ORIGINAL ARTICLE Safety and Tolerability of Intravenous
Total Page：16
File Type：pdf, Size：1020Kb
ORIGINAL ARTICLE Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study Robert Townsend, PhD,a Amit Desai, PhD,a Diane Rammelsberg, BS,b Donna Kowalski, MS,a Neal Simmons, PhD,c and Therese M. Kitt, MDa a Astellas Pharma Global Development, Inc., Northbrook, IL b Randstad Pharma, Deerfield, IL c Astellas Research Institute of America, Bioanalysis-US, Skokie, IL Received Jun 5, 2015; accepted Oct 16, 2015 doi:10.1007/s12350-015-0327-9 Background. Regadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed. Method and Results. Healthy males and females were randomized to receive intravenous regadenoson [100 lg (3 doses), 200 lg (3 doses), or 400 lg (2 doses)], or placebo (2 or 3 doses; 0.9% sodium chloride); all doses 10 minutes apart. The primary endpoint was vital sign measurements (blood pressure and heart rate). Secondary endpoints included 12-lead electrocardiogram mea- surements, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and adverse events. Thirty-six subjects were randomized and completed the study. Plasma concentrations of regadenoson increased in a dose-related manner and with successive doses. No consistent effect was observed for systolic blood pressure, although diastolic blood pressure was slightly lower than placebo for all regadenoson groups. Transient, dose-dependent increases in heart rate were observed in all regadenoson groups. There were no serious adverse events; 27 adverse events occurred in 14 regadenoson-treated subjects vs two events in two placebo-treated subjects. Conclusion. Repeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects. (J Nucl Cardiol 2017;24:57–65.) Key Words: Myocardial perfusion imaging Æ regadenoson Æ repeated doses Æ safety Æ tolerability Abbreviations MPI Myocardial perfusion imaging AE Adverse event SD Standard deviation BMI Body mass index IV Intravenous See related editorial, pp. 66–68 INTRODUCTION These data were previously presented at the 2014 American College of Patients who are unable to perform adequate exer- Clinical Pharmacology Annual Meeting, September 14–17, Atlanta, cise stress for myocardial perfusion imaging (MPI) are GA. generally administered a pharmacologic stress agent Reprint requests: Robert Townsend, PhD, Astellas Pharma Global 1 Development, Inc., 1 Astellas Way, Northbrook, IL 60062; Robert. such as adenosine, dipyridamole, or regadenoson. [email protected] Adenosine and regadenoson exert dilatory effects on 1071-3581/$34.00 the coronary vasculature via activation of the A2A Copyright Ó 2015 The Author(s). This article is published with open adenosine receptor, but adenosine can also cause access at Springerlink.com 57 58 Townsend et al. Journal of Nuclear CardiologyÒ Safety and tolerability of intravenous regadenoson in healthy subjects January/February 2017 unwanted systemic vascular and hemodynamic effects multiple and/or severe allergies to drugs or foods, or a history primarily via activation of other adenosine receptor of severe anaphylactic reactions; a history of smoking within 6 months prior to first dose of regadenoson; treatment with any subtypes. Regadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide MPI in prescribed or nonprescribed drugs in the 2 weeks prior to day 1 patients unable to undergo adequate exercise stress.2 In (except occasional use of acetaminophen, B2 g/day); partic- ipation in any interventional clinical study or treatment with phase 3 clinical studies, single doses of regadenoson 3,4 any investigational drugs within 30 days or five half-lives, were found to be equally efficacious as adenosine. whichever was longer, prior to screening; participation in a The safety and tolerability of regadenoson have also prior study with regadenoson; or history of consuming more been confirmed in various special populations of than 14 units of alcoholic beverages per week within 6 months patients, including those with kidney, liver and airway prior to screening or history of alcoholism or drug/chemi- diseases.5-9 cal/substance abuse within past 2 years prior to screening or a During intravenous (IV) administration, regadeno- positive test at screening or 1 day prior to study start for son may infiltrate into subcutaneous tissues in the arm, alcohol or drugs of abuse. thus requiring cessation of delivery and the possibility of repeating the procedure. The safety and tolerability of Study Design and Assessments repeat consecutive doses of regadenoson, as well as the associated plasma concentrations, have not been sys- Subjects were randomized to receive IV regadenoson tematically