Clinical L~harmacolowof nicorandil in patients with conge& heart failure Nicorandil is a nicotinamide derivative with a potential role in human therapeutics because of its potent vasodilating properties. The pharmacokinetics of oral nicorandil administration and the relationships between plasma nicorandil concentration and hemodynamic responses were examined in 25 patients with moderate to severe congestive heart failure. The dose range from 10 to 60 mg was studied. Elimination half-life for this dose range was substantially longer than that previously reported in normal volunteers. Total area under the curve increased in a curvilinear fashion with progressive dose increments, indicating a disproportionate increase in systemically available drug at higher doses. Hemodynamic responses generally correlated well with plasma nicorandil concentration, with rapid loss of cardiovascular activity corresponding to the efficient clearance of nicorandil. (CLINPHARMACOLTHER 1992;52:496-503.)
Frank D. Tice, MD, Gail L. Jungbluth, PhD, Philip F. Bindley, MD, Janis J. MacKichan, PharmD, J. Scott Mohrland, PhD, Daniel L. Wolf, MS, and Carl V. Leier, MD Columbus, Ohw,and Kalamazoo, Mich. Nicorandil is a recently developed nicotinamide derivative (see Structure) with potent coronary and peripheral vascular dilating activity. l Preliminary studies in patients with congestive heart failure have shown that oral nicorandil produces acute hemodynamic changes that should be beneficial to this patient popuati ion.*-^ The current investigation was designed to determine (1) the pharmacokinetic characteristics of orally administered nicorandil in patients with heart failure and (2) the relationship between plasma nicorandil concentration and cardiovascular responses in this clinical condition.
METHODS Patient population. Twenty-five patients (22 men and three women) with a mean age of 51 years (age range, 25 to 74 years) were enrolled in the study. All patients had moderate to severe congestive heart failure (12 patients, functional class 11; 10 patients, functional class 111; three patients, functional class IV; From the Division of Cardiology, Ohio State University College of Medicine, and the Ohio State University College of Pharmacy, Columbus, and The Upjohn Company, Kalamazoo. Supported by a grant from the Upjohn Pharmaceutical Company, Kalamazoo, Mich. Received for publication March 30, 1992; accepted July 14, 1992. Reprint requests: Carl V. Leier, MD, Division of Cardiology, Ohio State University College of Medicine, 669 Means Hall, 1654 Upham Dr., Columbus, OH 43210. 1311/41076
O I
I
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I
H
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Molecular structure of nicorandil (N-[2-hydroxyethyll-nicotinamide nitrate). New York Heart Association classification). Twelve patients had ischemic cardiomyopathy, 12 patients had idiopathic congestive cardiomyopathy, and one patient had an alcoholic cardiomyopathy. All diagnoses were documented by cardiac catheterization. Study protocol and procedures. The protocol was approved by the Institutional Human Subjects Research Review Committee, and each patient gave written informed consent. Angiotensin converting enzyme inhibitors and P-adrenergic blocking drugs were withdrawn 48 hours or more before initiation of the study. Digitalis, diuretics, nitrates, and other vasodilators were withheld for 12 hours or more before the investigation. The clinical condition of many of the patients precluded a more prolonged discontinuation of their medications for heart failure. Oral nicorandil was evaluated over a dose range from 10 to 60 mg. A double-blind, randomized,
VOLUME 52 NUMBER 5
Clinical phamacology of nicorandil 49 7
Table I. Predose baseline values for the five treatment groups (n congestive heart failure Output
Placebo
Cardiac index (L/minlm2) Stroke volume index (ml/systole/m2) Heart rate (systole/min) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Total SVR (dynes . sec/cm5) Pulmonary systolic pressure (mm Hg) Pulmonary diastolic pressure (mm Hg) Total PVR (dynes . sec/cm5) PCWP (mm Hg) Right atrial pressure (mm Hg)
1.85 + 20 + 91 + 109 + 80 + 2043 + 51
0.56 11
16 5 7 614
2 11
26 t 8 821 2 4 0 2 25 + 8 11 + 4
=
10 mg
1.88 ? 0.43 21 2 5 92 + 17 119 + 22 80 + 9 2219 t 719 62 + 7 26 + 4 911 2 303 24 t 4 13 ? 6
5 in each group) of the subjects with Nicorandil groups 20 mg 40 mg
2.06 ? 0.51 23+ 7 91 + 12 132 + 32 86 2 20 2173 2 763 56 + 26 27 + 9 863 + 411 26 + 11 8+4
1.91 t 0.41 22 + 3 86 + 16 116 + 10 79 + 14 2253 + 610 50 2 1 1 24 + 6 865 + 296 23 + 6 12 + 5
60 mg
1.90 + 0.56 19 + 7 99 + 12 120 + 12 87 + 9 2361 + 865 56 + 10 31 + 7 988 ? 457 26 2 8 13 2 7
Data are mean values 2 SD. SVR, Systemic vascular resistance; PVR, pulmonary vascular resistance; PCWP, pulmonary capillary wedge pressure
placebo-controlled, block design was used. Each dose level was completed and its safety affirmed before proceeding to the next dose: within level one, five patients received 10 mg nicorandil randomized with two patients who received identically appearing placebo; at level two, five patients received 20 mg nicorandil and one patient received placebo; at level three, five patients received 40 mg nicorandil and one patient received placebo; and at level four, five patients received 60 mg nicorandil and one patient received placebo. On the day before the study, a triple-lumen, flowdirected thermodilution catheter was percutaneously introduced into the subclavian vein and positioned in the pulmonary artery. This catheter was interfaced with Spacelabs 90303A pressure amplifiers and 90409 recording systems (Spacelabs, Redmond, Wash.). Cardiac outputs were obtained by way of a thermodilution technique with use of a COMl computer (American Edwards Laboratory, Santa Ana, Calif.). Systemic blood pressure was measured with an inflatable cuff and mercury column sphygmomanometer. Heart rate and rhythm were continuously monitored with a precordial electrocardiographic lead. Derived parameters, calculated from standard formulas, include the following: Cardiac index
