Healthy Subjects and Quinidine

The data from this study was conducted by Benton et al and published in 2000 (PDF). The study aimed at determining wether there is a gender-specific difference in the effect of quinidine on cardiac repolarization. Twelve women and 12 men received a single intravenous dose of quinidine gluconate (4 mg/kg), a single oral dose of quinidine sulfate (300 or 400mg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. The study confirmed a longer QT interval duration at baseline than men: (mean ± SD; 407 ± 7 versus 395 ± 9 ms, P < .05). The slope of the relationship between change in the QTc interval (ΔQTc) after intravenous quinidine from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean ± SE; 42.2 ± 3.4 versus 29.3 ± 2.6 ms/μg per mL, P < .001). The study concluded that intravenously administered Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. Therefore, the detected difference in QT between gender may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval.

Study Design:

Twenty-four healthy nonsmoking volunteers (12 men and 12 women) between 18 and 35 years old gave written informed consent to participate in this study. The study protocol was approved by the Institutional Review Board of Georgetown University Medical Center
and the Research in Human Subjects Committee of the US Food and Drug Administration. There were no clinically significant abnormalities in the subjects' medical histories, physical examinations, blood chemistries, hematologic tests (including a screen for glucose-6- phosphate dehydrogenase deficiency), or ECGs. A negative result from a urine pregnancy test was required for
each of the female subjects. All women had regular menstrual cycles and none was taking oral contraceptives. Subjects ate their usual diets but were asked to refrain from alcohol, grapefruit juice, and caffeine-containing beverages during the period of the study.

The protocol was a randomized single-blinded comparison of single doses of intravenous quinidine gluconate (4 mg/kg of base, Eli Lilly, Indianapolis, IN), oral quinidine sulfate or intravenous placebo (saline). All doses were taken from the same manufacturer's lot number. To control for any potential influence of the menstrual cycle to variability among women, the first infusion was given within 5 days of the first day of menstruation. The subjects received the infusions at 8 AM and after fasting overnight. A 20- gauge intravenous catheter was inserted in each arm of each subject. One catheter was used for blood drawing and the other was used for the infusion of intravenous quinidine or placebo. Quinidine gluconate (80 mg/mL) was diluted to a total volume of 20 mL with normal saline solution and infused over 20 minutes. The subjects remained in the supine position for the first 3 hours after drug or placebo administration and were asked to rest in the supine position at least 15 minutes before each ECG.

Study Population:  The mean ages of the women (27 ± 8 years) and men (30 ± 7 years; difference not significant) were similar. The weight of the men was greater than that of the women (75 ± 13 versus 64 ± 11 kg; P < .05). The men were taller than the women (178 ± 7 versus 167 ± 7 cm; P < .05).

QT interval measurements: At the beginning of the study a standard 12-lead ECG was obtained for each subject and the QT interval was measured manually in each precordial lead (VI to V6). The precordial lead with the longest mean QT interval was selected for all
further rhythm strips for all ECGs in a given subject. For each subsequent ECG, the RR interval and QT interval were measured for the first 5 consecutive normal and technically acceptable beats, and the results were averaged to provide the RR interval and QT interval
for the tracing. The ECG tracings were placed on a digitizing pad (SummaSketch III,, Summagraphics, Seymour, Conn.) and a cross-hair type pointing device was used to mark the beginning and end of each ECG interval. The data were transmitted to an IBM model 50 PS/2 computer (IBM, Armonck, N.Y.) for analysis and storage. The QT duration was measured on the rhythm strips from three leads simultaneously (I, II, and the precordial lead with the longest QT) with use of the earliest beginning of the QRS complex to the end of the longest T wave in any of the three simultaneous leads. The end of the
T wave was determined for each beat by manually drawing (with a fine pencil) a tangent to the steepest portion of the downsloping T wave. The point at which the tangent intersected with the isoelectric line was used to designate the end of the T wave.

ECG Number of Leads: 12 leads standard configuration. (Marquette MACVue bedside recorder)

ECG Sampling Frequency : 500 Hz

• XX -2 digits: Subject ID
• Y-1 Letter: A for placebo, C for Oral, D for IV arms, O for outside protocol
• ZZZZ- 4 digits: time post-dose (first 2 digits for hours and last 2 for minutes)
• AA- 2 (or 3) digits: offset in minutes within the proposed time-point.
• R (optional) when replicate within the same minute

Note: there are a set of ECG recorded within the same minute. These recording have an additional "R" letter to the end of the file name. These recordings are :

• 01-D-0100-00
• 01-A-0900-00
• 07-D-0130-01
• 09-D-1200-00
• 10-A-0330-00
• 13-D-0005-00
• 16-D-0500-00
• 19-D-1200-04
• 23-D-1100-01
• 24-D-0020-01

ECG Amplitude coding: 16 bits

Clinical Information:Time points,gender, quinidine fre fraction, RR, QT,QTc (Bazett), QTc (Fridericia). These measurements are available for the placebo, IV and oral dose of quinidine.

Publications based on the data:

1) Benton RE, Sale M, Flockhart DA, Woosley RL. Greater quinidine-induced QTc interval prolongation in women. Clin Pharmacol Ther 2000 April;67(4):413-8: PDF