- Email: [email protected]
An assessment of the pharmacokinetics and pharmacodynamics of single doses of amlodipine in elderly normotensives
Phormuc~nlogic~ul
Research.
3.3
Vol. 26, No. I, 1992
AN ASSESSMENT OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OF SINGLE DOSES OF AMLODIPINE IN ELDERLY NORMOTENSIVES H. L. ELLIOTT, S. T. GREEN, J. VINCENT and P. A. MEREDITH University Department of Medicine and Therapeutics, Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, G lasgoHp,G l I 6NT, UK Received
in final form 3 January
1992
SUMMARY
This study characterizes the single dose pharmacokinetic characteristics of the dihydropyridine calcium antagonist drug amlodipine in a group of 16 elderly subjects, aged 65 to 86 years (8 M:8 F). The most notable pharmacokinetic features were a prolonged terminal elimination half life of 48+16 hours and a delayed t,,, of 7.3k1.3 hours. Consistent with the time to achieve peak plasma drug concentrations, there was a modest but significant reduction in blood pressure at 6-8 hours after dosing. Comparison of these results with those of published data for young subjects indicate not only a greater degree of intersubject variability but also a longer half life in the elderly, suggestive of reduced drug clearance, which may lead to higher plasma drug concentrations particularly at steady state. KEY WORDS: amlodipine, elderly, pharmacokinetics,
INTRODUCTION
Amlodipine is a dihydropyridine type of calcium antagonist drug which has been recently marketed for the treatment of hypertension and angina pectoris. Studies in animals have shown that the pharmacological effects of amlodipine are of gradual onset and of prolonged duration and occur in association with a prolonged terminal elimination half life of up to 30 hours [l-4]. Preliminary studies in man have identified a similar pharmacokinetic profile following oral and intravenous administration with elimination half lives of more than 30 hours in young normotensive human volunteers [5,6]. This profile of pharmacokinetics and pharmacodynamics is not shared by any other available dihydropyridine drug. The proportion of the patient population aged over 65 years is increasing in both relative and absolute terms in developed Western countries and so it follows that a sizable number of potential amlodipine recipients will fall into the ‘elderly’ Correspondenceto: Dr H. L. Elliott. 1013-66 18/92/050033-07/$0.1.00/0
0 1992 The Italian Pharmacological Society
34
Pharmacological
Research,
Vol. 26, No. I, 1992
category. Since the pathophysiological changes associated with increasing age may significantly alter the absorption, distribution and clearance of drugs [7] it is important to specifically investigate the clinical pharmacological characteristics of any newly developed drug in such an older population. The principal aim of this study was to characterize the pharmacokinetics of amlodipine in a group of elderly subjects and to make a preliminary assessmentof its subjective acceptability.
METHODS
Sixteen healthy normotensive elderly volunteers who were living independently in the community took part in this study. There were eight males and eight females aged 73f5 years (range 65-86 years) and weighing 63f9 kg (range 50-82 kg). Each subject was considered healthy and free of clinically significant disease on the basis ,of detailed physical, biochemical and haematological indices and electrocardiography. All subjects were free of medication for at least 2 weeks prior to entering the study. The protocol was approved by the Research and Ethics Committee of the Northern District of the Greater G lasgow Health Board and each subject gave informed written consent for his/her participation. Subjects reported to the Clinical Pharmacology Research Unit (CPRU) having avoided food, alcohol and all caffeine-containing drinks from 22.00 on the previous evening. Subjects were allowed standardized light meals at 5 and 9 hours after drug dosing. In a randomized crossover manner each subject received amlodipine 5 mg and a matching placebo on two study days at least 2 weeks apart. Subjects remained under full medical supervision in the CPRU for a minimum