=
Cardiac output/Body surface area
Stroke volume index
=
Cardiac indexiHeart rate
Total systemic vascular resistance = Mean arterial blood pressure
X
80ICardiac output
Total pulmonic vascular resistance = Mean pulmonary artery pressure
X
80lCardiac output
Administration of the study drug was performed at 8 AM with patients in the fasting state. Mixed venous blood was drawn into heparinized vacuum tubes (by way of the distal port of the pulmonary artery catheter) at 0 Gust before dosing), Y2, 1, 11/2, 2, 3, 4. 6, 8, 10, 12, and 24 hours after the nicorandil dose. All samples were immediately placed on ice, and plasma was harvested after centrifugation within 30 minutes of collection. The samples were immediately frozen and stored at -20" C until assayed for nicorandil. Nicorandil plasma concentrations were determined by a sensitive and specific gas chromatography/mass spectrometry method at Pharmaco Analytical Laboratories, Richmond, Va. This assay is linear over the calibration range of 1 to 400 nglml by use of a linear weighted (liconcentration) least-squares regression. Interassay accuracy and precision were monitored by analyzation of aliquots of three plasma quality control sample pools in duplicate with each analytic run. Average concentrations (n = 15) of 4.23, 28.5, and 288 ngiml with coefficients of variation of 9.4%, 5.5%, and 4.4% were found for theoretic plasma concentrations of 4.02, 30.1, and 301 ngiml. Central hemodynamic measurements were obtained with patients in the supine position at 45, 30, and 15 minutes before drug administration (and averaged for baseline), and at 1/2, 1 , 1%, 2, 3, 4, 6, and 8 hours after drug administration. The baseline predrug hemodynamic variables are presented in Table I. Calculations and analysis. Pharmacokinetic parameters were calculated by use of moment analysis metho d ~ The . ~ terminal elimination rate constant (A,) was estimated by least-squares regression of nicorandil plasma concentration-time points lying in the termi-
CLIN I'HARMACOL THER NOVEMRER 1992
498 Tice et al.
Time (hrs) Fig. 1. Plasma concentrations (mean 4 SD) of nicorandil after oral administration of a single dose
in patients with congestive heart failure. Five patients were studied at each dose level. nal log-linear region of the curves after the oral dose. The data were fitted to the equation:
in which C, is the nicorandil concentration at time t and C, is the concentration at time zero that results from extrapolation of the regression line to time zero (when the dose was administered). The observed maximum nicorandil plasma concentration (C,,,) and the time of C,,,, (t,,,) were determined by inspection of the concentration-time data. The area under the plasma concentration-time curve from time zero (when the dose was administered) to t hours after the dose [t = time of last qualified concentration, AUC(0-t)], was calculated by numeric integration by use of the linear trapezoidal rule. The AUC(0-w) was estimated by adding AUC(0-t) and AUC(t-w), in which AUC(t-w) was extrapolated by use of C,/A,. The apparent elimination half-life (t,,,) was calculated by use of the formula:
Pharmacokinetic parameters were averaged for each dose group. Dose-adjusted AUC and C,, were calculated by dividing the parameter estimate by the dose administered (10, 20, 40, or 60 mg). The betweentreatment differences in parameter estimates were assessed by analysis of variance (ANOVA). The Waller-
Duncan K-ratio t test procedure was used for pairwise comparison of treatment means. The best-fit formula, coefficient of correlation (r), and the statistical significance of the correlation between mean plasma nicorandil concentrations and the corresponding mean cardiovascular responses were determined from the best-fit regression model (linear and nonlinear models were tested). Placebo and predrug baseline values and data obtained at unmeasurably low plasma levels (specifically, 8 hours after drug administration) were not included in these regression and correlation calculations to avert inappropriate weighing of data in the region of no plasma concentrations to extremely low plasma concentrations.
RESULTS The mean +- SD plasma concentrations of nicorandil at each sampling time are shown in Fig. l . The average pharmacokinetic parameter estimates with percentage coefficient of variation (CV) are summarized for each dose group in Table 11. These data show that the pharmacokinetics of nicorandil after oral dosing is highly variable between subjects (>30% CV). Anticipated rank-order relationships between dose and AUC and C,, (statistically significantly higher AUC and C,, with each successive higher dose) were not observed between all dose groups. t,, was independent of dose. A longer tv2and greater than
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Clinical phamnacology
of nicorandil 499
Table 11. Average CV nicorandil pharmacokinetic parameters after a single oral dose in the subjects with heart failure Nicorandil dose* Parameter
C,
(ngw Lax(hr) AUC (ng . hrlml) Az (hr- I )
10 mg ( A ) 20 mg ( B ) 40 mg ( C ) 60 mg Average CV (%) Average CV (%) Average CV (%) Average CV I % )
35 0.6 57 0.21 3.2 tl/2 (hr) 3.5 Dose-adjusted , , ,C Dose-adjusted AUC 5.7
57 37 45 32 57 45
135 0.6 191 0.31 2.3 6.7 9.5
29 37 8 42 29 8
443 0.8 740 0.08 8.5 11.1 18.5
47 84 43 15 46 43
592 0.8 1164 0.09 7.5 9.9 19.4
37 56 33 29
ANOVA Pairwise p value? comparison# 0.0001 0.7858 0.0001 0.0004 -
37 33
0.0139 0.0017
--
AB CD
NS -AB CD
AB CD -
AB CD
CV, Coefficient of variation; C,,,,, maximum plasma concentration; t,,,, time to reach C,,,, AUC. area under the plasma concentration- tlme curve; A,, terniinal elimination rate constant; half-life. * n = 5 subjects per dose group. ?'One-way ANOVA significance level of difference. $Treatments sharing an overhead bar are not significantly different at the 95% confidence level.
