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Impact of food on the pharmacokinetics and electrocardiographic effects of sustained release verapamil in normal subjects
CARWOVASCULAR PHARMACOLOGY
Impact of Food on the Pharmacokinetics and Electrocardiographic Effects of Sustained Release Verapamil in Normal Subjects Timothy J. Hoon, PharmD, Patrick L. McCollam, PharmD, Karen J. Beckman, MD, Robert J. Hariman, MD, and Jerry L. Bauman, PharmD
To evaluate the impact of food on the pharmacokinetics and electrocardiographic effects of sustained retease (SR) verapamil tablets, 9 healthy men each received 3 dngte doses of verapamil in a randomixed, crossover manner: 10 mg of intravenous verapamil, 240 mg SR verapamil on an empty stomach, and 240 mg SR verapamil with a standardized meal. PR intervals and racemic verapamil serum concentrations were measured serially over 30 hours after administration. The time to peak concentration was longer (7.5 f 3.0 VI 4.4 f 2.3 hours), resulthtg In a lower peak verapamil serum concentration (118 f 43 vs 175 f SO &ml) when SR verapamil was administered with food (p
concern with once-daily sustained release (SR) dosageforms is the potential for a precipitous release of a relatively large amount of drug. This could causeeither abrupt toxicity shortly after ingestion or loss of therapeutic effect, or both, by the end of the dosing interval. Although it is recommendedto take the original SR verapamil tablet with food,* it is unclear if this problem exists when the tablet is given in the fasting state. The original SR tablet is designedto releaseverapamil in a constant fashion1v2;however, the consequencesof coadministration with food on the cardiovascular effectshave only recently beenreported and further clarification is nee&d3 This study characterizes the pharmacokinetics of verapamil when administered to healthy subjectswith the oral SR tablet in the fasting and nonfasting states. Furthermore, the change in PR interval was measuredto evaluate the impact of administration condition on drug effect.
A
MEWOOS proee&~ This study was approved -m-d by the University Institutional Review Board for Human Investigations and all subjectsprovided written informed consent before study entry. Nine healthy, nonsmoking men (aged 25 f 3 years, weight 73.9 f 10.1 kg) were studied. A medical history, physical examination, 1Zlead electrocardiogram, serum chemistries and complete blood cell count were performed to evaluate the health of each volunteer. Subjectswere askedto ab stain from any alcohol, medication or caffeine use for 48 hours before the start of each study phase until its completion. The subjects participated in each of 3 phasesin a randomized, open-label, crossovermanner with at least a l-week washout betweeneachphase.The 3 phaseswere: (1) 10 mg of verapamil administered intravenously; (2) a single dose of SR verapamil 240 mg (Isoptin SR@,Knoll Pharmaceuticals) administered on an empty stomach; and (3) a single doseof SR verapamil 240 mg (Isoptin SR@,Knoll Pharmaceuticals) administered immediately after a standardized breakfast. All subjectsfasted for 3 hours after dosing. Each study day began after an overnight fast. An intravenous catheter flushed with a dilute heparin soluFrom the Departmentsof Pharmacy Practice and Medicine, Sectionof tion was placed in the arm of each subject for blood Cardiology, The University of Illinois at Chicago, Chicago, Illinois. This study was supportedin part by a grant from the American Heart sampling. A Holter monitor was also placed on each Association of Metropolitan Chicago, Chicago, Illinois. Manuscript subject to continuously record a lead II rhythm strip receivedJanuary 21.1992; revisedmanuscript receivedJune 17.1992, throughout the lO-hour study day. Blood pressuremeaand acceptedJune 22. Address for reprints: Jerry L. Bauman, PharmD, Department of surementswere obtained in duplicate with an automatPharmacy Practice, The University of Illinois at Chicago, 833 S. Wood ed blood pressure device (HealthTeam model 8175, M.E. Team Inc., South Plainfield, New Jersey) to deStreet (M/C 886), Chicago, Illinois 60612. 1072
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crease measurement variability. Subjects were placed in a supine position starting I15 minutes before intravenous verapamil and remained supine until 2 hours after administration. After a baseline blood pressure and blood sample were obtained, 10 mg of verapamil was administered through an intravenous catheter, in the arm contralateral to that of blood sampling, over 5 minutes via a volumetric syringe pump. Blood pressure and a 10 ml blood sample were obtained at 5, 10, 15, 30,45 and 60 minutes, and at 1.5, 2, 4, 6, 8, 10 and 24 hours after infusion. The event marker of the Holter monitor was depressed at the time of blood sampling. Blood samples were allowed to clot at room temperature, then centrifuged and separated. The serum was stored at -70°C until the time of analysis. These procedures were repeated for each of the 2 oral verapamil phases, except