of 12 hours after dosing and blood was withdrawn from a indwelling intravenous cannula at 0, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120 and 168 hours following drug administration. At times corresponding to blood sampling, blood pressure and heart rate were measured in duplicate by a semiautomated sphygmomanometer (Sentron Bard Medical) after resting supine for at least 10 minutes and after standing for up to 5 minutes. Pharmacokinetic analysis Plasma concentrations of amlodipine were analysed by gas chromatography with electron capture detection using the method described in detail by Beresford et al. [8]. The disposition characteristics of amlodipine were analysed by model dependent means using non-linear least squares fitting of a hierarchy of models to the drug concentration time data. In all subjects a two compartment model, with first order input accounting for absorption, was most appropriately fitted to the data and it was not necessary to include a time lag associated with absorption. The following parameters were derived: the achieved peak concentration (C,,,), the time to peak concentration (T,,,), the elimination half life (Ketli2) and the area under the plasma concentration-time curve to infinity (AUC). The apparent oral clearance (clearance divided by bioavailability, F) was calculated as dose divided by AUC, while the apparent volume of distribution (Vd/F) was calculated from the
Pharmacdo,~ical
Research,
Vol. 26, No. I. 1992
3s
apparent oral clearance divided by the elimination rate constant, K,. The analysis was extended to predict the plasma drug concentrations at steady state by simulations based upon the fitted kinetic parameters and the two compartment model for acute dosing. These predictions were based on the assumption that the drug obeys linear kinetics and that there were no changes in the apparent oral clearance in translation from acute to steady state therapy. Both these assumptions can be justified based on previous experience with this agent in normotensive and hypertensive patients [3, 5, 61. O ther measurements Eight hours after drug administration on each study day a 12-lead ECG was performed in all subjects and at 120 hours after dosing biochemical and haematological tests and urinalysis were re-assessed in each subject. Creatinine clearance was estimated in individual subjects using average serum creatinine values from the above blood samples. Statistics Results throughout are expressed as mean&so. The statistical evaluation of the blood pressure and heart rate profiles was on the basis of repeated measures analysis of variance. The pharmacokinetic parameters were compared by analysis of variance with Bonferroni corrections where appropriate. RESULTS General subjective tolerance Overall, amlodipine 5 mg was well tolerated by all subjects and, apart from minor complaints of mild headacheor tiredness which were comparable with those of the placebo day, no significant adverse events were volunteered. There were no significant alterations in the electrocardiographic, biochemical, haematological or renal indices in any of the individuals. Blood pressure and heart rate In the 12 hours following administration of amlodipine there were small but statistically significant reductions in both supine and erect blood pressure. Generally, as illustrated in Fig. 1 for erect systolic blood pressure, the maximal effects on blood pressure were observed between 6 and 8 hours post-dosing (PcO.01 1’splacebo). There were no corresponding, significant changes in supine or erect heart rate over the 12 hours. Beyond 12 hours, both blood pressure and heart rate were comparable for amlodipine and placebo. Pharmacokinetics The derived pharmacokinetic parameters are shown in Table I and the concentration-time profile is shown in Fig. 2. A summary of the results from this analysis has been published previously [9]. Volume of distribution (Vd/F) and
Pharmacological
36
Research, Vol. 26, No. I,1992
80 75 70 65 60 0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
IO
12
Time (h)
Fig. 1. Meanerectsystolic bloodpressureanderectheartrate following the administrationof amlodipineandplacebo.
