Morimoto B.H.,Celerion Inc |
Castelloe E.,Erin N Castelloe |
Fox A.W.,King's College London
Handbook of Experimental Pharmacology | Year: 2015
Safety pharmacology is essential throughout the spectrum of drug discovery and development. Prior to first-in-human studies, safety pharmacology assays, tests, and models predict the clinical risk profile of a potential new drug. During clinical development, safety pharmacology can be used to explore—and potentially explain—both predicted and unpredicted side effects (e.g., adverse events, changes in vital signs, abnormal laboratory values) in order to refine the original clinical risk profile. This chapter will introduce the reader to safety pharmacology’s role in translational medicine: the science of translating potential drugs’ on- and off-target nonclinical properties to clinical consequences in order to select the best drug candidates to move into early clinical testing. Case studies will be used to illustrate the importance of safety pharmacology testing throughout all phases of drug development. © Springer-Verlag Berlin Heidelberg 2015.
O'Connell G.,Fontem Ventures B.V |
Graff D.W.,Celerion Inc |
D'Ruiz C.D.,Fontem Ventures
Toxicology Mechanisms and Methods | Year: 2016
Changes in fifteen urine, blood and exhaled breath BoEs of HPHCs representing classes of compounds reported by FDA to be significant contributors to smoking-associated disease risks were measured in 105 clinical-confined subjects following randomization and a five-day forced-switch from usual brand conventional combustible cigarettes to: (i) exclusive commercial e-cigarette use; (ii) dual-use of commercial e-cigarettes and the subject’s usual cigarette brand; or (iii) discontinued use of all tobacco or nicotine products. Levels of urinary biomarkers in subjects that completely substituted their usual cigarette with e-cigarettes were significantly lower (29–95%) after 5 days. Percent reductions in eight of nine urinary BoEs were indistinguishable to smokers who had quit smoking, except for nicotine equivalents, which declined by 25–40%. Dual users who halved self-reported daily cigarette consumption with e-cigarettes exhibited reductions (7–38%) in eight of nine urinary biomarkers, but had increase (1–20%) in nicotine equivalents. Reductions were broadly proportional to the reduced numbers of cigarettes smoked. Dual user urinary nicotine equivalents were slightly higher, but not statistically significant. After 5 days, blood nicotine biomarker levels were lower in the cessation (75–96%) and exclusive use groups (11–83%); with dual users experiencing no significant reductions. All subjects experienced significant decreases in exhaled CO. Decreases in the cessation and exclusive groups ranged from 88–89% and 27–32% in dual users. Exhaled NO increased in the cessation and exclusive groups (46–63% respectively), whereas the dual users experienced minimal changes. Overall, smokers who completely or partially substituted conventional cigarettes with e-cigarettes over five days, experienced reductions in HPHCs. © 2016 Fontem Ventures, B.V.
Mendell J.,Daiichi Sankyo |
Lee F.,Celerion Inc. |
Chen S.,Daiichi Sankyo |
Worland V.,Celerion Inc. |
And 3 more authors.
Journal of Cardiovascular Pharmacology | Year: 2013
Edoxaban is an oral factor Xa (FXa) inhibitor in clinical development for stroke prevention in patients with atrial fibrillation, an elderly population that frequently receives aspirin (ASA) and/or nonsteroidal anti-inflammatory drugs for concurrent illnesses. Three studies were conducted to evaluate the pharmacokinetic and pharmacodynamic interactions of edoxaban 60 mg coadministered with low-dose (100 mg) ASA, high-dose (325 mg) ASA, or naproxen (500 mg) in healthy subjects (n = 126). Template bleeding times (BT) were measured. Mean baseline (predose) BT for the 3 studies ranged from 4.72 to 6.13 minutes. Edoxaban administered alone increased BT by 21%-35% (4 hours post dose) from baseline. Concomitant administration of edoxaban with high-dose ASA, low-dose ASA, or naproxen increased BT approximately 2-fold showing an additive effect greater than either agent administered alone. Edoxaban pharmacokinetics were not affected by concomitant low-dose ASA or naproxen, but high-dose ASA increased systemic exposure of edoxaban by approximately 30%. The effects of edoxaban on prothrombin time, activated partial thromboplastin time, international normalized ratio, anti-FXa, and intrinsic FXa activity were not influenced by administration with ASA or naproxen. Inhibition of platelet aggregation by high-dose ASA, low-dose ASA, or naproxen was not affected by edoxaban. Concomitant administration of edoxaban and ASA or naproxen was well tolerated. © 2013 by Lippincott Williams & Wilkins.