expected dose-adjusted AUC and Cma, values were observed in the two higher dose groups (40 and 60 mg). The baseline predose hemodynamic data (Table I) indicate that this study population was afflicted with substantial hemodynamic impairment. The degree of reduction of cardiac output and stroke volume, elevation of right and left ventricular filling pressures, and increase in systemic and pulmonary vascular resistances document the presence of moderate to severe cardiac-ventricular dysfunction. There were no statistically significant differences between the baseline values of the five treatment groups for any hemodynamic parameter. The relationships between plasma nicorandil concentration and drug-induced changes in the major hemodynamic parameters are presented in Fig. 2, A and B. Cardiac output and stroke volume increased with increasing plasma nicorandil levels (r = 0.66 and 0.56 respectively; both p < 0.001). There was no relationship between plasma nicorandil concentration and changes in heart rate. Systemic and pulmonary vascular resistances decreased in concert with increasing concentrations of nicorandil (respective r values = -0.84 and -0.83; both p < 0.001). Systemic and pulmonic diastolic pressures were inversely related to plasma nicorandil concentration (systemic r = -0.81, pulmonic r = -0.80; both p < 0.001); systolic pressures decreased in a slightly less predictable manner as nicorandil concentration increased (systemic r = -0.73, pulmonic r = -0.68; b o t h p < 0.01). Pulmonary capillary wedge pressure (left ventricular filling pressure) correlated well with plasma nicorandil concentration (r = -0.82; p < 0.001); mean right atrial
pressure (right ventricular filling pressure) showed a similar trend ( r = -0.65; p < 0.001).
DISCUSSION The elimination t,,? of nicorandil was substantially longer and the AUC and Cma, values were lower in the subjects with heart failure than the values reported in healthy volunteer^.^ Data available on the metabolism of nicorandil suggests that hepatic clearance is the primary elimination pathway with very little intact nicorandil recovered in the urine.6 Furthermore, nicorandil undergoes some first-pass metabolism because the total body clearance of intravenously administered nicorandil has been found to approach the value for liver plasma flow, and the systemic availability of orally administered nicorandil averages 75% of the dose.6 A nonlinear relationship between nicorandil dose and AUC and Cmaxwas observed (Fig. 3). Increasing doses of nicorandil produced a disproportionate increase in AUC and C,,,, indicating that a higher percentage of drug reached the systemic circulation. If it is assumed that the extent of nicorandil absorption was similar for all doses in these subjects with heart failure, the nonlinearity would indicate a lower clearance or less first-pass metabolism with the higher doses. This is possibly attributable to the fact that hepatic enzyme systems are relatively substrate specific and of finite capacity. Thus orally administered drugs may result in sufficiently high portal vein concentrations to saturate liver enzyme and AUC will increase in a curvilinear fashion, as was observed in our patients (Fig. 3). The plasma nicorandil concentrations in our patients
CLIN PHARMACOL THER NOVEMBER 1992
500 Tice et al.
4
Plasma Nicorandil Concentration (nglml)
0
100
200
300
400
500
600
Plasma Nicorandil Concentration (nglml)
Fig. 2, A. Graphs showing the relationships between mean changes (A) in major hemodynamic parameters (cardiac index, heart rate, systolic blood pressure, stroke volume index, total systemic vascular resistance, and diastolic blood pressure) and mean plasma nicorandil concentrations at '/2 to 7 hours after drug administration in patients with cardiac failure. The best-fit formula and coefficient of correlation (r) are provided for each relationship.
VOLUME 52 NUMBER 5
Clinical pharmacology
of nicorandil 50 1
0
400
100
200
300
500
600
Plasma Nicorandil Concentration (nglml)
Plasma Nicorandil Concentration (nglml) Fig. 2, B. Graphs showing the relationships between mean changes (A) in major hemodynamic parameters (systolic pulmonary artery pressure, total pulmonary vascular resistance, right atrial pressure, diastolic pulmonary artery pressure and pulmonary capillary wedge pressure) and mean plasma nicorandil concentrations at % to 7 hours after drug administration in patients with cardiac failure. The best-fit formula and coefficient of correlation ( r ) are provided for each relationship.