apparent oral clearance (clearance/F) were weight corrected. The standarized, derived kinetic parameters were comparable between the sexes and no major differences were observed between men and women although the peak concentration (C,,,) was significantly higher in women than in men (4.0f 1.3 rig/ml compared to 2.3kO.2 rig/ml; PcO.01) and volume of distribution tended to be smaller. There was considerable intersubject variability both in the apparent oral clearance which ranged from 0.21 to 1.50 l/h/kg and in the terminal elimination half life, which ranged from 30 to 81 hours. Pharmacokinetic predictions From the individually derived parameters following the single dose administration of amlodipine a profile of steady state dosing was constructed for individual subjects and the mean of these profiles is shown in Fig. 2. DISCUSSION In this study of amlodipine in elderly subjects the single dose pharmacokinetic results were broadly comparable to those published for younger subjects [5, 61 but there was a small and significant prolongation of terminal elimination half life and a tendency for apparent oral clearance to decline [9]. Additionally, in common with many other drugs, whether their elimination is dependent upon hepatic mechanisms or renal mechanisms, there was a greater degree of intersubject variability in the disposition characteristics in these elderly subjects. In the
Pharmadogic~al
Research,
Vol. 26, No. 1. 1992
37
Table I Derived pbarmacokinetic parameters sex
A&Y (Y)
Weight AUC (kg) (ng.h/ml)
C max W/ml)
VdIF (l/k< )
5.6 9.3 9.5 5.8 7.8 6.9 6.5 7.8
2.5 2.4 2.3 1.8 2.4 2.5 2.3 2.3
29.1 35 ._5 -_ 29.6 42.7 38. I 54.5 32.7 35.9
51f15
7.4L1.5
2.3kO.2
30 34 34 45 42 54 81 30
9.2 7.8 7.6 6.3 6.8 8.1 6.1 6.2
4.6 3.5 4.9 5.2 4.3 3.1 4.9 1.3
Cl/F (l/h/kg)
KeTw (h)
0.31 0.27 0.56 1.11 0.50 0.71 0.55 0.36
66 64 37 27 53 53 41 69
0.55f0.27 0.39 0.45 0.30 0.40 0.45 0.32 0.21 1.50
cnax (h)
74 72 67 78 72 75 66 85
76 82 63 65 59 60 60 64
216 222 143 70 169 117 151 218
fvtean+so 74f6
66k8
163f54
68 67 65 72 65 68 84 75
57 59 64 50 66 68 57 60
227 187 264 252 168 231 409 54
Mean&so 7 1+6
6Ok6
224flOO
0.50f0.41
44f17
7.321.1
4.0fl.3
27.8kl6.1
63+8
194f84
0.52kO.34
48f16
7.3f1.3
3.1k1.2
31.9k13.4
Overall
72f6
36.0fO.i 16.6 22.4 14.4 25.5 27.3 24.9 25.1 65.9
mean&so
absence of data from intravenous administra.tion, it is not possible to establish by this study whether these changes in apparent clearance reflect an increase in oral bioavailability or a reduction in the rate of hepatic metabolism. However, the results of a recent similar study, involving intravenous administration, have shown that the clearance of amlodipine was 24% lower in elderly subjects [lo]. In the absence of data from an intravenous formulation it is also difficult to make positive assertions in relation to the apparent sex differences observed in this study. However, based on inferential evidence it is reasonable to speculate that with a drug with a relatively large volume of distribution the differences observed between the sexes in terms of C,,, may be attributed to a difference in volume of distribution (which in itself did not attain a statistical difference) which is associated with the relative differences in weight between the sexes. This contention is supported by close correspondence in the weight-corrected oral clearances between the groups and an associated good agreement in the elimination half lives. The single doses of amlodipine administered in this study produced small but statistically significant reductions in both supine and erect blood pressures. These findings are directly comparable to those obtained with other calcium antagonist drugs which generally show only modest blood pressure lowering activity in
Pharmacological Research, Vol. 26, No. I. I992
38
=,E 8s : 6..a n 0 ,E
4-
OL Time(h)
Fig. 2. Mean plasma drug concentration-time profiles from all subjects: (a) following a single n , (b) predicted for steady state following 5 mg amlodipine dose of 5 mg amlodipine n A (95% confidence intervals are shown). daily A-
normotensive subjects. In this study the modest hypotensive effect of amlodipine was not accompanied by any statistically significant alteration in heart rate. While this may reflect the relatively impaired efficiency of the cardiovascular homeostatic mechanisms in the elderly compared to the young, it may also be related to the rate of onset of the vasodilator effect, as has been reported for nifedipine [I 11, whereby the gradual onset of the vasodilatation produced by amlodipine causes relatively little baroreflex-mediated cardioacceleration. Although the potential age-related pharmacokinetic differences are relatively modest at single doses, the projected steady state plasma concentration-time profiles indicate a relatively greater age-related differential. For example, assuming once daily administration of 5 mg amlodipine, the predicted concentrations at peak and trough are respectively 9.1k4.0 and 6.7k3.2 rig/ml in these elderly subjects and this compares with corresponding mean figures of 16 and 10 rig/ml which have been found in young subjects following a daily dose which was three-fold greater at 15 mg [.5]. Reports with other calcium antagonist drugs suggest that age-related pharmacokinetic differences are not uncommon [12-141. However, as with this study, these age-related differences have not been marked and the clinical impact appears negligible. Intersubject variability is often sufficient to obscure statistical confirmation of independent age-related effects and, to date, the clinical trial data with amlodipine suggest that there are no clinically significant age-related sequelae from these kinetic differences [ 151. In conclusion the results of this single dose study indicate that amlodipine (5 mg) was well tolerated by elderly normotensive subjects. There was a gradual onset of effect with modest reductions in blood pressure between 6 and 8 hours and this was consistent with gradual attainment of peak plasma drug
Ptwmacdo~ical
Researc,h. Vol. 26. No. I. 1992
30
concentrations. The terminal elimination half life of 48 hours was greater in these elderly subjects, in comparison to published figures of about 30-40 hours for younger subjects, and this appears most likely to reflect a reduction in drug clearance. While there are no reports of any clinically significant consequences of this small age-related pharmacokinetic difference, it seems prudent to favour lower doses in the elderly.