that the patients were studied in a sitting position after 15 minutes of rest. Blood pressure measurements and a 10 ml blood sample were obtained at 1, 2, 3,4, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 12, 24 and 30 hours after drug administration. Racemic verapamil serum concentrations were measured by reverse-phase, high-performance liquid chromatography using fluorescence detection. Serum samples were spiked with the internal standard (metoprolol) and extracted by the liquid-liquid method of Harapat and Kates4 Separation and quantitation of verapamil and norverapamil were performed by the method of Kuwada et a1,5 with the substitution of octane-sulfonic acid for heptanesulfonic acid in the mobile phase. The intra- and interday coefficients of variation were
mine the duration of pharmacologic effect. Percent changes from baseline were calculated for PR interval to compare the maximal effect and time to maximal effect between treatment phases. Statistical analysis: A nonparametric analysis was performed since the data were not normally distrib uted according to the Shapiro-Wilk test. The effect data were ranked within each phase, and an analysis of variance for repeated measures was performed on the ranked data to evaluate PR interval, heart rate and blood pressures over time. The Student-Newman-Keuls multiple comparison test was performed to determine which time points differed from baseline. The pharmacokinetic and electrocardiographic parameters of the 2 oral verapamil phases were compared using the Wilcoxon signed rank test.7 A p value <0.05 was considered significant for all comparisons. All data are reported as mean f standard deviation unless otherwise noted. RESULTS Pharmacokietiu: The rate and extent of oral ab sorption of verapamil from the SR tablet were quite variable regardless of administration condition. However, a precipitous release of verapamil from the SR tablet was not observed with either administration condition. Figure 1 demonstrates the spectrum of absorp tion profiles observed. More than 1 modal concentration was observed in 5 subjects. When this occurred, the largest modal concentration was selected as the peak concentration. The pharmacokinetic parameters for the intravenous reference dose and the 2 oral doses of verapamil are listed in Table I. Coadministration with food significantly reduced the rate of absorption of verapamil from the oral SR tablet, resulting in a prolongation in the time to peak concentration (7.5 f 3.0 vs 4.4 f 2.3 hours; p <0.05) and a reduction in the maximal observed verapamil concentration (118 f 43 vs 175 f 50 ng/ml; p <0.05) (Figure 2 and Table I). Although administration with food tended to reduce the bioavailability of verapamil from the SR tablet, this decrease was not statistically significant. There were also no significant differences between the apparent elimination halflives after oral administration with or without food, however, the apparent elimination half-life of verapamil after each oral dose was greater than that after intravenous administration. The verapamil/norverapamil ratio of the AUC for the fed and fasting states were similar since the norverapamil concentrations mirrored those of verapamil over time. EktrocardiograpKc
and hemodynamkeffec&No
significant changes in mean blood pressures or mean heart rate were observed over time. The magnitude and time course of PR interval prolongation between persons were quite variable. Significant prolongation of PR interval from baseline was observed in both the fed and fasting phases (Figure 2). However, significant prolongation was observed at only 2 time points after administration with food, whereas significant prolongation was evident for a 5.5-hour time period after administration on an empty stomach. Additionally, oral administration during a fasting state resulted in a greater maximal proVERAPAMIL-FOOD INTERACTION
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TABLE I Pharmacokinetic and Electrocardiographic Parameters Verapamil (10 mg intravenous)
Parameter Vss (liters/kg) CL (liters/hour/kg) Cmax (rig/ml) Tmax (hours) Bioavailability t%) Half-life (hours) AUC ratio (verapamil/ norverapamil)
Verapamil SR Oral Administration with Meal
Verapamil SR Oral Administration Fasting
p Value
3.03 2 0.63 0.919 f 0.161 175 -c 4.4 2 49e 7.6 2 0.82 k
2.9 f 0.39
Max % PR Tmax % PR (hours)
50 2.3 14 1.1 0.10
118k43 7.5 2 34 ‘6.6 2 0.82 2
21 28 5.5 + 2.1
p <0.05
3.0 12 2.8 0.17
p <0.05 p = 0.065
14 & 5 6.2 f 2.2
p <0.05
Data are expressed as mean k standard deviation. Parameters from the 2 oral doses were statistically compared with significance noted under p value. AUC ratio (verapamiI/norverapamll) = ratio of the areas under the concentration-time ewes of verapamil and norverapamil; CL = clearance; Cmax = peak serum concentration; Max % PR = maxrmal percent prolongation of PR interval; SR = sustained release: Tmax = time of peak serum concentration; Tmax % PR = time of maxlmal prolongation of PR Interval; Vss = volume of distribution at steady state.