CLIN PHARMACOL THER NOVEMBER 1992
502 Tice et al.
Nicorandil Dose (mg) Fig. 3. Relationship between total area under the plasma concentration-time curve (AUC) and oral nicorandil dose in patients with heart failure in our study group. The regression curve was generated from individual data points, which are reduced at each dose level to the mean value ? 1 SD.
with congestive heart failure were not typical of the concentrations reported in healthy v o ~ u n t e e r s .First, ~ more variability in the concentrations occurred in the patients with heart failure. This may be in part attributable to the rather heterogenous nature of subjects with heart failure with regard to cause, clinical severity, and pathophysiologic consequences of heart failure on the liver.' More dramatically, the nicorandil plasma concentrations were consistently lower than those reported in healthy subject^.^ Lower systemic bioavailability of orally administered nicorandil is the most likely explanation for the overall lower plasma concentrations and AUC values observed in our patients with heart failure.'-" Lower plasma concentrations or AUC can be caused by either lower bioavailability or higher clearance. The latter is unlikely, given reports in the literature of either unchanged or lower drug clearance in patients with congestive heart failure.lO." Decreased nicorandil clearance is consistent with the observation of longer apparent elimination tl/, values in our patients with heart failure compared with the values in normal subject^.^ On the other hand, decreased extent of absorption is a more likely explanation for the lower AUC values in patients with heart failure because of bowel wall edema,
lower gastrointestinal motility, or reduced blood flow to the intestines.538-" Decreases in ventricular afterload and preload, representing desirable therapeutic effects in heart failure, were elicited by nicorandil administration. Reductions in systemic and pulmonary vascular resistances (major determinants of left and right ventricular afterload) and diastolic pressures were the hemodynamic responses that correlated best with serum nicorandil concentrations. This is consistent with the direct arterial-arteriolar vasodilating activity of this compound. The close inverse correlation between left and right ventricular filling pressures, as measured by pulmonary capillary wedge and right atrial pressures (major determinants of left and right ventricular preload), and nicorandil concentrations suggest that this compound also evokes some venodilation, although druginduced augmentation of ventricular diastolic function cannot be excluded as a contributory factor. The less predictable effect on cardiac output and stroke volume indexes is likely related to the complex interplay between reductions in vascular resistances, ventricular filling pressures, and improvement in ventricular emptying. Previous work has suggested that nicorandil has no direct inotropic activity.I2 The return of hemody-
VOLUME 52 NUMBER 5
namic parameters to baseline corresponded closely with the disappearance of nicorandil from the plasma. We have reported previously that patients with heart failure require higher doses of nicorandil than either normal subjects or patients with ischemic heart disease (without heart failure) to produce consistent hemodynamic responses.' In the current study, doses of 20 mg and less did not significantly affect the hemodynamic parameters measured. These observations appear to be a consequence of the resistance of vasculature to vasodilating drugs and stimuli in patients with congestive heart failure,I3 as well as lower bioavailability. Doses of 40 to 60 mg were hemodynamically effective and generally well tolerated in our patient population. However, this study shows that investigations with even higher doses in patients with heart failure should be approached with caution because the amount of nicorandil available to the systemic circulation increases disproportionately relative to dosing increment. Larger nicorandil doses may be required in select patients with congestive heart failure, but because of the wide interpatient variability and nonlinearity in dose versus plasma concentrations, dose titration of the individual patient will be necessary. The findings of this investigation also indicate that nicorandil, as administered in this study, may have a limited role in the current therapeutics of human congestive heart failure. Although its vasodilating effects (preload and afterload reduction) are favorable properties in this clinical setting, similar responses have been well documented for converting enzyme inhibitors, the hydralazine-nitrate combination, and flosequinan. Nevertheless, nicorandil, perhaps because of its unique opening effect on the potassium channel, could be useful for the patient who is intolerant of or refractory to these particular agents. The rapid clearance and short pharrnacokinetic-pharmacodynamic ti,? of nicorandil are not favorable features for long-term medical management of chronic heart failure; this aspect could be modified by delay-release delivery systems. The interpatient variability of response to nicorandil and the widespread availability of various nitrate preparations and diuretics, as well as sodium nitroprusside and dobutamine, could also limit the role of nicorandil in the treatment of acute congestive heart failure.
Clinical phamacolgy of nicmandil 503 We thank Dr. Robert J. Cody for careful review of the manuscript, Mrs. Deborah Black for editorial assistance. and the nursing staff and houseofficers of the Coronary Care Unit for outstanding professional care of the study patients.
References I . Sakai K, Nakano H, Nagano H, Uchida Y. Nicorandil. In: Scriabine A, ed. New drugs annual: cardiovascular drugs (volume 1). New York: Raven Press, 1983:22742. 2. Tice FD, Binkley PF, Cody RJ, et al. Hemodynamic effects of oral nicorandil in congestive heart failure. Am J Cardiol 1 99O;65:I36 1-7. 3. Solal AC, Jaeger P, Bouthier J, Juliard JM, Dahan M, Gourgon R. Hemodynamic action of nicorandil in chronic congestive heart failure. Am J Cardiol 1989; 63:44J-85. 4. Galie N , Varani E, Maiello L, et al. Usefulness of nicorandil in congestive heart failure. Am J Cardiol 1990; 65:343-8. 5. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, Inc, 1982. 6. Frydman AM, Chapelle P, Diekmann H , et al. Pharmacokinetics of nicorandil. Am J Cardiol 1989;63:25J333. 7. MacKichan JJ, Pyszczynski DR, Jusko WJ. Dosedependent disposition of oral propranolol in normal subjects. Biopharm Drug Dispos 1980; 1: 159-66. 8. Leithe ME, Magonen RD, Hermiller JB. Unverferth DV, Leier CV. The relationship between central hemodynamics and regional blood flow in normal subjects and patients with congestive heart failure. Circulation 1984;69:57-64. 9. Benet LZ, Greither A, Meister W. Gastrointestinal absorption of drugs in patients with cardiac failure. In: Benet LZ, ed. The effect of disease states on pharmacokinetics. Washington, DC: American Pharmaceutical Association, 1976;33-50. 10. Benowitz NL, Meister W. Pharmacokinetics in patients with cardiac failure. Clin Pharmacokinet 1976; 1 :389405. 11. Shammas FV, Dickstein K. Clinical pharmacokinetics in heart failure: an updated review. Clin Pharmacokinet 1988;15:94-113. 12. Sakai K. Nicorandil: animal pharmacology. Am J Cardiol l989;63:2J- 105. 13. Zelis R, Mason DT, Braunwald E. A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 1968;47:960-8.