REFERENCES I. Burges RA, Gardiner DG, Carter AJ, McKay FF. Long term natriuretic and antihypertensive activity in spontaneously hypertensive rats with developing and established hypertension. Ann NY Acad Sci 1988; 522: 5 16-8. 2. Stopher DA, Beresford AP, Macrae PV, Humphrey MJ. The metabolism and 198X: pharmacokinetics of amlodipine in humans and animals. .I Cardiol,asc, Phurmacol 12 (Suppl. 7): s55-60. 3. Burges RA, Dodd MC, Gardiner DC. Pharmacological profile of amlodipine. Am .I Cardiol
1989; 89: 23543.
4. Dodd MG, Gardiner DG, Carter AJ, Sutton MR. Burges RA. The haemodynamic properties of amlodipine in anaesthetized and conscious dogs; comparison with nitrendipine and influence of beta-adrenergic blockage. Cardin,~asc Drugs Ther 1989: 3: 545-s. 5. Faulkner JK, McGibney D, Chasseaud LF, Perry JL, Taylor IW. The pharmacokinetica ot amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily. Br J C/in Pharmacvl 1986; 22: 2 I-S. 6. Williams DM, Cubeddu L. Amlodipine pharmacokinetics in healthy volunteers. .I C/i/r Pharmacol
1988; 28: 990-4.
7. Greenblatt DJ. Divoll M, Abernethy DR, Harmatz JS, Shader RI. Antipyrine kinetic.4 in the elderly: prediction of age-related changes in bensodiazepinc oxidizing capacity. .I Pharmacol Esp Ther 1982; 220: 120-6. 8. Beresford AP, Macrae PV, Stopher DA, Wood BA. Analysis of amlodipine in human plasma by gas chromatography. .I Chromatogr Biomed App 1987: 420: 178-X3. 9. Elliott HL. Meredith PA, Reid JL, Faulkner JK. A comparison of the disposition of single oral doses of amlodipine in young and elderly subjects. .I C’ardio~wsc Phc1r~~7~cd 1988; 12 (Suppl. 7): S64-6. IO. Abernethy DR, Gutkowska J, Winterbottom LM. Effect5 of amlodipine, a long-acting dihydropyridine calcium antagonist in aging hypertension: pharmacodynamic\ in relation to disposition. Clin Pharmacol Ther 1990; 48: 76-86. I I. Kleinbloesem CH, van Brummelen P, Danhof M, Faber H. Urquhart J. Breimer DD. Rate of increase in the plasma concentration of nifedipine as a major determinant of it\ hemodynamic effects in humans. Clin Phurmacol Thur 1987; 41: 26-N. 12. Abernethy DR. Schwartz JB, Todd EL, Luchi R, Snow E. Verapamil pharmacodynamlc\ and disposition in young and elderly hypertensive patients. AIIII lnt Med. 19X6: 5: 329-36. 13. Robertson DRC, Waller DG, Renwick AG, George CF. Age-related changes in the pharmacokinetics and pharmacodynamics of nifedipine. Br .I Clirr Plrarmawl 198X: 25: 297-30s. 14. Ahmed JH, Meredith PA. Elliott HL. The influence of age on the pharmacokinetlc\ ot verapamil. Pharmacol Ras 199 I ; 24: 227-33. IS. Osterloh H. The safety of amlodipine. Am Heart .I 1989; 118: I I l&20.