PubMed | Celerion Inc., University of Alberta and Cross Cancer Institute
Type: Journal Article | Journal: Medical physics | Year: 2016
To compare the radiation dose to normal organs from the radio-iodinated, hypoxia-binding radiosensitizer iodoazomycin arabinoside (IAZA) for three different isotopes of iodine.Dosimety studies with normal volunteers had been carried out with [Compared to Owing to the significant dose increase, caused by their longer half life and the approximately 10 times larger electronic dose deposited in tissue per nuclear decay, normal tissue doses of IAZA labeled with
Tyl B.,Robert Ballangers Hospital |
Azzam S.,Celerion Inc. |
Blanco N.,Clearstone Central Laboratories |
Wheeler W.,Celerion Inc.
Journal of Electrocardiology | Year: 2011
Background: Newer algorithms for automated QT interval measurements may be more reliable than previous algorithms. Objective: This study compares Bazett-corrected QTc obtained by an older algorithm (Old12SL) and by 2 newer ones (New12SL and v3.19) to semiautomated measurement performed by experienced cardiologists. Methods: A total of 6105 randomly selected electrocardiograms were classified by the cardiologists as normal (4227), borderline (1254), abnormal (575), or not analyzable (49). Errors of automated measurement were defined by more than 30 milliseconds of absolute difference between Bazett-corrected QTc obtained by automated algorithms and semiautomated measurement. Results: The Old12SL had approximately twice as many errors (5.25%) as the New12SL (2.33%) and v3.19 (2.30%), P < .0001. Abnormal tracings resulted in more errors than did normal ones (Old12SL: 16.52% vs 3.45%, New12SL: 7.30% vs 1.51%, and v3.19: 10.61% vs 1.21%). Conclusion: Newer automated algorithms for QT measurements are highly reliable in normal tracings. However, electrocardiogram abnormalities increase the risk of QT measurement errors. © 2011 Elsevier Inc.
Islam R.,Celerion Inc.
Bioanalysis | Year: 2013
Today's bioanalytical CROs face increasing global competition, highly variable demand, high fixed costs, pricing pressure, and increasing demand for quality and speed. Most bioanalytical laboratories have responded to these challenges by implementing automation and by implementing process improvement methodologies (e.g., Six Sigma). These solutions have not resulted in a significant improvement in productivity and profitability since none of them are able to predict the upturn or downturn in demand. High volatility of demand causes long lead times and high costs during peak demand and poor productivity during trough demand. Most bioanalytical laboratories lack the tools to align supply efficiently to meet changing demand. In this paper, sales and operation planning (S&OP) has been investigated as a tool to balance supply and demand. The S&OP process, when executed effectively, can be the single greatest determinant of profitability for a bioanalytical business.
Beaver C.J.,PharmaNet Canada Inc. |
Roby-Peters S.K.,Celerion Inc.
Bioanalysis | Year: 2011
Large-molecule drugs (therapeutic proteins, peptides, various forms of antibodies) are more frequently being seen in drug-development pipelines, the majority of which are measured using immunochemical/ligand-binding techniques. The assays utilized for analysis of large-molecule drugs rely heavily upon the quality of the components (e.g., reference materials, antibodies) that are critical to the performance of the assays. Commercially available research-grade materials and kits offer a convenient and simple solution, but also present some unique challenges. This article will explore some examples of issues encountered while employing commercially available kits and reagents. © 2011 Future Science Ltd.