Frank D. Tice, MD, Gail L. Jungbluth, PhD, Philip F. Bindley, MD, Janis J. MacKichan, PharmD, J. Scott Mohrland, PhD, Daniel L. Wolf, MS, and Carl V. Leier, MD Columbus, Ohw,and Kalamazoo, Mich. Nicorandil is a recently developed nicotinamide derivative (see Structure) with potent coronary and peripheral vascular dilating activity. l Preliminary studies in patients with congestive heart failure have shown that oral nicorandil produces acute hemodynamic changes that should be beneficial to this patient popuati ion.*-^ The current investigation was designed to determine (1) the pharmacokinetic characteristics of orally administered nicorandil in patients with heart failure and (2) the relationship between plasma nicorandil concentration and cardiovascular responses in this clinical condition.
METHODS Patient population. Twenty-five patients (22 men and three women) with a mean age of 51 years (age range, 25 to 74 years) were enrolled in the study. All patients had moderate to severe congestive heart failure (12 patients, functional class 11; 10 patients, functional class 111; three patients, functional class IV; From the Division of Cardiology, Ohio State University College of Medicine, and the Ohio State University College of Pharmacy, Columbus, and The Upjohn Company, Kalamazoo. Supported by a grant from the Upjohn Pharmaceutical Company, Kalamazoo, Mich. Received for publication March 30, 1992; accepted July 14, 1992. Reprint requests: Carl V. Leier, MD, Division of Cardiology, Ohio State University College of Medicine, 669 Means Hall, 1654 Upham Dr., Columbus, OH 43210. 1311/41076
O I
I
H
I
H
I
H I
Molecular structure of nicorandil (N-[2-hydroxyethyll-nicotinamide nitrate). New York Heart Association classification). Twelve patients had ischemic cardiomyopathy, 12 patients had idiopathic congestive cardiomyopathy, and one patient had an alcoholic cardiomyopathy. All diagnoses were documented by cardiac catheterization. Study protocol and procedures. The protocol was approved by the Institutional Human Subjects Research Review Committee, and each patient gave written informed consent. Angiotensin converting enzyme inhibitors and P-adrenergic blocking drugs were withdrawn 48 hours or more before initiation of the study. Digitalis, diuretics, nitrates, and other vasodilators were withheld for 12 hours or more before the investigation. The clinical condition of many of the patients precluded a more prolonged discontinuation of their medications for heart failure. Oral nicorandil was evaluated over a dose range from 10 to 60 mg. A double-blind, randomized,
VOLUME 52 NUMBER 5
Clinical phamacology of nicorandil 49 7
Table I. Predose baseline values for the five treatment groups (n congestive heart failure Output
Placebo
Cardiac index (L/minlm2) Stroke volume index (ml/systole/m2) Heart rate (systole/min) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Total SVR (dynes . sec/cm5) Pulmonary systolic pressure (mm Hg) Pulmonary diastolic pressure (mm Hg) Total PVR (dynes . sec/cm5) PCWP (mm Hg) Right atrial pressure (mm Hg)
1.85 + 20 + 91 + 109 + 80 + 2043 + 51
0.56 11
16 5 7 614
2 11
26 t 8 821 2 4 0 2 25 + 8 11 + 4
=
10 mg
1.88 ? 0.43 21 2 5 92 + 17 119 + 22 80 + 9 2219 t 719 62 + 7 26 + 4 911 2 303 24 t 4 13 ? 6
5 in each group) of the subjects with Nicorandil groups 20 mg 40 mg
2.06 ? 0.51 23+ 7 91 + 12 132 + 32 86 2 20 2173 2 763 56 + 26 27 + 9 863 + 411 26 + 11 8+4
1.91 t 0.41 22 + 3 86 + 16 116 + 10 79 + 14 2253 + 610 50 2 1 1 24 + 6 865 + 296 23 + 6 12 + 5
60 mg
1.90 + 0.56 19 + 7 99 + 12 120 + 12 87 + 9 2361 + 865 56 + 10 31 + 7 988 ? 457 26 2 8 13 2 7
Data are mean values 2 SD. SVR, Systemic vascular resistance; PVR, pulmonary vascular resistance; PCWP, pulmonary capillary wedge pressure
placebo-controlled, block design was used. Each dose level was completed and its safety affirmed before proceeding to the next dose: within level one, five patients received 10 mg nicorandil randomized with two patients who received identically appearing placebo; at level two, five patients received 20 mg nicorandil and one patient received placebo; at level three, five patients received 40 mg nicorandil and one patient received placebo; and at level four, five patients received 60 mg nicorandil and one patient received placebo. On the day before the study, a triple-lumen, flowdirected thermodilution catheter was percutaneously introduced into the subclavian vein and positioned in the pulmonary artery. This catheter was interfaced with Spacelabs 90303A pressure amplifiers and 90409 recording systems (Spacelabs, Redmond, Wash.). Cardiac outputs were obtained by way of a thermodilution technique with use of a COMl computer (American Edwards Laboratory, Santa Ana, Calif.). Systemic blood pressure was measured with an inflatable cuff and mercury column sphygmomanometer. Heart rate and rhythm were continuously monitored with a precordial electrocardiographic lead. Derived parameters, calculated from standard formulas, include the following: Cardiac index
=
Cardiac output/Body surface area
Stroke volume index
=
Cardiac indexiHeart rate
Total systemic vascular resistance = Mean arterial blood pressure
X
80ICardiac output
Total pulmonic vascular resistance = Mean pulmonary artery pressure
X
80lCardiac output