Research.
3.3
Vol. 26, No. I, 1992
AN ASSESSMENT OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OF SINGLE DOSES OF AMLODIPINE IN ELDERLY NORMOTENSIVES H. L. ELLIOTT, S. T. GREEN, J. VINCENT and P. A. MEREDITH University Department of Medicine and Therapeutics, Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, G lasgoHp,G l I 6NT, UK Received
in final form 3 January
1992
SUMMARY
This study characterizes the single dose pharmacokinetic characteristics of the dihydropyridine calcium antagonist drug amlodipine in a group of 16 elderly subjects, aged 65 to 86 years (8 M:8 F). The most notable pharmacokinetic features were a prolonged terminal elimination half life of 48+16 hours and a delayed t,,, of 7.3k1.3 hours. Consistent with the time to achieve peak plasma drug concentrations, there was a modest but significant reduction in blood pressure at 6-8 hours after dosing. Comparison of these results with those of published data for young subjects indicate not only a greater degree of intersubject variability but also a longer half life in the elderly, suggestive of reduced drug clearance, which may lead to higher plasma drug concentrations particularly at steady state. KEY WORDS: amlodipine, elderly, pharmacokinetics,
INTRODUCTION
Amlodipine is a dihydropyridine type of calcium antagonist drug which has been recently marketed for the treatment of hypertension and angina pectoris. Studies in animals have shown that the pharmacological effects of amlodipine are of gradual onset and of prolonged duration and occur in association with a prolonged terminal elimination half life of up to 30 hours [l-4]. Preliminary studies in man have identified a similar pharmacokinetic profile following oral and intravenous administration with elimination half lives of more than 30 hours in young normotensive human volunteers [5,6]. This profile of pharmacokinetics and pharmacodynamics is not shared by any other available dihydropyridine drug. The proportion of the patient population aged over 65 years is increasing in both relative and absolute terms in developed Western countries and so it follows that a sizable number of potential amlodipine recipients will fall into the ‘elderly’ Correspondenceto: Dr H. L. Elliott. 1013-66 18/92/050033-07/$0.1.00/0
0 1992 The Italian Pharmacological Society
34
Pharmacological
Research,
Vol. 26, No. I, 1992
category. Since the pathophysiological changes associated with increasing age may significantly alter the absorption, distribution and clearance of drugs [7] it is important to specifically investigate the clinical pharmacological characteristics of any newly developed drug in such an older population. The principal aim of this study was to characterize the pharmacokinetics of amlodipine in a group of elderly subjects and to make a preliminary assessmentof its subjective acceptability.
METHODS
Sixteen healthy normotensive elderly volunteers who were living independently in the community took part in this study. There were eight males and eight females aged 73f5 years (range 65-86 years) and weighing 63f9 kg (range 50-82 kg). Each subject was considered healthy and free of clinically significant disease on the basis ,of detailed physical, biochemical and haematological indices and electrocardiography. All subjects were free of medication for at least 2 weeks prior to entering the study. The protocol was approved by the Research and Ethics Committee of the Northern District of the Greater G lasgow Health Board and each subject gave informed written consent for his/her participation. Subjects reported to the Clinical Pharmacology Research Unit (CPRU) having avoided food, alcohol and all caffeine-containing drinks from 22.00 on the previous evening. Subjects were allowed standardized light meals at 5 and 9 hours after drug dosing. In a randomized crossover manner each subject received amlodipine 5 mg and a matching placebo on two study days at least 2 weeks apart. Subjects remained under full medical supervision in the CPRU for a minimum of 12 hours after dosing and blood was withdrawn from a indwelling intravenous cannula at 0, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120 and 168 hours following drug administration. At times corresponding to blood sampling, blood pressure and heart rate were measured in duplicate by a semiautomated sphygmomanometer (Sentron Bard Medical) after resting supine for at least 10 minutes and after standing for up to 5 minutes. Pharmacokinetic analysis Plasma concentrations of amlodipine were analysed by gas chromatography with electron capture detection using the method described in detail by Beresford et al. [8]. The disposition characteristics of amlodipine were analysed by model dependent means using non-linear least squares fitting of a hierarchy of models to the drug concentration time data. In all subjects a two compartment model, with first order input accounting for absorption, was most appropriately fitted to the data and it was not necessary to include a time lag associated with absorption. The following parameters were derived: the achieved peak concentration (C,,,), the time to peak concentration (T,,,), the elimination half life (Ketli2) and the area under the plasma concentration-time curve to infinity (AUC). The apparent oral clearance (clearance divided by bioavailability, F) was calculated as dose divided by AUC, while the apparent volume of distribution (Vd/F) was calculated from the