verapamil tablet in the fasting state, this study was undertaken to evaluate the impact of the administration condition on the disposition of verapamil, and the resulting cardiovascular effects, Pham The pharmacokinetic parameters of verapamil after intravenous administration were similar to those previously reported for healthy subjects.9-12 There was considerableinterindividual variability in the rate, pattern and extent of absorption of verapamil from the SR tablet when given in both the fed and fasting DISCUSSION Previous experience with SR dosage forms has states.However, alterations in absorption and resulting shown that food can have a significant impact on drug drug effect were not as dramatic as those reported for a releaseand absorpti0n.sAdministration of a SR theoph- SR theophylline products Administration during a fastylline preparation with food resulted in a precipitous re- ing state did result in faster absorption, accompaniedby lease of theophyllme, yielding a 57% increase in drug a 48% increase in peak concentration. This increase in absorption, a 118% increase in peak serum concentra- peak concentration is consistentwith previous reports of tions, and signs of toxicity in 4 of 8 subjects.To allevi- a 53 and 46% increase in peak concentration after the ate similar concernsregarding administration of the SR administration of the immediate releaseand SR dosage longation of the PR interval (21 f 8 vs 14 f 5%; p <0.05), although the time at which maximal prolongation occurred did not differ significantly (Table I). Oral administration of verapamil produced a headachein 6 of 9 subjects. This did not appear to be related to the administration condition since 3 subjectsexperienceda headacheduring the fasting phaseand 3 subjectsduring the fed phase.
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form, respectively, in the fasting state.3J3In both of these reports,3J3as well as in this study, a significant reduction in the time to peak concentration was observed in the fasting state. This observation may be explained by delayed gastric emptying or alterations in the interactions of intestinal fluids with the tablet surface after coadministration with food,* which would result in slower absorption and lower peak concentrations. A reduction in bioavailability could also explain decreased peak concentrations. Although a trend toward reduced bioavailability was observed after administration with food, this 30% decreasewas not statistically significant. A similar observation has been implied in a previous review.14The relative delivery of verapamil and norverapamil after administration in the fed and fasting state was similar: norverapamil concentration-time curves mirrored those of verapamil and the ratio of the respective AUCs did not differ. This suggeststhat the administration condition doesnot alter first-pass metab olism. Also, the apparent half-lives after the 2 oral phasesof the study did not differ from each other, suggesting that there is no alteration in the rate of elimination. Ekctmcadographk eMeetsr There was considerable variability in prolongation of the PR interval with respect to both magnitude and time course. This is not surprising considering the variability in the verapamil concentrations after administration of the SR tablet, and the demonstrated relation between PR interval prolongation and racemic verapamil serum concentrations9-’ WJ~ Administration of the SR verapamil tablet in the fasting state produced a greater maximal prolongation of PR interval, which paralleled the higher peak serum concentrations. Additionally, significant PR interval prolongation was maintained from 2 to 7.5 hours after administration in the fasting state. In comparison, significant PR prolongation was observedat only 7 and 8 hours after administration with food. Therefore, the greater effect seen earlier in the fasting state did not appear to result in a premature loss of effect. Rather, higher peak serum concentrations were obtained in the fasting state, resulting in a greater prolongation of PR interval, the decline of which paralleled the decline in serum concentrations. Translating the alterations of pharmacologic effect from controlled, single dose studies to the alterations of clinical effect with chronic administration is difficult. In addition to the expected drug accumulation on chronic dosing to steady-state, the clearance of verapamil ap pears to decreasewith continued administration.” One would therefore expect larger or more sustainedeffects with chronic dosing. Indeed, sustained blood pressure reductions with once-daily administration of SR verapamil have been shown.18J9However, the duration of action on the atrioventricular node lasted no >8 hours after a single dose in either the fasted or fed state. Based on this observation, one could question the wisdom of administering SR verapamil on a once-daily basis for the treatment of supraventricular arrhythmias. Evidence supporting once-daily administration of SR verapamil for the treatment of supraventricular arrhythmias
is scarce.2oThe clinical relevanceof the short duration of atrioventricular node effects may be minimized with chronic dosing; however,the potential for greater effects on atrioventricular node conduction should be considered when SR verapamil is given in the fasting state becausehigher peak concentrationsmay be consistently achieved. Although greater peak serum concentrations were observedin the fasting state, concernsregarding precipitous or exaggeratedabsorption of verapamil from the SR tablet when taken on an empty stomach appear unfounded. Administration in the fasting state significantly increased the rate of absorption and the effect on atrioventricular node conduction as measured by prolongation of the PR interval. This echoes the higher peak concentrationsobserved.Anticipating this food ef-
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1075
feet is of practical concernbecausemanipulationof the administration condition may be helpful in achieving desiredoutcomes.