Administration of the study drug was performed at 8 AM with patients in the fasting state. Mixed venous blood was drawn into heparinized vacuum tubes (by way of the distal port of the pulmonary artery catheter) at 0 Gust before dosing), Y2, 1, 11/2, 2, 3, 4. 6, 8, 10, 12, and 24 hours after the nicorandil dose. All samples were immediately placed on ice, and plasma was harvested after centrifugation within 30 minutes of collection. The samples were immediately frozen and stored at -20" C until assayed for nicorandil. Nicorandil plasma concentrations were determined by a sensitive and specific gas chromatography/mass spectrometry method at Pharmaco Analytical Laboratories, Richmond, Va. This assay is linear over the calibration range of 1 to 400 nglml by use of a linear weighted (liconcentration) least-squares regression. Interassay accuracy and precision were monitored by analyzation of aliquots of three plasma quality control sample pools in duplicate with each analytic run. Average concentrations (n = 15) of 4.23, 28.5, and 288 ngiml with coefficients of variation of 9.4%, 5.5%, and 4.4% were found for theoretic plasma concentrations of 4.02, 30.1, and 301 ngiml. Central hemodynamic measurements were obtained with patients in the supine position at 45, 30, and 15 minutes before drug administration (and averaged for baseline), and at 1/2, 1 , 1%, 2, 3, 4, 6, and 8 hours after drug administration. The baseline predrug hemodynamic variables are presented in Table I. Calculations and analysis. Pharmacokinetic parameters were calculated by use of moment analysis metho d ~ The . ~ terminal elimination rate constant (A,) was estimated by least-squares regression of nicorandil plasma concentration-time points lying in the termi-
CLIN I'HARMACOL THER NOVEMRER 1992
498 Tice et al.
Time (hrs) Fig. 1. Plasma concentrations (mean 4 SD) of nicorandil after oral administration of a single dose
in patients with congestive heart failure. Five patients were studied at each dose level. nal log-linear region of the curves after the oral dose. The data were fitted to the equation:
in which C, is the nicorandil concentration at time t and C, is the concentration at time zero that results from extrapolation of the regression line to time zero (when the dose was administered). The observed maximum nicorandil plasma concentration (C,,,) and the time of C,,,, (t,,,) were determined by inspection of the concentration-time data. The area under the plasma concentration-time curve from time zero (when the dose was administered) to t hours after the dose [t = time of last qualified concentration, AUC(0-t)], was calculated by numeric integration by use of the linear trapezoidal rule. The AUC(0-w) was estimated by adding AUC(0-t) and AUC(t-w), in which AUC(t-w) was extrapolated by use of C,/A,. The apparent elimination half-life (t,,,) was calculated by use of the formula:
Pharmacokinetic parameters were averaged for each dose group. Dose-adjusted AUC and C,, were calculated by dividing the parameter estimate by the dose administered (10, 20, 40, or 60 mg). The betweentreatment differences in parameter estimates were assessed by analysis of variance (ANOVA). The Waller-
Duncan K-ratio t test procedure was used for pairwise comparison of treatment means. The best-fit formula, coefficient of correlation (r), and the statistical significance of the correlation between mean plasma nicorandil concentrations and the corresponding mean cardiovascular responses were determined from the best-fit regression model (linear and nonlinear models were tested). Placebo and predrug baseline values and data obtained at unmeasurably low plasma levels (specifically, 8 hours after drug administration) were not included in these regression and correlation calculations to avert inappropriate weighing of data in the region of no plasma concentrations to extremely low plasma concentrations.
RESULTS The mean +- SD plasma concentrations of nicorandil at each sampling time are shown in Fig. l . The average pharmacokinetic parameter estimates with percentage coefficient of variation (CV) are summarized for each dose group in Table 11. These data show that the pharmacokinetics of nicorandil after oral dosing is highly variable between subjects (>30% CV). Anticipated rank-order relationships between dose and AUC and C,, (statistically significantly higher AUC and C,, with each successive higher dose) were not observed between all dose groups. t,, was independent of dose. A longer tv2and greater than
VOLUME 52 NUMBER 5
Clinical phamnacology
of nicorandil 499
Table 11. Average CV nicorandil pharmacokinetic parameters after a single oral dose in the subjects with heart failure Nicorandil dose* Parameter
C,
(ngw Lax(hr) AUC (ng . hrlml) Az (hr- I )
10 mg ( A ) 20 mg ( B ) 40 mg ( C ) 60 mg Average CV (%) Average CV (%) Average CV (%) Average CV I % )
35 0.6 57 0.21 3.2 tl/2 (hr) 3.5 Dose-adjusted , , ,C Dose-adjusted AUC 5.7
57 37 45 32 57 45
135 0.6 191 0.31 2.3 6.7 9.5
29 37 8 42 29 8
443 0.8 740 0.08 8.5 11.1 18.5
47 84 43 15 46 43
592 0.8 1164 0.09 7.5 9.9 19.4
37 56 33 29
ANOVA Pairwise p value? comparison# 0.0001 0.7858 0.0001 0.0004 -
37 33
0.0139 0.0017
--
AB CD
NS -AB CD
AB CD -
AB CD
CV, Coefficient of variation; C,,,,, maximum plasma concentration; t,,,, time to reach C,,,, AUC. area under the plasma concentration- tlme curve; A,, terniinal elimination rate constant; half-life. * n = 5 subjects per dose group. ?'One-way ANOVA significance level of difference. $Treatments sharing an overhead bar are not significantly different at the 95% confidence level.