Pharmacdo,~ical
Research,
Vol. 26, No. I. 1992
3s
apparent oral clearance divided by the elimination rate constant, K,. The analysis was extended to predict the plasma drug concentrations at steady state by simulations based upon the fitted kinetic parameters and the two compartment model for acute dosing. These predictions were based on the assumption that the drug obeys linear kinetics and that there were no changes in the apparent oral clearance in translation from acute to steady state therapy. Both these assumptions can be justified based on previous experience with this agent in normotensive and hypertensive patients [3, 5, 61. O ther measurements Eight hours after drug administration on each study day a 12-lead ECG was performed in all subjects and at 120 hours after dosing biochemical and haematological tests and urinalysis were re-assessed in each subject. Creatinine clearance was estimated in individual subjects using average serum creatinine values from the above blood samples. Statistics Results throughout are expressed as mean&so. The statistical evaluation of the blood pressure and heart rate profiles was on the basis of repeated measures analysis of variance. The pharmacokinetic parameters were compared by analysis of variance with Bonferroni corrections where appropriate. RESULTS General subjective tolerance Overall, amlodipine 5 mg was well tolerated by all subjects and, apart from minor complaints of mild headacheor tiredness which were comparable with those of the placebo day, no significant adverse events were volunteered. There were no significant alterations in the electrocardiographic, biochemical, haematological or renal indices in any of the individuals. Blood pressure and heart rate In the 12 hours following administration of amlodipine there were small but statistically significant reductions in both supine and erect blood pressure. Generally, as illustrated in Fig. 1 for erect systolic blood pressure, the maximal effects on blood pressure were observed between 6 and 8 hours post-dosing (PcO.01 1’splacebo). There were no corresponding, significant changes in supine or erect heart rate over the 12 hours. Beyond 12 hours, both blood pressure and heart rate were comparable for amlodipine and placebo. Pharmacokinetics The derived pharmacokinetic parameters are shown in Table I and the concentration-time profile is shown in Fig. 2. A summary of the results from this analysis has been published previously [9]. Volume of distribution (Vd/F) and
Pharmacological
36
Research, Vol. 26, No. I,1992
80 75 70 65 60 0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
IO
12
Time (h)
Fig. 1. Meanerectsystolic bloodpressureanderectheartrate following the administrationof amlodipineandplacebo.
apparent oral clearance (clearance/F) were weight corrected. The standarized, derived kinetic parameters were comparable between the sexes and no major differences were observed between men and women although the peak concentration (C,,,) was significantly higher in women than in men (4.0f 1.3 rig/ml compared to 2.3kO.2 rig/ml; PcO.01) and volume of distribution tended to be smaller. There was considerable intersubject variability both in the apparent oral clearance which ranged from 0.21 to 1.50 l/h/kg and in the terminal elimination half life, which ranged from 30 to 81 hours. Pharmacokinetic predictions From the individually derived parameters following the single dose administration of amlodipine a profile of steady state dosing was constructed for individual subjects and the mean of these profiles is shown in Fig. 2. DISCUSSION In this study of amlodipine in elderly subjects the single dose pharmacokinetic results were broadly comparable to those published for younger subjects [5, 61 but there was a small and significant prolongation of terminal elimination half life and a tendency for apparent oral clearance to decline [9]. Additionally, in common with many other drugs, whether their elimination is dependent upon hepatic mechanisms or renal mechanisms, there was a greater degree of intersubject variability in the disposition characteristics in these elderly subjects. In the
Pharmadogic~al
Research,
Vol. 26, No. 1. 1992
37
Table I Derived pbarmacokinetic parameters sex
A&Y (Y)
Weight AUC (kg) (ng.h/ml)
C max W/ml)
VdIF (l/k< )
5.6 9.3 9.5 5.8 7.8 6.9 6.5 7.8
2.5 2.4 2.3 1.8 2.4 2.5 2.3 2.3