10. McAllister RG, Kirsten ED. The pharmacologyof verapamil. IV. Kinetic and dynamic effects after single intravenous and oral doses.Clin Pharmacof Ther 1982;31:418-426. II. Reiter MJ, Shand DG, Pritchett ELC. Comparisonof intravenousand oral verapamil dceing. Clin Pharmacol Ther 1982;32:71l-720. 12. SchoenMD, Parker RB, Hoon TJ, Hariman RJ, BaumanJL, BeckmanKJ. Evaluation of the pharmacokineticsand electrocardiographiceffects of intrave nous verapamil with calcium chloride pretreatment in normal subjects.Am J Cardiol 1991;67:300-304. 13. WoodcockBG, Kraemer N, Rietbrock N. Effect of a high protein mealon the REFERENCES 1. Packageinsert, Isoptin SRo. Knoll Pharmaceuticals,Whippany, New Jersey. bioavailability of verapamil. Br J Clin Pharmacol 1986;21:337-338. 2. McEwen J, Dumin C, McMurdo MET, Moreland TA. Sustained-release 14. Klein MD, Weiner DA. Treatment of angina pectorisand hypertensionwith verapamil: multipledose pharmacokineticscomparisonof 120-mgand 240-mg sustained-releasecalcium channel-blocking drugs. Circulution 1987;75(suppl v):v-11o-v-113. tablets and the effect of halving a 240-mg tablet. J Curdiouasc Pharmacol IS. Eichelbaum M, Birkel P, Gmbe E, GutgemannU, Somogyi A. Effects of 1989;12(sup~l4):S57-S59. 3. Conway EL, Phillips PA, Drummer OH, Louis WJ. Inlluence of food on the verapamil on P-R-intervals in relation to verapamil plasmalevelsfollowing single iv. and oral administration and during chronic treatment. Klin Wochenrchr bioavailability of a sustained release verapomil preparation. J Phwm Sci 1980;58:919-925. 1990;79:228-231. 18. BarbarashRA, BaumanJL, Fischer JH, KondosGT, BatenhorstRL. Near4. Harapt SR, Kates RE. High-performanceliquid chromatographicanalysisof verapamil: II. Simultaneousquantification of verapamil and its active metabolite, total reduction in verapamil bioavailability by rifampin: electrccardiographic correlates. Chest 1988;94:954-959. norverapamil. J Chromatogr 1980;181:484-489. 17. Shand DG, Hammill SC, Aaronsen L, Pritchett ELC. Reducedverapamil S. Kuwada M, Tateyama T, Tsutsumi J. Simultaneousdetermination of verapa clearanceduring long-term oral administration. Clin Phormacol Ther 1981;30: mil and its seven metabolites by high-performance liquid chromatography. J 701-703. Chromatogr 1981;222:507-511. 6. Gibaldi M, Per&r D. Pharmacokinetics.2nd ed. New York: Marcel Dekker, 18. Zachariah PK. ShepsSG, Schriger A. Efftcacy of sustained-releaseverapamil: automatic ambulatory blood pressuremonitoring. J Clin ffypertens 1986; 1982:45-l 11, 409-417. 7. Ear JH. Biostatistical Analysis. 2nd ed. New York: Prentice-Hall, 1984: 3:133s-142s. IS. McMahon FG, Reder RF. The relationship of doseto the antihypertensive 150-156,190-191.206-231. 8. HendelesL, Weinberger M, Milavetz G, Hill M, Vaughan L. Food-induced responseof verapamil-sustainedreleasein patientswith mild to moderateessential “dosedumping” from a once-a-daytheophyllinc product as a causeof theophyl- hypertension.J Clin Pharmacol 1989;29:1003-1007. 20. Molgaard H, Bjerregaard P, JorgensenHS, Klitgaard NA. 24hour antiarline toxicity. Chesr 1985;87:758-765. 9. EchizenH, EichelbaumM. Clinical pharmacokinetia of verapamil, nifedipine rhythmic effect of conventionaland slow-releaseverapamil in chronic atrial fibrillation. Eur J Clin Pharmacol 1987;33:447-453. and dihiazem. Clin Pharmacokinet 1986;11:425-449.