expected dose-adjusted AUC and Cma, values were observed in the two higher dose groups (40 and 60 mg). The baseline predose hemodynamic data (Table I) indicate that this study population was afflicted with substantial hemodynamic impairment. The degree of reduction of cardiac output and stroke volume, elevation of right and left ventricular filling pressures, and increase in systemic and pulmonary vascular resistances document the presence of moderate to severe cardiac-ventricular dysfunction. There were no statistically significant differences between the baseline values of the five treatment groups for any hemodynamic parameter. The relationships between plasma nicorandil concentration and drug-induced changes in the major hemodynamic parameters are presented in Fig. 2, A and B. Cardiac output and stroke volume increased with increasing plasma nicorandil levels (r = 0.66 and 0.56 respectively; both p < 0.001). There was no relationship between plasma nicorandil concentration and changes in heart rate. Systemic and pulmonary vascular resistances decreased in concert with increasing concentrations of nicorandil (respective r values = -0.84 and -0.83; both p < 0.001). Systemic and pulmonic diastolic pressures were inversely related to plasma nicorandil concentration (systemic r = -0.81, pulmonic r = -0.80; both p < 0.001); systolic pressures decreased in a slightly less predictable manner as nicorandil concentration increased (systemic r = -0.73, pulmonic r = -0.68; b o t h p < 0.01). Pulmonary capillary wedge pressure (left ventricular filling pressure) correlated well with plasma nicorandil concentration (r = -0.82; p < 0.001); mean right atrial
pressure (right ventricular filling pressure) showed a similar trend ( r = -0.65; p < 0.001).
DISCUSSION The elimination t,,? of nicorandil was substantially longer and the AUC and Cma, values were lower in the subjects with heart failure than the values reported in healthy volunteer^.^ Data available on the metabolism of nicorandil suggests that hepatic clearance is the primary elimination pathway with very little intact nicorandil recovered in the urine.6 Furthermore, nicorandil undergoes some first-pass metabolism because the total body clearance of intravenously administered nicorandil has been found to approach the value for liver plasma flow, and the systemic availability of orally administered nicorandil averages 75% of the dose.6 A nonlinear relationship between nicorandil dose and AUC and Cmaxwas observed (Fig. 3). Increasing doses of nicorandil produced a disproportionate increase in AUC and C,,,, indicating that a higher percentage of drug reached the systemic circulation. If it is assumed that the extent of nicorandil absorption was similar for all doses in these subjects with heart failure, the nonlinearity would indicate a lower clearance or less first-pass metabolism with the higher doses. This is possibly attributable to the fact that hepatic enzyme systems are relatively substrate specific and of finite capacity. Thus orally administered drugs may result in sufficiently high portal vein concentrations to saturate liver enzyme and AUC will increase in a curvilinear fashion, as was observed in our patients (Fig. 3). The plasma nicorandil concentrations in our patients
CLIN PHARMACOL THER NOVEMBER 1992
500 Tice et al.
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Plasma Nicorandil Concentration (nglml)
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Plasma Nicorandil Concentration (nglml)
Fig. 2, A. Graphs showing the relationships between mean changes (A) in major hemodynamic parameters (cardiac index, heart rate, systolic blood pressure, stroke volume index, total systemic vascular resistance, and diastolic blood pressure) and mean plasma nicorandil concentrations at '/2 to 7 hours after drug administration in patients with cardiac failure. The best-fit formula and coefficient of correlation (r) are provided for each relationship.
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Clinical pharmacology
of nicorandil 50 1
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Plasma Nicorandil Concentration (nglml)
Plasma Nicorandil Concentration (nglml) Fig. 2, B. Graphs showing the relationships between mean changes (A) in major hemodynamic parameters (systolic pulmonary artery pressure, total pulmonary vascular resistance, right atrial pressure, diastolic pulmonary artery pressure and pulmonary capillary wedge pressure) and mean plasma nicorandil concentrations at % to 7 hours after drug administration in patients with cardiac failure. The best-fit formula and coefficient of correlation ( r ) are provided for each relationship.
CLIN PHARMACOL THER NOVEMBER 1992
502 Tice et al.
Nicorandil Dose (mg) Fig. 3. Relationship between total area under the plasma concentration-time curve (AUC) and oral nicorandil dose in patients with heart failure in our study group. The regression curve was generated from individual data points, which are reduced at each dose level to the mean value ? 1 SD.
