Cardiovascular Effects of Intravenous Cocaine in Human Volunteers
1
CLINICALPHAI~ViACOLOGY & THERAPEUTICS VOLUME 73, NUMBEK2 American Society for Clinical Pharmacology and Therapeutics P3 1 PII-6 CARDIOVASCULAR EFFECTS OF INTRAVENOUS CO- CAINE 1N HUMAN VOLUNTEERS. M. M. Medlock, MD, L. Cantilena, Jr, MD, PhD, M. Haigney, MD, M. Riel, MD, R. Kahn, MD, A. Elkashef, MD, C. N. Chiang, PhD, USUHS, NIDA, Be- thesda, MD. Objective: To characterize the cardiovascular (CV) effects of IV cocaine. Methods: 37 cocaine-experienced volunteers who were enrolled in two inpatient trials using IV cocaine infusions were given cocaine in an infusion-sequence, double-blinded design with placebo and 20 mg cocaine on Day 1 followed by placebo and 40 mg cocaine on Day 2. CV data (heart rate-HR, systolic blood pressure-SP, and diastolic blood pressure-DP) were collected prior to and after the infusions. The data were analyzed as change from baseline for each timepoint. Peak change, times to peak change, and AUC from 0 to 50 minutes post infusion were determined. A subset of subjects (n= 17) received an identical second separate set of cocaine infusions be- tween 2 and 21 days later allowing comparison to the original infusion set. Results: CV responses to IV cocaine varied widely among the subjects. Cocaine, at either 20 or 40 rag, significantly increased HR, SP, and DP compared to placebo (p<0.05). Cocaine at 40 mg produced a significantly greater increase than 20 mg for peak change of HR and SP; AUC was significantly greater for HR, SP and DP. Mean maximal increases of HR, SP, and DP after 40 mg were 40.4 beats/rain, 29.0 mmHg, and 19.1 mmHg, respectively. There were no significant differences in CV responses for subjects receiving a second, duplicate infusion set. Conclusions: IV cocaine produces dose dependent CV responses. Intra-subject CV responses between infusion sessions are fairly consistent. PII-7 AMBULATORY CARDIAC MONITORING (ACM) 1S IMPOR- TANT IN THE EVALUATION OF NEW CHEMICAL ENTITIES. D. H. Wessels, MBChB, F. Gray, MBChB, A. Koch, MBChB, P. Jordaan, MBChB, Mined, M. A. Potgieter, PhD, J. Lambert, MD, PhD, PAREXEL, FARMOVS-PAREXEL, Harrow, United Kingdom (Great Britain). Purpose of Abstract Non-cardiac as well as cardiac drugs could affect the physiology of cardiac cells. ACM is frequently used in Phase I research to assess the safety of a New Chemical Entity (NCE). The interpretation safety data may be complicated by existing cardiac pathology and it is thus important to exclude such subjects. The aim of this study is to assess the prevalence of arrhyttmaias observed in 'healthy' volunteers during 24 hour and 48 hour ACM. Methods used The PAREXEL Clinical Pharmacology Research Unit recruits healthy volunteers for Phase I studies. ACM (24hr and 48hr Holter) is performed routinely as part of the screening procedures at the unit. The ACM was performed with a Spacelabs recorder. A Cardiol- ogist reviewed all abnormal findings. Results Fifty-two 48hr recordings and 54 24hr ACM recordings in a total of 105 male volunteers were examined. The mean age of the volun- teers was 27 years and 5 months (age range 18-51 years). Sinus tachycardia (100%), Ventricular ectopic beats (67.9%), Atrial ectop- ics (62.3%) and sinus bradycardia (44.3%) were the most common observations. One episode of ventricular tachycardia was observed during the 48-hr Holter recordings. Abnormalities were observed more frequently in the 48hr compared to the 24hr ACM (4.7 versus 3.7 observations per recording respectively). Conclusion Ambulatory cardiac monitoring is recommended as an important safety parameter in the evaluation of volunteers used in Phase I NCE