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Impact of Food on the Pharmacokinetics and Electrocardiographic Effects of Sustained Release Verapamil in Normal Subjects Timothy J. Hoon, PharmD, Patrick L. McCollam, PharmD, Karen J. Beckman, MD, Robert J. Hariman, MD, and Jerry L. Bauman, PharmD
To evaluate the impact of food on the pharmacokinetics and electrocardiographic effects of sustained retease (SR) verapamil tablets, 9 healthy men each received 3 dngte doses of verapamil in a randomixed, crossover manner: 10 mg of intravenous verapamil, 240 mg SR verapamil on an empty stomach, and 240 mg SR verapamil with a standardized meal. PR intervals and racemic verapamil serum concentrations were measured serially over 30 hours after administration. The time to peak concentration was longer (7.5 f 3.0 VI 4.4 f 2.3 hours), resulthtg In a lower peak verapamil serum concentration (118 f 43 vs 175 f SO &ml) when SR verapamil was administered with food (p
concern with once-daily sustained release (SR) dosageforms is the potential for a precipitous release of a relatively large amount of drug. This could causeeither abrupt toxicity shortly after ingestion or loss of therapeutic effect, or both, by the end of the dosing interval. Although it is recommendedto take the original SR verapamil tablet with food,* it is unclear if this problem exists when the tablet is given in the fasting state. The original SR tablet is designedto releaseverapamil in a constant fashion1v2;however, the consequencesof coadministration with food on the cardiovascular effectshave only recently beenreported and further clarification is nee&d3 This study characterizes the pharmacokinetics of verapamil when administered to healthy subjectswith the oral SR tablet in the fasting and nonfasting states. Furthermore, the change in PR interval was measuredto evaluate the impact of administration condition on drug effect.
A
MEWOOS proee&~ This study was approved -m-d by the University Institutional Review Board for Human Investigations and all subjectsprovided written informed consent before study entry. Nine healthy, nonsmoking men (aged 25 f 3 years, weight 73.9 f 10.1 kg) were studied. A medical history, physical examination, 1Zlead electrocardiogram, serum chemistries and complete blood cell count were performed to evaluate the health of each volunteer. Subjectswere askedto ab stain from any alcohol, medication or caffeine use for 48 hours before the start of each study phase until its completion. The subjects participated in each of 3 phasesin a randomized, open-label, crossovermanner with at least a l-week washout betweeneachphase.The 3 phaseswere: (1) 10 mg of verapamil administered intravenously; (2) a single dose of SR verapamil 240 mg (Isoptin SR@,Knoll Pharmaceuticals) administered on an empty stomach; and (3) a single doseof SR verapamil 240 mg (Isoptin SR@,Knoll Pharmaceuticals) administered immediately after a standardized breakfast. All subjectsfasted for 3 hours after dosing. Each study day began after an overnight fast. An intravenous catheter flushed with a dilute heparin soluFrom the Departmentsof Pharmacy Practice and Medicine, Sectionof tion was placed in the arm of each subject for blood Cardiology, The University of Illinois at Chicago, Chicago, Illinois. This study was supportedin part by a grant from the American Heart sampling. A Holter monitor was also placed on each Association of Metropolitan Chicago, Chicago, Illinois. Manuscript subject to continuously record a lead II rhythm strip receivedJanuary 21.1992; revisedmanuscript receivedJune 17.1992, throughout the lO-hour study day. Blood pressuremeaand acceptedJune 22. Address for reprints: Jerry L. Bauman, PharmD, Department of surementswere obtained in duplicate with an automatPharmacy Practice, The University of Illinois at Chicago, 833 S. Wood ed blood pressure device (HealthTeam model 8175, M.E. Team Inc., South Plainfield, New Jersey) to deStreet (M/C 886), Chicago, Illinois 60612. 1072
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crease measurement variability. Subjects were placed in a supine position starting I15 minutes before intravenous verapamil and remained supine until 2 hours after administration. After a baseline blood pressure and blood sample were obtained, 10 mg of verapamil was administered through an intravenous catheter, in the arm contralateral to that of blood sampling, over 5 minutes via a volumetric syringe pump. Blood pressure and a 10 ml blood sample were obtained at 5, 10, 15, 30,45 and 60 minutes, and at 1.5, 2, 4, 6, 8, 10 and 24 hours after infusion. The event marker of the Holter monitor was depressed at the time of blood sampling. Blood samples were allowed to clot at room temperature, then centrifuged and separated. The serum was stored at -70°C until the time of analysis. These procedures were repeated for each of the 2 oral verapamil phases, except that the patients were studied in a sitting position after 15 minutes of rest. Blood pressure measurements and a 10 ml blood sample were obtained at 1, 2, 3,4, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 12, 24 and 30 hours after drug administration. Racemic verapamil serum concentrations were measured by reverse-phase, high-performance liquid chromatography using fluorescence detection. Serum samples were spiked with the internal standard (metoprolol) and extracted by the liquid-liquid method of Harapat and Kates4 Separation and quantitation of verapamil and norverapamil were performed by the method of Kuwada et a1,5 with the substitution of octane-sulfonic acid for heptanesulfonic acid in the mobile phase. The intra- and interday coefficients of variation were