with congestive heart failure were not typical of the concentrations reported in healthy v o ~ u n t e e r s .First, ~ more variability in the concentrations occurred in the patients with heart failure. This may be in part attributable to the rather heterogenous nature of subjects with heart failure with regard to cause, clinical severity, and pathophysiologic consequences of heart failure on the liver.' More dramatically, the nicorandil plasma concentrations were consistently lower than those reported in healthy subject^.^ Lower systemic bioavailability of orally administered nicorandil is the most likely explanation for the overall lower plasma concentrations and AUC values observed in our patients with heart failure.'-" Lower plasma concentrations or AUC can be caused by either lower bioavailability or higher clearance. The latter is unlikely, given reports in the literature of either unchanged or lower drug clearance in patients with congestive heart failure.lO." Decreased nicorandil clearance is consistent with the observation of longer apparent elimination tl/, values in our patients with heart failure compared with the values in normal subject^.^ On the other hand, decreased extent of absorption is a more likely explanation for the lower AUC values in patients with heart failure because of bowel wall edema,
lower gastrointestinal motility, or reduced blood flow to the intestines.538-" Decreases in ventricular afterload and preload, representing desirable therapeutic effects in heart failure, were elicited by nicorandil administration. Reductions in systemic and pulmonary vascular resistances (major determinants of left and right ventricular afterload) and diastolic pressures were the hemodynamic responses that correlated best with serum nicorandil concentrations. This is consistent with the direct arterial-arteriolar vasodilating activity of this compound. The close inverse correlation between left and right ventricular filling pressures, as measured by pulmonary capillary wedge and right atrial pressures (major determinants of left and right ventricular preload), and nicorandil concentrations suggest that this compound also evokes some venodilation, although druginduced augmentation of ventricular diastolic function cannot be excluded as a contributory factor. The less predictable effect on cardiac output and stroke volume indexes is likely related to the complex interplay between reductions in vascular resistances, ventricular filling pressures, and improvement in ventricular emptying. Previous work has suggested that nicorandil has no direct inotropic activity.I2 The return of hemody-
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namic parameters to baseline corresponded closely with the disappearance of nicorandil from the plasma. We have reported previously that patients with heart failure require higher doses of nicorandil than either normal subjects or patients with ischemic heart disease (without heart failure) to produce consistent hemodynamic responses.' In the current study, doses of 20 mg and less did not significantly affect the hemodynamic parameters measured. These observations appear to be a consequence of the resistance of vasculature to vasodilating drugs and stimuli in patients with congestive heart failure,I3 as well as lower bioavailability. Doses of 40 to 60 mg were hemodynamically effective and generally well tolerated in our patient population. However, this study shows that investigations with even higher doses in patients with heart failure should be approached with caution because the amount of nicorandil available to the systemic circulation increases disproportionately relative to dosing increment. Larger nicorandil doses may be required in select patients with congestive heart failure, but because of the wide interpatient variability and nonlinearity in dose versus plasma concentrations, dose titration of the individual patient will be necessary. The findings of this investigation also indicate that nicorandil, as administered in this study, may have a limited role in the current therapeutics of human congestive heart failure. Although its vasodilating effects (preload and afterload reduction) are favorable properties in this clinical setting, similar responses have been well documented for converting enzyme inhibitors, the hydralazine-nitrate combination, and flosequinan. Nevertheless, nicorandil, perhaps because of its unique opening effect on the potassium channel, could be useful for the patient who is intolerant of or refractory to these particular agents. The rapid clearance and short pharrnacokinetic-pharmacodynamic ti,? of nicorandil are not favorable features for long-term medical management of chronic heart failure; this aspect could be modified by delay-release delivery systems. The interpatient variability of response to nicorandil and the widespread availability of various nitrate preparations and diuretics, as well as sodium nitroprusside and dobutamine, could also limit the role of nicorandil in the treatment of acute congestive heart failure.
Clinical phamacolgy of nicmandil 503 We thank Dr. Robert J. Cody for careful review of the manuscript, Mrs. Deborah Black for editorial assistance. and the nursing staff and houseofficers of the Coronary Care Unit for outstanding professional care of the study patients.
References I . Sakai K, Nakano H, Nagano H, Uchida Y. Nicorandil. In: Scriabine A, ed. New drugs annual: cardiovascular drugs (volume 1). New York: Raven Press, 1983:22742. 2. Tice FD, Binkley PF, Cody RJ, et al. Hemodynamic effects of oral nicorandil in congestive heart failure. Am J Cardiol 1 99O;65:I36 1-7. 3. Solal AC, Jaeger P, Bouthier J, Juliard JM, Dahan M, Gourgon R. Hemodynamic action of nicorandil in chronic congestive heart failure. Am J Cardiol 1989; 63:44J-85. 4. Galie N , Varani E, Maiello L, et al. Usefulness of nicorandil in congestive heart failure. Am J Cardiol 1990; 65:343-8. 5. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, Inc, 1982. 6. Frydman AM, Chapelle P, Diekmann H , et al. Pharmacokinetics of nicorandil. Am J Cardiol 1989;63:25J333. 7. MacKichan JJ, Pyszczynski DR, Jusko WJ. Dosedependent disposition of oral propranolol in normal subjects. Biopharm Drug Dispos 1980; 1: 159-66. 8. Leithe ME, Magonen RD, Hermiller JB. Unverferth DV, Leier CV. The relationship between central hemodynamics and regional blood flow in normal subjects and patients with congestive heart failure. Circulation 1984;69:57-64. 9. Benet LZ, Greither A, Meister W. Gastrointestinal absorption of drugs in patients with cardiac failure. In: Benet LZ, ed. The effect of disease states on pharmacokinetics. Washington, DC: American Pharmaceutical Association, 1976;33-50. 10. Benowitz NL, Meister W. Pharmacokinetics in patients with cardiac failure. Clin Pharmacokinet 1976; 1 :389405. 11. Shammas FV, Dickstein K. Clinical pharmacokinetics in heart failure: an updated review. Clin Pharmacokinet 1988;15:94-113. 12. Sakai K. Nicorandil: animal pharmacology. Am J Cardiol l989;63:2J- 105. 13. Zelis R, Mason DT, Braunwald E. A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 1968;47:960-8.
