prospective controlled study of qtc prolongation by droperidol in healthy volunteers
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Prospective controlled study of QTc prolongation by droperidol in healthy volunteers. Anesthetic & Life Support Drugs Advisory Committee Meeting November 18, 2003 Mehul Desai, M.D. Medical Officer Division of Cardiovascular and Renal Drugs. Center for Drug Evaluation and Research. - PowerPoint PPT PresentationTRANSCRIPT
Prospective controlled study of QTc prolongation by droperidol in healthy volunteers
Anesthetic & Life Support Drugs Advisory Committee MeetingAnesthetic & Life Support Drugs Advisory Committee Meeting
November 18, 2003November 18, 2003
Mehul Desai, M.D. Mehul Desai, M.D. Medical OfficerMedical OfficerDivision of Cardiovascular and Renal DrugsDivision of Cardiovascular and Renal Drugs
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
Study Objective
• To determine the effect of 0.625, 2.5, 5 mg bolus doses of intravenous droperidol, relative to placebo, on the heart rate corrected QT interval in young, healthy volunteers.
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Study Design
• 4 period, placebo controlled, blinded, randomized, crossover study of 20 healthy volunteers
• 0.625 mg, 2.5 mg, 5 mg, and placebo (IV bolus over 30 seconds)
• Healthy subjects between ages 19-40 years on no prescription or over the counter medications; Normal baseline electrocardiograms.
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Study Methods• ECG’s: Baseline, 1, 2, 3, 4, 5, 8, 10, 15, 20, 40, 60, 120, 240, 480,
and 720 minutes post dose.
• Read blinded to time, treatment, and subject identity.
• Originally the QT and RR intervals were measured manually in conjunction with a digitizer board. Heart rate was corrected using Fridericia’s method.
• Subsequently, the ECG’s were re-analyzed using digital technology and a subject specific heart rate correction. In addition, the impact of heart rate trending was also considered. (Dr. Malik)
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Results: Subject characteristics
Age (years)
Gender Ethnicity Placebo 0.625 mg 2.5 mg 5 mg
1 30 M AA X X X X
2 39 F A X X X X
3 33 M C X X
4 35 F C X
5 19 F AA X X X
6 23 M C X X X
7 25 F C X X
8 25 F AA X X
A = Asian, AA = African American, C = Caucasian, F = Female, M = MaleAnesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Results(Adverse Events)
• Neuropsychiatric adverse events lead to early study termination
• Restlessness, anxiety, difficulty concentrating, claustrophobia, etc.
• One subject was unable to work the day following the study due to persistent symptoms
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Results: Heart rate
-10
-5
0
5
10
15
20
25
1 10 100 1000Time point of the study [min]
Cha
nge
from
pre
-dos
e ba
selin
e [b
pm] (
mea
n ±
SE
M)
PlaceboDose 0.625 mgDose 2.500 mgDose 5.000 mg
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Results: Individually corrected QTc
-20
-15
-10
-5
0
5
10
15
20
25
30
35
40
1 10 100 1000
Time point of the study [min]
Cha
nge
from
pre
-dos
e ba
selin
e [m
s] (m
ean
± S
EM
) PlaceboDose 0.625 mgDose 2.500 mgDose 5.000 mg
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
0.000 0.625 2.500 5.000
Dose [mg]
Cha
nge
from
bas
elin
e [m
s] (m
ean
+ S
EM
)
Results: Average changes in individual QTc 10 – 60 minutes post dose
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
0
5
10
15
20
25
30
35
40
0.000 0.625 2.500 5.000
Dose [mg]
Cha
nge
from
bas
elin
e [m
s] (m
ean
+ S
EM
)Results: Maximal changes in individual QTc
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Conclusions
• This study was underpowered secondary to early termination
• There is a strong suggestion that relatively low doses of droperidol prolong the QTc interval.
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003
Acknowledgements
Indiana University: Adegboyega A, Gorski JC, Hall SD, Hilligoss J, Pinto A
FDA:Collins JM, Jenkins JK, Honig PK, Haidar S, Huang SM, Hung HMJ, Kweder SL, Lee IP, Lesko LJ, Machado SG, Malinowski H, McCormick
C, Pollock M, Sevka M, Temple R, Throckmorton DC
St. Georges Hospital Medical School, London, UK:Malik M
Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee November 18 and 19, 2003November 18 and 19, 2003