29.1 35 ._5 -_ 29.6 42.7 38. I 54.5 32.7 35.9
51f15
7.4L1.5
2.3kO.2
30 34 34 45 42 54 81 30
9.2 7.8 7.6 6.3 6.8 8.1 6.1 6.2
4.6 3.5 4.9 5.2 4.3 3.1 4.9 1.3
Cl/F (l/h/kg)
KeTw (h)
0.31 0.27 0.56 1.11 0.50 0.71 0.55 0.36
66 64 37 27 53 53 41 69
0.55f0.27 0.39 0.45 0.30 0.40 0.45 0.32 0.21 1.50
cnax (h)
74 72 67 78 72 75 66 85
76 82 63 65 59 60 60 64
216 222 143 70 169 117 151 218
fvtean+so 74f6
66k8
163f54
68 67 65 72 65 68 84 75
57 59 64 50 66 68 57 60
227 187 264 252 168 231 409 54
Mean&so 7 1+6
6Ok6
224flOO
0.50f0.41
44f17
7.321.1
4.0fl.3
27.8kl6.1
63+8
194f84
0.52kO.34
48f16
7.3f1.3
3.1k1.2
31.9k13.4
Overall
72f6
36.0fO.i 16.6 22.4 14.4 25.5 27.3 24.9 25.1 65.9
mean&so
absence of data from intravenous administra.tion, it is not possible to establish by this study whether these changes in apparent clearance reflect an increase in oral bioavailability or a reduction in the rate of hepatic metabolism. However, the results of a recent similar study, involving intravenous administration, have shown that the clearance of amlodipine was 24% lower in elderly subjects [lo]. In the absence of data from an intravenous formulation it is also difficult to make positive assertions in relation to the apparent sex differences observed in this study. However, based on inferential evidence it is reasonable to speculate that with a drug with a relatively large volume of distribution the differences observed between the sexes in terms of C,,, may be attributed to a difference in volume of distribution (which in itself did not attain a statistical difference) which is associated with the relative differences in weight between the sexes. This contention is supported by close correspondence in the weight-corrected oral clearances between the groups and an associated good agreement in the elimination half lives. The single doses of amlodipine administered in this study produced small but statistically significant reductions in both supine and erect blood pressures. These findings are directly comparable to those obtained with other calcium antagonist drugs which generally show only modest blood pressure lowering activity in
Pharmacological Research, Vol. 26, No. I. I992
38
=,E 8s : 6..a n 0 ,E
4-
OL Time(h)
Fig. 2. Mean plasma drug concentration-time profiles from all subjects: (a) following a single n , (b) predicted for steady state following 5 mg amlodipine dose of 5 mg amlodipine n A (95% confidence intervals are shown). daily A-
normotensive subjects. In this study the modest hypotensive effect of amlodipine was not accompanied by any statistically significant alteration in heart rate. While this may reflect the relatively impaired efficiency of the cardiovascular homeostatic mechanisms in the elderly compared to the young, it may also be related to the rate of onset of the vasodilator effect, as has been reported for nifedipine [I 11, whereby the gradual onset of the vasodilatation produced by amlodipine causes relatively little baroreflex-mediated cardioacceleration. Although the potential age-related pharmacokinetic differences are relatively modest at single doses, the projected steady state plasma concentration-time profiles indicate a relatively greater age-related differential. For example, assuming once daily administration of 5 mg amlodipine, the predicted concentrations at peak and trough are respectively 9.1k4.0 and 6.7k3.2 rig/ml in these elderly subjects and this compares with corresponding mean figures of 16 and 10 rig/ml which have been found in young subjects following a daily dose which was three-fold greater at 15 mg [.5]. Reports with other calcium antagonist drugs suggest that age-related pharmacokinetic differences are not uncommon [12-141. However, as with this study, these age-related differences have not been marked and the clinical impact appears negligible. Intersubject variability is often sufficient to obscure statistical confirmation of independent age-related effects and, to date, the clinical trial data with amlodipine suggest that there are no clinically significant age-related sequelae from these kinetic differences [ 151. In conclusion the results of this single dose study indicate that amlodipine (5 mg) was well tolerated by elderly normotensive subjects. There was a gradual onset of effect with modest reductions in blood pressure between 6 and 8 hours and this was consistent with gradual attainment of peak plasma drug
Ptwmacdo~ical
Researc,h. Vol. 26. No. I. 1992
30
concentrations. The terminal elimination half life of 48 hours was greater in these elderly subjects, in comparison to published figures of about 30-40 hours for younger subjects, and this appears most likely to reflect a reduction in drug clearance. While there are no reports of any clinically significant consequences of this small age-related pharmacokinetic difference, it seems prudent to favour lower doses in the elderly.