Matsushima N.,Daiichi Sankyo |
Lee F.,Celerion Inc. |
Sato T.,Daiichi Sankyo |
Weiss D.,Celerion Inc. |
Mendell J.,Daiichi Sankyo
Clinical Pharmacology in Drug Development | Year: 2013
Background: Edoxaban is an oral, once-daily, direct factor Xa inhibitor under investigation for stroke prevention in patients with atrial fibrillation and for treatment and secondary prevention of venous thromboembolism. This study evaluated edoxaban absolute bioavailability and effects of the P-glycoprotein inhibitor quinidine on edoxaban pharmacokinetics after intravenous edoxaban administration. Methods: Healthy volunteers received three treatments in a randomized sequence: single oral 60-mg edoxaban dose, single intravenous 30-mg edoxaban dose, and concomitant single intravenous 30-mg edoxaban dose with quinidine 300mg every 8hours for 4 days. The primary objective was to determine absolute bioavailability of edoxaban. Secondary objectives included pharmacokinetics and pharmacodynamics of edoxaban after oral or intravenous administration, quinidine effect on intravenous edoxaban pharmacokinetics, and safety. Results: Thirty-six subjects were randomized; five discontinued (three for adverse events [AEs]). Edoxaban oral absolute bioavailability was 61.8%. With concomitant quinidine, total edoxaban exposure increased ∼35% and total clearance decreased ∼25%. Coagulation parameters increased after edoxaban administration in most subjects, but returned to baseline within 24hours postdose. No deaths, serious AEs, or bleeding-related AEs occurred. Conclusions: Absolute bioavailability of edoxaban in healthy volunteers was established (61.8%). Edoxaban, administered orally or intravenously, appeared to be safe and well tolerated. © 2013, The American College of Clinical Pharmacology.
PubMed | Celerion Inc. and Daiichi Sankyo
Type: Journal Article | Journal: Clinical pharmacology in drug development | Year: 2016
Edoxaban is an oral, once-daily, direct factor Xa inhibitor under investigation for stroke prevention in patients with atrial fibrillation and for treatment and secondary prevention of venous thromboembolism. This study evaluated edoxaban absolute bioavailability and effects of the P-glycoprotein inhibitor quinidine on edoxaban pharmacokinetics after intravenous edoxaban administration.Healthy volunteers received three treatments in a randomized sequence: single oral 60-mg edoxaban dose, single intravenous 30-mg edoxaban dose, and concomitant single intravenous 30-mg edoxaban dose with quinidine 300mg every 8hours for 4 days. The primary objective was to determine absolute bioavailability of edoxaban. Secondary objectives included pharmacokinetics and pharmacodynamics of edoxaban after oral or intravenous administration, quinidine effect on intravenous edoxaban pharmacokinetics, and safety.Thirty-six subjects were randomized; five discontinued (three for adverse events [AEs]). Edoxaban oral absolute bioavailability was 61.8%. With concomitant quinidine, total edoxaban exposure increased 35% and total clearance decreased 25%. Coagulation parameters increased after edoxaban administration in most subjects, but returned to baseline within 24hours postdose. No deaths, serious AEs, or bleeding-related AEs occurred.Absolute bioavailability of edoxaban in healthy volunteers was established (61.8%). Edoxaban, administered orally or intravenously, appeared to be safe and well tolerated.
PubMed | Celerion Inc.
Type: Journal Article | Journal: Expert review of clinical pharmacology | Year: 2016
hERG assays and thorough ECG trials have been mandated since 2005 to evaluate the QT interval and potential proarrhythmic risk of new chemical entities. The high cost of these studies and the shortcomings inherent in these binary and limited approaches to drug evaluation have prompted regulators to search for more cost effective and mechanistic paradigms to assess drug liability as exemplified by the CiPA initiative and the exposure response ICH E14(R3) guidance document. Areas covered: This review profiles the changing regulatory landscape as it pertains to early drug development and outlines the analyses that can be performed to characterize preclinical and early clinical cardiovascular risk. Expert commentary: It is further acknowledged that the narrow focus on the QT interval needs to be expanded to include a more comprehensive evaluation of cardiovascular risk since unanticipated off target effects have led to the withdrawal of multiple drugs after they had been approved and marketed.