with a single dose of PSE in healthy subjects was generally well tolerated. While CC112273 and CC1084037 selectively inhibited monoamine oxidase (MAO)-B in vitro, both active metabolites do not inhibit platelet MAO-B activity in vivo. CONCLUSION: Concomitant administration of ozanimod with PSE, a sympathomimetic agent, did not potentiate the effects on blood pressure. TRIAL REGISTRATION: NCT03644576.

Single-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites Alone and in Combination with Gemfibrozil, Itraconazole, or Rifampin in Healthy Subjects: A Randomized, Parallel-Group, Open-Label Study.

INTRODUCTION: The aims of this study were to characterize the single-dose pharmacokinetics (PK) of the major active metabolites of ozanimod, CC112273 and CC1084037, and to evaluate the effect of gemfibrozil (a strong inhibitor of cytochrome P450 [CYP] 2C8), itraconazole (a strong inhibitor of CYP3A and P-glycoprotein [P-gp]), and rifampin (a strong inducer of CYP3A/P-gp and moderate inducer of CYP2C8) on the single-dose PK of ozanimod and its major active metabolites in healthy subjects. METHODS: This was a phase 1, randomized, parallel-group, open-label study with two parts. In part 1, 40 subjects were randomized to receive a single oral dose of ozanimod 0.46 mg (group A, n = 20) or oral doses of gemfibrozil 600 mg twice daily for 17 days with a single oral dose of ozanimod 0.46 mg on day 4 (group B, n = 20). In part 2, 60 subjects were randomized to receive a single oral dose of ozanimod 0.92 mg (group C, n = 20), oral doses of itraconazole 200 mg once daily for 17 days with a single oral dose of ozanimod 0.92 mg on day 4 (group D, n = 20), or oral doses of rifampin 600 mg once daily for 21 days with a single oral dose of ozanimod 0.92 mg on day 8 (group E, n = 20). Plasma PK parameters for ozanimod, CC112273, and CC1084037 were estimated using noncompartmental methods. RESULTS: Dose-proportional increases in maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) were observed for ozanimod, CC112273, and CC1084037. The mean terminal elimination half-life (t1/2) for ozanimod was approximately 20-22 h while the mean t1/2 for CC112273 and CC1084037 were approximately 10 days. CC112273 and CC1084037 exposures were highly correlated with or without interacting drugs. Itraconazole increased ozanimod AUC by approximately 13% while rifampin reduced ozanimod AUC by approximately 24%, suggesting a minor role of CYP3A and P-gp in the overall disposition of ozanimod. Gemfibrozil increased the AUC for CC112273 and CC1084037 by approximately 47% and 69%, respectively. Rifampin reduced the AUC for CC112273 and CC1084037, primarily via CYP2C8 induction, by approximately 60% and 55%, respectively. CONCLUSIONS: Ozanimod's major active metabolites, CC112273 and CC1084037, exhibited similar single-dose PK properties and their exposures were highly correlated. CYP2C8 is one of the important enzymes in the overall disposition of CC112273 and subsequently its direct metabolite CC1084037. TRIAL REGISTRATION: Clinical trial: NCT03624959.

Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.

OBJECTIVE: To better understand ozanimod's mechanism of action (MOA), we conducted exploratory analyses from a phase 1 study to characterize ozanimod's effect on circulating leukocyte subsets in patients with relapsing multiple sclerosis. METHODS: An open-label pharmacodynamic study randomized patients to oral ozanimod hydrochloride (HCl) 0.5 (n = 13) or 1 mg/d (n = 11) for ∼12 weeks (including 7-day dose escalation). Circulating leukocyte subsets were quantified using flow cytometry (days 28, 56, and 85) and epigenetic cell counting (days 2, 5, 28, 56, and 85) and compared with baseline (day 1) using descriptive statistics. RESULTS: Ozanimod caused dose-dependent reductions in absolute lymphocyte counts. Observed by both methodologies, circulating CD19+ B- and CD3+ T-cell counts were reduced by >50% with ozanimod HCl 0.5 mg and >75% with 1 mg at day 85. Based on flow cytometry, ozanimod HCl 1 mg showed greater decreases in CD4+ than CD8+ T cells, greater decreases in both CD4+ and CD8+ central memory vs effector memory T cells, and reductions in mean CD4+ and CD8+ naive T cells by ≥90% at day 85. In the flow cytometry analysis, changes in monocytes, natural killer, and natural killer T cells were minimal. Using epigenetic cell counting, greater reductions for Th17 than T regulatory cells were determined. CONCLUSION: Ozanimod induced dose-dependent reductions in circulating B- and T-cell counts and differential effects on naive and memory CD4+ and CD8+ T cells and CD19+ B cells. Data characterized with both a novel epigenetic cell-counting method and flow cytometry support ozanimod's MOA. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT02797015.

