Prospective controlled study of QTc prolongation by droperidol in healthy volunteers

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

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 = Male

Anesthetics 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 1000

Time 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]

Ch

an

ge

fro

m p

re-d

ose

ba

selin

e [

ms]

(m

ea

n ±

SE

M) Placebo

Dose 0.625 mg

Dose 2.500 mg

Dose 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] (

mea

n +

SE

M)

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] (

mea

n +

SE

M)

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