A-3561. A Thorough QT Study to Define the ECG Effects of Cethromycin (CER) Using a Clinical and a Supratherapeutic Dose Compared to Placebo and Moxifloxacin (MFX) in Healthy Subjects (CL07-001)
Session: Slide Session: Human Pharmacodynamics of Effect and Toxicity
Monday, October 27, 2008: 12:00 AM
Room: Constitution B (Grand Hyatt)
Background: The objective of this trial was to evaluate the effect of CER on cardiac repolarization, as measured by QTc prolongation in healthy subjects. Methods: 238 subjects were randomly assigned to receive the therapeutic CER dose (300 mg QD), a supratherapeutic CER dose (900 mg QD), MFX (400 mg x1) or placebo. Digital ECGs were obtained on day -1 (baseline) and on day 5 of therapy. PK sampling took place on day 1 and day 5. The primary endpoint was the time-matched change from baseline in QTc interval based on an individual correction (QTcI) method that provides an optimization of QT correction for heart rate as compared to the fixed exponent approaches of Bazett or Fridericia. Results: The ECG results summarizing the mean change from baseline at day 5 steady state are shown below.
All SubjectsPlaceboMFX
400 mg x1
CER
300 mg QD
CER
900 mg QD
Total N59595956
ΔQTcI* (ms)-1.64.9-0.40.9
Heart Rate in bpm1.62.64.411.3
QTcI new >500 ms N01 (2%)00
QTcI new >480 ms N (%)0000
QTcI 30-60 ms inc N (%)1 (2%)4 (7%)1 (2%)1 (2%)
QTcI >60 ms inc (N)0000

*based on time-averaged analyses
Assay sensitivity was demonstrated and no confidence intervals exceeded 10 ms in the CER dose groups. PK/PD modelling did not show any exposure effect relationship. Conclusions: CER showed no signal of any effect on AV conduction, depolarization or cardiac repolarization as measured by the PR, QRS or QTcI or QTcF interval durations. There was no effect on heart rate in the CER therapeutic dose group at steady state. However, in the supratherapeutic dose group there was a 10 bpm increase requiring use of the primary QTcI endpoint for detection of any effect on cardiac repolarization. The MFX positive control group demonstrated the expected small change in QTc duration and the placebo group’s change from baseline was within 2 ms for QTcI.
Christine Fredericks1, David Eiznhamer, PhD2, Joel Morganroth3, Marci English1, Michael Flavin, PhD2, Nancy Milanesio1, Nestor Rohowsky1, Z Xu1 and  D. A. Eiznhamer,
Advanced Life Sciences Role(s): Employee, Shareholder (excluding diversified mutual funds), Received: Salary., (1)Advanced Life Sciences, (2)Advanced Life Sciences, Woodridge, IL, (3)eResearch Technology

Michael L. Leski
EMPLOYMENT
Advanced Life Sciences
April 2006-Present
Senior Medical Writer
University of Nevada at Reno
Aug. 2004-July 2005
Department of Biology
Visiting Assistant Professor
Shantou University-Shantou, China
Mar. 2004-July 2004
Multidisciplinary Research Center
Visiting Professor
McLean Hospital-Belmont, MA
July 1999-Aug. 2003
Consolidated Department of Psychiatry
Instructor
McLean Hospital-Belmont, MA
Jan. 1997-June 1999
Consolidated Department of Psychiatry Research Fellow
University of Texas Medical Branch-Galveston, TX Mar. 1996-Dec. 1996
Department of Neurology Post-Doctoral Research Associate
University of Virginia-Charlottesville, VA June 1993-Sep. 1995
Department of Neuroscience
Post-Doctoral Research Associate
University of Michigan-Ann Arbor, MI Sep. 1988-May 1993
Department of Biological Chemistry Graduate Student Research Assistant
Abbott Laboratories-North Chicago, IL
June 1984-July 1988
Pharmaceutical Products Research & Design Research Assistant
Morco, Inc.-Forest View, IL Sep. 1981-May 1984
Quality Control Laboratory Analytical Chemist
EDUCATION
University of Michigan-Ann Arbor, MI 1988-1993 Ph.D. in Biochemistry
DePaul University-Chicago, IL 1979-1982 M.S. in Chemistry
DePaul University-Chicago, IL 1975-1979
B.S. in Biology
BIBLIOGRAPHY
1. Barnathan, E.S., Kuo, A., Rosenfeld, L., Kariko, K., Leski, M., Robbiati, F., Nolli, M.L., Henkin, J. and Cines, D.B.: Interaction of single-chain urokinase-type plasminogen activator with human endothelial cells. J. Biol. Chem. 1990; 265:2865-72.
2. Leski, M.L. and Agranoff, B.W.: Purification and characterization gp68/70, regeneration-associated proteins from goldfish brain. J. Neurochem. 1994; 62:1182-1191.
3. Ballestero, P.R., Wilmot, G.R., Leski, M.L., Uhler, M.D. and Agranoff, B.W.: Isolation of cDNA clones encoding RICH: a protein induced during goldfish optic nerve regeneration with homology to mammalian CNPases. Proc. Nat. Acad. Sci. USA 1995; 92:8621-8625.
4. Leski, M.L. and Steward, O.: Ionic and neurotransmitter modulation of protein synthesis in synaptodendrosomes. Neurochem. Res. 1996; 21:681-690.
5. Leski, M.L., Valentine, S.L. and Coyle, J.T.: L-type voltage-gated calcium channels modulate kainic acid neurotoxicity in cerebellar granule cells. Brain Res. 1999; 828:27-40.
6. Leski, M.L., Valentine, S.L., Baer, J.D. and Coyle, J.T.: Insulin-like Growth Factor I prevents the development of sensitivity to kainate neurotoxicity in cerebellar granule cells. J. Neurochem. 2000; 75:1548-1556.
7. Leski, M.L., Bao, F., Wu, L., Qian, H., Sun, D. and Liu, D.: Protein and DNA oxidation in spinal injury: Neurofilaments-an oxidation target. Free Rad. Biol. Med. 2001; 30:613-624.
8. Leski, M.L., Hassinger, L., Valentine, S.L., Baer, J.D. and Coyle, J.T.: L-type calcium channels reduce ROS generation in cerebellar granule cells following kainate exposure. Synapse. 2002; 43:30-41.
9. Luo, M., Leski, M. and Andreadis A. Tau Isoforms which Contain the Domain Encoded by Exon 6 and their Role in Neurite Elongation. J. Cell. Biochem. 2004, 91:880-895.
Book Chapters:
1. Coyle, J.T., Leski, M.L. and Morrison, J.H.: The diverse roles of L-glutamic acid in brain signal transduction. In: Neuropsychopharmacology, The Fifth Generation of Progress. Kenneth L. Davis, Dennis Charney, Joseph T. Coyle and Charles Nemeroff, Eds. Lippincott, Williams & Wilkins, Philadelphia, PA. 2002.