studies. Cardiac arrhythmias in healthy volunteers are common and this assessment during screening examination, as well as during drug administration is important to interpret the safety of a new drug. PII-8 A RANDOMIZED, PLACEBO-CONTROLLED, CROSSOVER, ASCENDING DOSE TOLERANCE AND PHARMACOKINETIC STUDY OF CVT-3146: A NOVEL AGENT FOR POTENTIAL USE IN MYOCARDIAL PERFUSION IMAGING. R.O. Cannon, MD, S. Freestone, MD, S. J. Mair, MBCLB, M. Jerling, MD, PhD, S. L. Skettino, MD, L. Bellardinelli, MD, A. A. Wolff, MD, FACC, CVT Therapeutics, Inc., Inveresk Research, Palo Alto, CA. CVT-3146 is a novel short-acting selective A2A adenosine receptor agortist under clinical investigation for use as a coronary vasodilator in pharmacological stress SPECT myocardial perfusion imaging studies. Maximum tolerated dose (MTD) and pharmacokinetics of a single CVT-3t46 IV bolus were evaluated in healthy male subjects (N= 36) randomized to receive either CVT-3146 (0.1, 0.3, 1, 3, 10, 20, or 30 Ixg/kg) or placebo on day t (D1) supine, then crossover treatment on D2 supine. D3 they received CVT-3146 or placebo standing, then crossover treatment on D4 standing. CVT-3146 caused no clinically significant changes in laboratory values and was asso- ciated with dose-dependent HR increases (25-60 bpm). CVT-3146 was well tolerated at -<10 ixg/kg, supine and standing. MTD was 20 Ixg/kg supine; 10 Ixg/kg standing. Dose-limiting adverse events (AEs) were palpitations, flushing, nausea, vomiting, hypervelrtilation, and headache. Syncope/near syncope was observed at 20 Ixg/kg standing. Overall, AEs were short lived and mild to moderate. With a 3-compartment open model, initial tt/z was 2-4 min, intermediate tt/2 30 rain and terminal t~/2 2 h. There was no dose-dependency on CL, t~/2. V c, or V~. CL was not correlated with body weight; Vo increased only marginally with body weight. These results suggest CVT-3146 is a potent, short acting coronary vasodilator with a good safety profile that does not require weight-adjusted dosing. PII-9 REPRODUCIBILITY OF QT INTERVAL MEASUREMENTS FROM HOLTER RECORDINGS. T. Callahan, PhD, K. Friday, MD, H. Gomez, MD, PhD, Phase 5 Sciences, Stanford University Hospital, Burbank, CA. Background. Although Holter recordings (AECG) have been increasingly used to determine the state of ventricalar repolarization via the QT and QTc-interval measurement, reproducibility of these measurements is not well described. The aim of this analysis is to determine the reproducibility of beat-to-beat QT-interval measure- ments from AECG. Methods. Fifteen healthy men, ages 41 to 72 years on no medi- cation were enrolled in a randomized, single ascending dose, double blind, crossover design Phase 1 clinical trial. A 24-hour AECG was done at baseline and at each of 4 weekly study visits. At one of the four visits, each subject received a placebo. Correlations were calcu- lated between mean selected QT variables (mean QT and QTc- intervals, and % of beats during the AECG that demonstrate QT or QTc-intervals greater than 450 milliseconds). Results. The time between the baseline and placebo AECG was 17.5 + 8.1 days. Correlations between the variables are listed in table t. Baseline Placebo r p Mean QT 370±26 366_+29 0.97 <0.001 Mean QTc 384+16 385_+16 0.94 <0.001 %QT >450 ms 1.72+6.33 3.31 ± 11.79 0.99 <0.001 %QTc >450 ms 0.47_+0.67 0.43+~0.88 0.49 <0.05 Conclusions. These data suggest that the QT and QTc-interval measurements are stable over time, and are not affected by the administration of a placebo. Therefore, use of AECG in the drug- development process is a viable alternative to the use of 12-lead ECG's for measuring the QT and QTc-intervals.