REFERENCES I. Burges RA, Gardiner DG, Carter AJ, McKay FF. Long term natriuretic and antihypertensive activity in spontaneously hypertensive rats with developing and established hypertension. Ann NY Acad Sci 1988; 522: 5 16-8. 2. Stopher DA, Beresford AP, Macrae PV, Humphrey MJ. The metabolism and 198X: pharmacokinetics of amlodipine in humans and animals. .I Cardiol,asc, Phurmacol 12 (Suppl. 7): s55-60. 3. Burges RA, Dodd MC, Gardiner DC. Pharmacological profile of amlodipine. Am .I Cardiol
1989; 89: 23543.
4. Dodd MG, Gardiner DG, Carter AJ, Sutton MR. Burges RA. The haemodynamic properties of amlodipine in anaesthetized and conscious dogs; comparison with nitrendipine and influence of beta-adrenergic blockage. Cardin,~asc Drugs Ther 1989: 3: 545-s. 5. Faulkner JK, McGibney D, Chasseaud LF, Perry JL, Taylor IW. The pharmacokinetica ot amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily. Br J C/in Pharmacvl 1986; 22: 2 I-S. 6. Williams DM, Cubeddu L. Amlodipine pharmacokinetics in healthy volunteers. .I C/i/r Pharmacol
1988; 28: 990-4.
7. Greenblatt DJ. Divoll M, Abernethy DR, Harmatz JS, Shader RI. Antipyrine kinetic.4 in the elderly: prediction of age-related changes in bensodiazepinc oxidizing capacity. .I Pharmacol Esp Ther 1982; 220: 120-6. 8. Beresford AP, Macrae PV, Stopher DA, Wood BA. Analysis of amlodipine in human plasma by gas chromatography. .I Chromatogr Biomed App 1987: 420: 178-X3. 9. Elliott HL. Meredith PA, Reid JL, Faulkner JK. A comparison of the disposition of single oral doses of amlodipine in young and elderly subjects. .I C’ardio~wsc Phc1r~~7~cd 1988; 12 (Suppl. 7): S64-6. IO. Abernethy DR, Gutkowska J, Winterbottom LM. Effect5 of amlodipine, a long-acting dihydropyridine calcium antagonist in aging hypertension: pharmacodynamic\ in relation to disposition. Clin Pharmacol Ther 1990; 48: 76-86. I I. Kleinbloesem CH, van Brummelen P, Danhof M, Faber H. Urquhart J. Breimer DD. Rate of increase in the plasma concentration of nifedipine as a major determinant of it\ hemodynamic effects in humans. Clin Phurmacol Thur 1987; 41: 26-N. 12. Abernethy DR. Schwartz JB, Todd EL, Luchi R, Snow E. Verapamil pharmacodynamlc\ and disposition in young and elderly hypertensive patients. AIIII lnt Med. 19X6: 5: 329-36. 13. Robertson DRC, Waller DG, Renwick AG, George CF. Age-related changes in the pharmacokinetics and pharmacodynamics of nifedipine. Br .I Clirr Plrarmawl 198X: 25: 297-30s. 14. Ahmed JH, Meredith PA. Elliott HL. The influence of age on the pharmacokinetlc\ ot verapamil. Pharmacol Ras 199 I ; 24: 227-33. IS. Osterloh H. The safety of amlodipine. Am Heart .I 1989; 118: I I l&20.