Timing and Risk Factors for Venous Thromboembolism After Rotator Cuff Repair in the 30-Day Perioperative Period.

PURPOSE: To analyze the American College of Surgeons National Surgical Quality Improvement Program database to evaluate the incidence of deep venous thrombosis and pulmonary embolism in patients undergoing rotator cuff repair surgery. In addition, we aim to identify risk factors associated with the development of thromboembolic events following rotator cuff repair. METHODS: A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program database was performed. Current Procedural Terminology codes were used to identify patients who underwent rotator cuff repair between 2005 and 2017. The presence of deep venous thrombosis or pulmonary embolism during the 30-day perioperative period were the primary outcomes assessed. Logistic regression analysis was performed to identify risk factors for postoperative venous thromboembolic events (VTEs). RESULTS: In total, 39,825 rotator cuff repairs (RCRs) were performed and 117 (0.3%) VTE events occurred. VTE was identified at a mean of 11.5 ± 7.4 days. A total of 31,615 RCRs were performed arthroscopically. There was no significant difference of VTE between groups comparing arthroscopic RCR VTE 0.3% (94) with open RCR 0.3% (23) (P = .81). RCR in patients with an American Society of Anesthesiologists classification of III or IV was associated with >1.5-fold increase risk of VTE (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.14-2.45). Increased risks of VTE included surgery >80 minutes (OR 2.10, 95% CI 1.42-3.15), performed under general anesthesia (OR 4.38, 95% CI 1.18-36.6), and in the outpatient setting (OR 6.09, 95% CI 1.06-243.7), male sex (OR 1.53, 95% CI 1.01-2.33), bleeding disorders (OR 2.87, 95% CI 1.17-7.05), or dyspnea (OR 1.51, 95% CI 1.02-2.23). The biggest risk for VTE was unplanned reoperation OR 16.6 (95% CI 5.13-53.5). CONCLUSIONS: Venous thromboembolism is a rare complication following rotator cuff repair 0.3%. Understanding the risk factors: duration of surgery >80 minutes, male sex, body mass index >30 kg/m2, ASA III or IV, RCR as an inpatient under general anesthesia, bleeding disorder, or dyspnea may be useful in guiding treatment to prevent VTE. The largest risk for VTE is a patient with unplanned reoperation. RCR surgery performed in an outpatient setting resulted in a significantly lower incidence of VTE. LEVEL OF EVIDENCE: III Retrospective Comparative Study.

Hormetic Effects of Early Juvenile Radiation Exposure on Adult Reproduction and Offspring Performance in the Cricket (Acheta domesticus).

Exposure to low-dose ionizing radiation can have positive impacts on biological performance-a concept known as hormesis. Although radiation hormesis is well-documented, the predominant focus has been medical. In comparison, little research has examined potential effects of early life radiation stress on organismal investment in life history traits that closely influence evolutionary fitness (eg, patterns of growth, survival, and reproduction). Evaluating the fitness consequences of radiation stress is important, given that low-level radiation pollution from anthropogenic sources is considered a major threat to natural ecosystems. Using the cricket (Acheta domesticus), we tested a wide range of doses to assess whether a single juvenile exposure to radiation could induce hormetic benefits on lifetime fitness measures. Consistent with hormesis, we found that low-dose juvenile radiation positively impacted female fecundity, offspring size, and offspring performance. Remarkably, even a single low dose of radiation in early juvenile development can elicit a range of positive fitness effects emerging over the life span and even into the next generation.

Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

Ozanimod is a novel, selective, oral sphingosine-1-phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double-blind, placebo-controlled, positive-controlled, parallel-group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of moxifloxacin 400 mg or placebo was administered on days 2 and 17. The primary end point was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF). A total of 113/124 (91.1%) subjects completed the study. The upper limits of the 2-sided 90% confidence intervals for ΔΔQTcF for both ozanimod 1 and 2 mg were below the 10-millisecond regulatory threshold. No QTcF >480 milliseconds or postdose change in QTcF of >60 milliseconds was observed. There was no evidence of a positive relationship between concentrations of ozanimod and its active metabolites and ΔΔQTcF. Although ozanimod blunted the observed diurnal increase in heart rate, excursions below predose heart rates were no greater than with placebo. Results demonstrate that ozanimod does not prolong the QTc interval or cause clinically significant bradycardia, supporting ozanimod's evolving favorable cardiac safety profile.