mine the duration of pharmacologic effect. Percent changes from baseline were calculated for PR interval to compare the maximal effect and time to maximal effect between treatment phases. Statistical analysis: A nonparametric analysis was performed since the data were not normally distrib uted according to the Shapiro-Wilk test. The effect data were ranked within each phase, and an analysis of variance for repeated measures was performed on the ranked data to evaluate PR interval, heart rate and blood pressures over time. The Student-Newman-Keuls multiple comparison test was performed to determine which time points differed from baseline. The pharmacokinetic and electrocardiographic parameters of the 2 oral verapamil phases were compared using the Wilcoxon signed rank test.7 A p value <0.05 was considered significant for all comparisons. All data are reported as mean f standard deviation unless otherwise noted. RESULTS Pharmacokietiu: The rate and extent of oral ab sorption of verapamil from the SR tablet were quite variable regardless of administration condition. However, a precipitous release of verapamil from the SR tablet was not observed with either administration condition. Figure 1 demonstrates the spectrum of absorp tion profiles observed. More than 1 modal concentration was observed in 5 subjects. When this occurred, the largest modal concentration was selected as the peak concentration. The pharmacokinetic parameters for the intravenous reference dose and the 2 oral doses of verapamil are listed in Table I. Coadministration with food significantly reduced the rate of absorption of verapamil from the oral SR tablet, resulting in a prolongation in the time to peak concentration (7.5 f 3.0 vs 4.4 f 2.3 hours; p <0.05) and a reduction in the maximal observed verapamil concentration (118 f 43 vs 175 f 50 ng/ml; p <0.05) (Figure 2 and Table I). Although administration with food tended to reduce the bioavailability of verapamil from the SR tablet, this decrease was not statistically significant. There were also no significant differences between the apparent elimination halflives after oral administration with or without food, however, the apparent elimination half-life of verapamil after each oral dose was greater than that after intravenous administration. The verapamil/norverapamil ratio of the AUC for the fed and fasting states were similar since the norverapamil concentrations mirrored those of verapamil over time. EktrocardiograpKc
and hemodynamkeffec&No
significant changes in mean blood pressures or mean heart rate were observed over time. The magnitude and time course of PR interval prolongation between persons were quite variable. Significant prolongation of PR interval from baseline was observed in both the fed and fasting phases (Figure 2). However, significant prolongation was observed at only 2 time points after administration with food, whereas significant prolongation was evident for a 5.5-hour time period after administration on an empty stomach. Additionally, oral administration during a fasting state resulted in a greater maximal proVERAPAMIL-FOOD INTERACTION
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TABLE I Pharmacokinetic and Electrocardiographic Parameters Verapamil (10 mg intravenous)
Parameter Vss (liters/kg) CL (liters/hour/kg) Cmax (rig/ml) Tmax (hours) Bioavailability t%) Half-life (hours) AUC ratio (verapamil/ norverapamil)
Verapamil SR Oral Administration with Meal
Verapamil SR Oral Administration Fasting
p Value
3.03 2 0.63 0.919 f 0.161 175 -c 4.4 2 49e 7.6 2 0.82 k
2.9 f 0.39
Max % PR Tmax % PR (hours)
50 2.3 14 1.1 0.10
118k43 7.5 2 34 ‘6.6 2 0.82 2
21 28 5.5 + 2.1
p <0.05
3.0 12 2.8 0.17
p <0.05 p = 0.065
14 & 5 6.2 f 2.2
p <0.05
Data are expressed as mean k standard deviation. Parameters from the 2 oral doses were statistically compared with significance noted under p value. AUC ratio (verapamiI/norverapamll) = ratio of the areas under the concentration-time ewes of verapamil and norverapamil; CL = clearance; Cmax = peak serum concentration; Max % PR = maxrmal percent prolongation of PR interval; SR = sustained release: Tmax = time of peak serum concentration; Tmax % PR = time of maxlmal prolongation of PR Interval; Vss = volume of distribution at steady state.