Transcript of Cardiovascular Effects of Intravenous Cocaine in Human Volunteers
CLINICAL PHAI~ViACOLOGY & THERAPEUTICS VOLUME 73, NUMBEK2 American Society for Clinical Pharmacology and Therapeutics P 3 1
PII-6 CARDIOVASCULAR EFFECTS OF INTRAVENOUS CO-
CAINE 1N HUMAN VOLUNTEERS. M. M. Medlock, MD, L. Cantilena, Jr, MD, PhD, M. Haigney, MD, M. Riel, MD, R. Kahn, MD, A. Elkashef, MD, C. N. Chiang, PhD, USUHS, NIDA, Be- thesda, MD.
Objective: To characterize the cardiovascular (CV) effects of IV cocaine. Methods: 37 cocaine-experienced volunteers who were enrolled in two inpatient trials using IV cocaine infusions were given cocaine in an infusion-sequence, double-blinded design with placebo and 20 mg cocaine on Day 1 followed by placebo and 40 mg cocaine on Day 2. CV data (heart rate-HR, systolic blood pressure-SP, and diastolic blood pressure-DP) were collected prior to and after the infusions. The data were analyzed as change from baseline for each timepoint. Peak change, times to peak change, and AUC from 0 to 50 minutes post infusion were determined. A subset of subjects (n= 17) received an identical second separate set of cocaine infusions be- tween 2 and 21 days later allowing comparison to the original infusion set. Results: CV responses to IV cocaine varied widely among the subjects. Cocaine, at either 20 or 40 rag, significantly increased HR, SP, and DP compared to placebo (p<0.05). Cocaine at 40 mg produced a significantly greater increase than 20 mg for peak change of HR and SP; AUC was significantly greater for HR, SP and DP. Mean maximal increases of HR, SP, and DP after 40 mg were 40.4 beats/rain, 29.0 mmHg, and 19.1 mmHg, respectively. There were no significant differences in CV responses for subjects receiving a second, duplicate infusion set. Conclusions: IV cocaine produces dose dependent CV responses. Intra-subject CV responses between infusion sessions are fairly consistent.
PII-7 AMBULATORY CARDIAC MONITORING (ACM) 1S IMPOR-
TANT IN THE EVALUATION OF NEW CHEMICAL ENTITIES. D. H. Wessels, MBChB, F. Gray, MBChB, A. Koch, MBChB, P. Jordaan, MBChB, Mined, M. A. Potgieter, PhD, J. Lambert, MD, PhD, PAREXEL, FARMOVS-PAREXEL, Harrow, United Kingdom (Great Britain).
Purpose of Abstract Non-cardiac as well as cardiac drugs could affect the physiology
of cardiac cells. ACM is frequently used in Phase I research to assess the safety of a New Chemical Entity (NCE). The interpretation safety data may be complicated by existing cardiac pathology and it is thus important to exclude such subjects. The aim of this study is to assess the prevalence of arrhyttmaias observed in 'healthy' volunteers during 24 hour and 48 hour ACM.
Methods used The PAREXEL Clinical Pharmacology Research Unit recruits
healthy volunteers for Phase I studies. ACM (24hr and 48hr Holter) is performed routinely as part of the screening procedures at the unit.
The ACM was performed with a Spacelabs recorder. A Cardiol- ogist reviewed all abnormal findings.
Results Fifty-two 48hr recordings and 54 24hr ACM recordings in a total
of 105 male volunteers were examined. The mean age of the volun- teers was 27 years and 5 months (age range 18-51 years). Sinus tachycardia (100%), Ventricular ectopic beats (67.9%), Atrial ectop- ics (62.3%) and sinus bradycardia (44.3%) were the most common observations. One episode of ventricular tachycardia was observed during the 48-hr Holter recordings. Abnormalities were observed more frequently in the 48hr compared to the 24hr ACM (4.7 versus 3.7 observations per recording respectively).
Conclusion Ambulatory cardiac monitoring is recommended as an important
safety parameter in the evaluation of volunteers used in Phase I NCE studies. Cardiac arrhythmias in healthy volunteers are common and this assessment during screening examination, as well as during drug administration is important to interpret the safety of a new drug.