assessed. In the present study, we evaluated [100 lg (3 doses), 200 lg (3 doses), or 400 lg (2 doses)] or these parameters in healthy supine subjects after IV placebo (2 or 3 doses; 0.9% sodium chloride) at a ratio of 3:1 (regadenoson to placebo) for each group. Subjects were bolus doses of 100, 200, and 400 lg repeated up to three required to abstain from eating and drinking (except water) times at 10-minute intervals. for 8 hours prior to drug administration. Subjects received The study will provide information on the safety each dose (over approximately 10 s) in a supine position and tolerability of re-dosing regadenoson. administered 10 minutes apart followed by a 5 mL 0.9% saline flush. The first cohort (9 regadenoson, 3 placebo) started with the lowest dose of regadenoson, and after a favorable review of METHODS safety, the regadenoson dose was escalated stepwise in This was a randomized, double-blind, dose escalation, subsequent cohorts. parallel-group, placebo-controlled, repeat dose-tolerance clin- Blood samples for pharmacokinetic analyses were ical study of regadenoson in healthy, nonsmoking subjects obtained prior to study drug administration and at 3, 9, 13, performed in the United States between May and August 2013 19, 23, and 29 minutes, and at 1, 2, 4, 8, and 12 hours after the (ClinicalTrials.gov identifier, NCT01918995). The study was initial administration. Serial blood pressure and heart rate approved by an institutional review board and was conducted measurements for pharmacodynamic analyses were obtained in accordance with Good Clinical Practice and International prior to dosing, at 1, 3, 5, 7, 9, 11, 13, 17, 19, 21, 23, 25, 27, Conference on Harmonization guidelines.10 and 29 minutes during dosing, and at 0.75, 1, 1.5, 2, 4, 8, 12, and 24 hours postdose. Using the maximum and/or minimum values for all post-baseline assessments, hemodynamic effects Subjects were defined using the following criteria: heart rate of Eligible subjects were healthy men and women, aged 18- C100 bpm or an increase of[40 bpm; systolic blood pressure 60 years with a body weight of C45 kg and body mass index of\90 mm Hg or C200 mm Hg, or decreased by[35 mm Hg, between 18 and 32 kg/m2, both inclusive; Fridericia-corrected or increased by C50 mm Hg, or C180 mm Hg at baseline and QT interval of B430 msec (males) or B450 msec (females); an increase of C20 mm Hg; diastolic blood pressure of and normal aspartate aminotransferase, alanine aminotrans- \50 mm Hg or C115 mm Hg, or decreased by [25 mm Hg, ferase, and total bilirubin levels. Female subjects of or increased by C30 mm Hg. childbearing potential were required to use highly effective The primary endpoint of the study was safety as evaluated birth control from Screening through 28 days after the end of by vital signs (blood pressure and heart rate). Secondary the study, and male subjects were required to use highly endpoints included 12-lead electrocardiogram (ECG) measure- effective contraception from Screening through 90 days after ments, clinical laboratory evaluations (hematology, chemistry, final study drug administration. Exclusion criteria included a and urinalysis), and adverse events (AEs). Plasma concentra- history of unexplained syncope, cardiac arrest, unexplained tions of regadenoson were included as an exploratory endpoint. cardiac arrhythmia or torsade de pointes, structural heart disease, or family history of either short or long QT syndrome; a positive result for hepatitis B surface antigen, hepatitis C Bioanalysis antibodies at screening or known human immunodeficiency Frozen plasma samples, containing sodium heparin as the virus infection; known or suspected allergy to regadenoson or anticoagulant, were shipped to Worldwide Clinical Trials any of the components of the trial products, or a history of (Austin, TX, USA) for analysis using a validated LC-MS/MS Journal of Nuclear CardiologyÒ Townsend et al. 59 Volume 24, Number 1;57–65 Safety and tolerability of intravenous regadenoson in healthy subjects method. Regadenoson was measured over the calibration range 0.1-40 ng/mL using a 0.2 mL plasma sample volume and a stable isotope-labeled internal standard (d3-regadenoson). Sample purification used Strata-X (Phenomenex, Torrance, CA, USA) 10 mg solid phase extraction 96-well plates followed by chromatographic separation on a Luna C18(2) 3 lm29 20 mm HPLC column (Phenomenex, Torrance, CA). The elution profile was a gradient of acetonitrile and water-containing formic acid. A Sciex API5000 (Applied Biosystems, Foster City, CA, USA) mass spectrometer was used to monitor the mass transitions (m/z) 391 ? 259 (regadenoson)