verapamil tablet in the fasting state, this study was undertaken to evaluate the impact of the administration condition on the disposition of verapamil, and the resulting cardiovascular effects, Pham The pharmacokinetic parameters of verapamil after intravenous administration were similar to those previously reported for healthy subjects.9-12 There was considerableinterindividual variability in the rate, pattern and extent of absorption of verapamil from the SR tablet when given in both the fed and fasting DISCUSSION Previous experience with SR dosage forms has states.However, alterations in absorption and resulting shown that food can have a significant impact on drug drug effect were not as dramatic as those reported for a releaseand absorpti0n.sAdministration of a SR theoph- SR theophylline products Administration during a fastylline preparation with food resulted in a precipitous re- ing state did result in faster absorption, accompaniedby lease of theophyllme, yielding a 57% increase in drug a 48% increase in peak concentration. This increase in absorption, a 118% increase in peak serum concentra- peak concentration is consistentwith previous reports of tions, and signs of toxicity in 4 of 8 subjects.To allevi- a 53 and 46% increase in peak concentration after the ate similar concernsregarding administration of the SR administration of the immediate releaseand SR dosage longation of the PR interval (21 f 8 vs 14 f 5%; p <0.05), although the time at which maximal prolongation occurred did not differ significantly (Table I). Oral administration of verapamil produced a headachein 6 of 9 subjects. This did not appear to be related to the administration condition since 3 subjectsexperienceda headacheduring the fasting phaseand 3 subjectsduring the fed phase.
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form, respectively, in the fasting state.3J3In both of these reports,3J3as well as in this study, a significant reduction in the time to peak concentration was observed in the fasting state. This observation may be explained by delayed gastric emptying or alterations in the interactions of intestinal fluids with the tablet surface after coadministration with food,* which would result in slower absorption and lower peak concentrations. A reduction in bioavailability could also explain decreased peak concentrations. Although a trend toward reduced bioavailability was observed after administration with food, this 30% decreasewas not statistically significant. A similar observation has been implied in a previous review.14The relative delivery of verapamil and norverapamil after administration in the fed and fasting state was similar: norverapamil concentration-time curves mirrored those of verapamil and the ratio of the respective AUCs did not differ. This suggeststhat the administration condition doesnot alter first-pass metab olism. Also, the apparent half-lives after the 2 oral phasesof the study did not differ from each other, suggesting that there is no alteration in the rate of elimination. Ekctmcadographk eMeetsr There was considerable variability in prolongation of the PR interval with respect to both magnitude and time course. This is not surprising considering the variability in the verapamil concentrations after administration of the SR tablet, and the demonstrated relation between PR interval prolongation and racemic verapamil serum concentrations9-’ WJ~ Administration of the SR verapamil tablet in the fasting state produced a greater maximal prolongation of PR interval, which paralleled the higher peak serum concentrations. Additionally, significant PR interval prolongation was maintained from 2 to 7.5 hours after administration in the fasting state. In comparison, significant PR prolongation was observedat only 7 and 8 hours after administration with food. Therefore, the greater effect seen earlier in the fasting state did not appear to result in a premature loss of effect. Rather, higher peak serum concentrations were obtained in the fasting state, resulting in a greater prolongation of PR interval, the decline of which paralleled the decline in serum concentrations. Translating the alterations of pharmacologic effect from controlled, single dose studies to the alterations of clinical effect with chronic administration is difficult. In addition to the expected drug accumulation on chronic dosing to steady-state, the clearance of verapamil ap pears to decreasewith continued administration.” One would therefore expect larger or more sustainedeffects with chronic dosing. Indeed, sustained blood pressure reductions with once-daily administration of SR verapamil have been shown.18J9However, the duration of action on the atrioventricular node lasted no >8 hours after a single dose in either the fasted or fed state. Based on this observation, one could question the wisdom of administering SR verapamil on a once-daily basis for the treatment of supraventricular arrhythmias. Evidence supporting once-daily administration of SR verapamil for the treatment of supraventricular arrhythmias
is scarce.2oThe clinical relevanceof the short duration of atrioventricular node effects may be minimized with chronic dosing; however,the potential for greater effects on atrioventricular node conduction should be considered when SR verapamil is given in the fasting state becausehigher peak concentrationsmay be consistently achieved. Although greater peak serum concentrations were observedin the fasting state, concernsregarding precipitous or exaggeratedabsorption of verapamil from the SR tablet when taken on an empty stomach appear unfounded. Administration in the fasting state significantly increased the rate of absorption and the effect on atrioventricular node conduction as measured by prolongation of the PR interval. This echoes the higher peak concentrationsobserved.Anticipating this food ef-
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VERAPAMIL-FOOD INTERACTION
1075
feet is of practical concernbecausemanipulationof the administration condition may be helpful in achieving desiredoutcomes.