Michael L. Leski
EMPLOYMENT
Advanced Life Sciences
April 2006-Present
Senior Medical Writer
University of Nevada at Reno
Aug. 2004-July 2005
Department of Biology
Visiting Assistant Professor
Shantou University-Shantou, China
Mar. 2004-July 2004
Multidisciplinary Research Center
Visiting Professor
McLean Hospital-Belmont, MA
July 1999-Aug. 2003
Consolidated Department of Psychiatry
Instructor
McLean Hospital-Belmont, MA
Jan. 1997-June 1999
Consolidated Department of Psychiatry Research Fellow
University of Texas Medical Branch-Galveston, TX Mar. 1996-Dec. 1996
Department of Neurology Post-Doctoral Research Associate
University of Virginia-Charlottesville, VA June 1993-Sep. 1995
Department of Neuroscience
Post-Doctoral Research Associate
University of Michigan-Ann Arbor, MI Sep. 1988-May 1993
Department of Biological Chemistry Graduate Student Research Assistant
Abbott Laboratories-North Chicago, IL
June 1984-July 1988
Pharmaceutical Products Research & Design Research Assistant
Morco, Inc.-Forest View, IL Sep. 1981-May 1984
Quality Control Laboratory Analytical Chemist
EDUCATION
University of Michigan-Ann Arbor, MI 1988-1993 Ph.D. in Biochemistry
DePaul University-Chicago, IL 1979-1982 M.S. in Chemistry
DePaul University-Chicago, IL 1975-1979
B.S. in Biology
BIBLIOGRAPHY
1. Barnathan, E.S., Kuo, A., Rosenfeld, L., Kariko, K., Leski, M., Robbiati, F., Nolli, M.L., Henkin, J. and Cines, D.B.: Interaction of single-chain urokinase-type plasminogen activator with human endothelial cells. J. Biol. Chem. 1990; 265:2865-72.
2. Leski, M.L. and Agranoff, B.W.: Purification and characterization gp68/70, regeneration-associated proteins from goldfish brain. J. Neurochem. 1994; 62:1182-1191.
3. Ballestero, P.R., Wilmot, G.R., Leski, M.L., Uhler, M.D. and Agranoff, B.W.: Isolation of cDNA clones encoding RICH: a protein induced during goldfish optic nerve regeneration with homology to mammalian CNPases. Proc. Nat. Acad. Sci. USA 1995; 92:8621-8625.
4. Leski, M.L. and Steward, O.: Ionic and neurotransmitter modulation of protein synthesis in synaptodendrosomes. Neurochem. Res. 1996; 21:681-690.
5. Leski, M.L., Valentine, S.L. and Coyle, J.T.: L-type voltage-gated calcium channels modulate kainic acid neurotoxicity in cerebellar granule cells. Brain Res. 1999; 828:27-40.
6. Leski, M.L., Valentine, S.L., Baer, J.D. and Coyle, J.T.: Insulin-like Growth Factor I prevents the development of sensitivity to kainate neurotoxicity in cerebellar granule cells. J. Neurochem. 2000; 75:1548-1556.
7. Leski, M.L., Bao, F., Wu, L., Qian, H., Sun, D. and Liu, D.: Protein and DNA oxidation in spinal injury: Neurofilaments-an oxidation target. Free Rad. Biol. Med. 2001; 30:613-624.
8. Leski, M.L., Hassinger, L., Valentine, S.L., Baer, J.D. and Coyle, J.T.: L-type calcium channels reduce ROS generation in cerebellar granule cells following kainate exposure. Synapse. 2002; 43:30-41.
9. Luo, M., Leski, M. and Andreadis A. Tau Isoforms which Contain the Domain Encoded by Exon 6 and their Role in Neurite Elongation. J. Cell. Biochem. 2004, 91:880-895.
Book Chapters:
1. Coyle, J.T., Leski, M.L. and Morrison, J.H.: The diverse roles of L-glutamic acid in brain signal transduction. In: Neuropsychopharmacology, The Fifth Generation of Progress. Kenneth L. Davis, Dennis Charney, Joseph T. Coyle and Charles Nemeroff, Eds. Lippincott, Williams & Wilkins, Philadelphia, PA. 2002.