PII-8 A RANDOMIZED, PLACEBO-CONTROLLED, CROSSOVER,
ASCENDING DOSE TOLERANCE AND PHARMACOKINETIC STUDY OF CVT-3146: A NOVEL AGENT FOR POTENTIAL USE IN MYOCARDIAL PERFUSION IMAGING. R.O. Cannon, MD, S. Freestone, MD, S. J. Mair, MBCLB, M. Jerling, MD, PhD, S. L. Skettino, MD, L. Bellardinelli, MD, A. A. Wolff, MD, FACC, CVT Therapeutics, Inc., Inveresk Research, Palo Alto, CA.
CVT-3146 is a novel short-acting selective A2A adenosine receptor agortist under clinical investigation for use as a coronary vasodilator in pharmacological stress SPECT myocardial perfusion imaging studies. Maximum tolerated dose (MTD) and pharmacokinetics of a single CVT-3t46 IV bolus were evaluated in healthy male subjects (N= 36) randomized to receive either CVT-3146 (0.1, 0.3, 1, 3, 10, 20, or 30 Ixg/kg) or placebo on day t (D1) supine, then crossover treatment on D2 supine. D3 they received CVT-3146 or placebo standing, then crossover treatment on D4 standing. CVT-3146 caused no clinically significant changes in laboratory values and was asso- ciated with dose-dependent HR increases (25-60 bpm). CVT-3146 was well tolerated at -<10 ixg/kg, supine and standing. MTD was 20 Ixg/kg supine; 10 Ixg/kg standing. Dose-limiting adverse events (AEs) were palpitations, flushing, nausea, vomiting, hypervelrtilation, and headache. Syncope/near syncope was observed at 20 Ixg/kg standing. Overall, AEs were short lived and mild to moderate. With a 3-compartment open model, initial tt/z was 2-4 min, intermediate tt/2 30 rain and terminal t~/2 2 h. There was no dose-dependency on CL, t~/2. V c, or V~. CL was not correlated with body weight; Vo increased only marginally with body weight. These results suggest CVT-3146 is a potent, short acting coronary vasodilator with a good safety profile that does not require weight-adjusted dosing.
PII-9 REPRODUCIBILITY OF QT INTERVAL MEASUREMENTS
FROM HOLTER RECORDINGS. T. Callahan, PhD, K. Friday, MD, H. Gomez, MD, PhD, Phase 5 Sciences, Stanford University Hospital, Burbank, CA.
Background. Although Holter recordings (AECG) have been increasingly used to determine the state of ventricalar repolarization via the QT and QTc-interval measurement, reproducibility of these measurements is not well described. The aim of this analysis is to determine the reproducibility of beat-to-beat QT-interval measure- ments from AECG.
Methods. Fifteen healthy men, ages 41 to 72 years on no medi- cation were enrolled in a randomized, single ascending dose, double blind, crossover design Phase 1 clinical trial. A 24-hour AECG was done at baseline and at each of 4 weekly study visits. At one of the four visits, each subject received a placebo. Correlations were calcu- lated between mean selected QT variables (mean QT and QTc- intervals, and % of beats during the AECG that demonstrate QT or QTc-intervals greater than 450 milliseconds).
Results. The time between the baseline and placebo AECG was 17.5 + 8.1 days. Correlations between the variables are listed in table t.
Baseline Placebo r p
Mean QT 370±26 366_+29 0.97 <0.001 Mean QTc 384+16 385_+16 0.94 <0.001 %QT >450 ms 1.72+6.33 3.31 ± 11.79 0.99 <0.001 %QTc >450 ms 0 .47_+0 .67 0.43+~0.88 0.49 <0.05
Conclusions. These data suggest that the QT and QTc-interval measurements are stable over time, and are not affected by the administration of a placebo. Therefore, use of AECG in the drug- development process is a viable alternative to the use of 12-lead ECG's for measuring the QT and QTc-intervals.