10. McAllister RG, Kirsten ED. The pharmacologyof verapamil. IV. Kinetic and dynamic effects after single intravenous and oral doses.Clin Pharmacof Ther 1982;31:418-426. II. Reiter MJ, Shand DG, Pritchett ELC. Comparisonof intravenousand oral verapamil dceing. Clin Pharmacol Ther 1982;32:71l-720. 12. SchoenMD, Parker RB, Hoon TJ, Hariman RJ, BaumanJL, BeckmanKJ. Evaluation of the pharmacokineticsand electrocardiographiceffects of intrave nous verapamil with calcium chloride pretreatment in normal subjects.Am J Cardiol 1991;67:300-304. 13. WoodcockBG, Kraemer N, Rietbrock N. Effect of a high protein mealon the REFERENCES 1. Packageinsert, Isoptin SRo. Knoll Pharmaceuticals,Whippany, New Jersey. bioavailability of verapamil. Br J Clin Pharmacol 1986;21:337-338. 2. McEwen J, Dumin C, McMurdo MET, Moreland TA. Sustained-release 14. Klein MD, Weiner DA. Treatment of angina pectorisand hypertensionwith verapamil: multipledose pharmacokineticscomparisonof 120-mgand 240-mg sustained-releasecalcium channel-blocking drugs. Circulution 1987;75(suppl v):v-11o-v-113. tablets and the effect of halving a 240-mg tablet. J Curdiouasc Pharmacol IS. Eichelbaum M, Birkel P, Gmbe E, GutgemannU, Somogyi A. Effects of 1989;12(sup~l4):S57-S59. 3. Conway EL, Phillips PA, Drummer OH, Louis WJ. Inlluence of food on the verapamil on P-R-intervals in relation to verapamil plasmalevelsfollowing single iv. and oral administration and during chronic treatment. Klin Wochenrchr bioavailability of a sustained release verapomil preparation. J Phwm Sci 1980;58:919-925. 1990;79:228-231. 18. BarbarashRA, BaumanJL, Fischer JH, KondosGT, BatenhorstRL. Near4. Harapt SR, Kates RE. High-performanceliquid chromatographicanalysisof verapamil: II. Simultaneousquantification of verapamil and its active metabolite, total reduction in verapamil bioavailability by rifampin: electrccardiographic correlates. Chest 1988;94:954-959. norverapamil. J Chromatogr 1980;181:484-489. 17. Shand DG, Hammill SC, Aaronsen L, Pritchett ELC. Reducedverapamil S. Kuwada M, Tateyama T, Tsutsumi J. Simultaneousdetermination of verapa clearanceduring long-term oral administration. Clin Phormacol Ther 1981;30: mil and its seven metabolites by high-performance liquid chromatography. J 701-703. Chromatogr 1981;222:507-511. 6. Gibaldi M, Per&r D. Pharmacokinetics.2nd ed. New York: Marcel Dekker, 18. Zachariah PK. ShepsSG, Schriger A. Efftcacy of sustained-releaseverapamil: automatic ambulatory blood pressuremonitoring. J Clin ffypertens 1986; 1982:45-l 11, 409-417. 7. Ear JH. Biostatistical Analysis. 2nd ed. New York: Prentice-Hall, 1984: 3:133s-142s. IS. McMahon FG, Reder RF. The relationship of doseto the antihypertensive 150-156,190-191.206-231. 8. HendelesL, Weinberger M, Milavetz G, Hill M, Vaughan L. Food-induced responseof verapamil-sustainedreleasein patientswith mild to moderateessential “dosedumping” from a once-a-daytheophyllinc product as a causeof theophyl- hypertension.J Clin Pharmacol 1989;29:1003-1007. 20. Molgaard H, Bjerregaard P, JorgensenHS, Klitgaard NA. 24hour antiarline toxicity. Chesr 1985;87:758-765. 9. EchizenH, EichelbaumM. Clinical pharmacokinetia of verapamil, nifedipine rhythmic effect of conventionaland slow-releaseverapamil in chronic atrial fibrillation. Eur J Clin Pharmacol 1987;33:447-453. and dihiazem. Clin Pharmacokinet 1986;11:425-449.
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
OCTOBER 15, 1992