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Effects of type II diabetes mellitus on the comparative pharmacokinetics and pharmacodynamics of amlodipine in hypertensive patients
AJH–April 2001–VOL. 14, NO. 4, PART 2
POSTERS: Antihypertensive Drugs
men and 500 women) with essential hypertension who received monotherapy with one of the following ACEIs. Main data are reported in the table: [table] SE of ACEIs were more often in women (p⬍0.0002) and led them to discontinue their treatment more often (p⫽0.0004). Women had also more often cough (p⫽0.0002) while attenuation of libido was reported in 12 men (1,85%). Exanthema with or without itching had 10 (0.87%) patients, gastric troubles 6 (0.52%) and edema of the lips 4 (0.35%). It is concluded that antihypertensive treatment with ACEIs often has SE which lead patients to discontinue their drugs, while cough is the most common SE mainly in women. ACEIs
n
CAPTOPRIL CILAZAPRIL ENALAPRIL FOSINOPRIL LISINOPRIL PERINDOPRIL QUINAPRIL TRANDOLAPRIL Men Women Total
110 87 304 124 191 152 125 58 650 500 1150
SE n
%
discontinuation n %
cough n %
16 13 50 10 35 27 23 10 81 103 184
14,5 14,9 16,4 8,1 18,3 17,8 18,4 17,2 12,5 20,6 16
13 10 35 9 26 20 19 7 59 80 139
10 9 44 10 28 20 15 8 61 83 144
11,8 11,5 11,5 7,3 13,6 13,2 15,2 12,1 9,1 16 12,1
9,1 10,3 14,5 8,1 14,7 13,2 12,0 13,8 9,4 16,6 12,5
Key Words: Side effects, ACE inhibitors, Antihypertensive therapy
P-258 THE REASON PROJECT: BLOOD PRESSURE EVALUATION R. Asmar, G. London, A. Be´ne´tos, J. M. Mallion, N. De Luca, J. P. Ollivier, M. O’Rourke, M. Safar. 1Hoˆpital Broussais, Paris, France The aim of the REASON (REgression of Arterial Stiffness with perindOpril/iNdapamide fixed low-dose combination) project was to compare the antihypertensive effects of a fixed low-dose combination of perindopril 2 mg/indapamide 0.625 mg (Per/Ind), versus atenolol 50 mg (ATE) in patients with essential mild-to-moderate and uncomplicated hypertension, as well as effects on arterial stiffness through tonometry and pulse wave velocity evaluation and carotid ultrasonography. The projects included also 24-h ABPM, echocardiography, 24-h ECG holter, and genotypes identification. The REASON project was a 12-month international (13 countries) multicentre, randomized, parallel groups double-blind study. Treatment was given OD over one year and dosage doubled if uncontrolled casual BP. At intermediary visits (M0, M1, M3, M6, M9, M12) BP was measured at rest in a supine position using sphygmomanometer 24-h after the last drug intake. Enrolled patients were aged between 18 and 85 years with uncomplicated essential hypertension defined as 95ⱕ DBP⬍ 110 mm Hg and 160 mm Hgⱕ SBP⬍ 210 mm Hg. Evaluation criteria were change (⌬) in SBP, DBP, PP, MBP and percentage of responders. Enrolled patients: 562; randomized : 471 ; treatment duration:11.7 ⫾ 2.0 months, age: 54.2 ⫾ 12.3 years, men: 66.7%. Preliminary results from 469 patients (ITT) are shown: Brachial BP (mm Hg) N⫽ 235 SBP
Per/Ind
ATE
N⫽ 234
[95%]
Baseline ⱖ⌬ DBP Baseline ⱖ⌬ MBP Baseline ⱖ⌬ PP Baseline ⱖ⌬ HR Baseline ⱖ⌬ Responder N (%)
163.1 ⫾ 13.4 -22.0 ⫾ 15.6 98.6 ⫾ 6.8 -12.6 ⫾ 8.9 120.1 ⫾ 6.4 -15.7 ⫾ 10.1 64.5 ⫾ 14.9 -9.4 ⫾ 12.2 72.2 ⫾ 9.7 -1.1 ⫾ 9.0 180 (77.9%)
Difference (Per/Ind-ATE) 161.4 ⫾ 14.8 -15.0 ⫾ 16.3 98.6 ⫾ 7.0 -12.0 ⫾ 9.7 119.5 ⫾ 7.0 -13.0 ⫾ 10.6 62.9 ⫾ 16.0 -3.1 ⫾ 13.2 72.4 ⫾ 9.5 -7.2 ⫾ 9.5 166 (72.8%)
mean ⴞ sd
-6.4[-9.2,-3.6] -0.6[-2.2,1.0] -2.7[-4.6,-0.9] -6.5[-9.1,-4.0] 6.1(4.4,7.8]
The 95% confidential interval shows a statistical superiority of the fixed low-dose combination of Per 2 mg/ Ind 0.625 mg treatment group
115A
on SBP, PP and MBP versus atenolol. This observation is of importance when considering the prognosis value of SBP and PP. Heart rate was significantly decrease with Atenolol but not with Per/Ind. These results confirm the efficacy of the fixed low-dose combination Per 2 mg/Ind 0.625 mg as first line therapy in Hypertension. Key Words: ACE-inhibitor, Diuretic, Pulse pressure
P-259 EFFECTS OF TYPE II DIABETES MELLITUS ON THE COMPARATIVE PHARMACOKINETICS AND PHARMACODYNAMICS OF AMLODIPINE IN HYPERTENSIVE PATIENTS Richard A. Preston, Menger Chung, Michael Gaffney, Alberto Alonso, Neyton M. Baltodano, Murray Epstein. 1Division of Clinical Pharmacology, Department of Medicine, University of Miami School of Medicine, Miami, FL, United States, 2Global Research and Development, Pfizer, Inc., New York, NY, United States Introduction: Recent clinical trials aimed at attenuating complications in diabetes mellitus have generated interest in the impact of drug formulation on altered pharmacokinetics (PK) and pharmacodynamics (PD) in diabetes. This study investigates the PK and PD of amlodipine in hypertensive subjects with and without diabetes mellitus to determine whether the diabetic state alters these parameters. Methods: Two-week placebo wash-out phase, two week titration phase, and two-week maintenance phases. Patients included 18 hypertensive patients with Type II diabetes mellitus and 10 nondiabetic hypertensive patients. Patients were admitted to the University of Miami Division of Clinical Pharmacology Research Center for 24-hour PK and PD studies. AUC, Cmax, and Tmax were analyzed for differences between hypertensive patients with and without diabetes on day 28 when all 28 subjects received amlodipine 5 mg and at day 42 for the 21 subjects who received amlodpine 10mg. The acute PD response to amlodipine was assessed by systolic and diastolic blood pressure changes and by telemetric heart rate monitoring. Results: There were no significant differences for either amlodipine 5 or 10 mg in AUC, Cmax, and Tmax between diabetic and non-diabetic hypertensive subjects. The 24-hour pharmacodynamic effects of amlodipine on systolic blood pressure, diastolic blood pressure, and telemetric heart rate did not differ between diabetic and nondiabetic subjects as assessed by repeated measures analysis of variance. Conclusion: Because of the theoretical basis for anticipating that diabetes mellitus may provoke important pharmacokinetic and pharmacodynamic alterations, our study provides an important data base in clearly demonstrating that the diabetic milieu did not alter the pharmacokinetics or pharmacodynamics of amlodipine. Whether diabetes mellitus alters the PK or PD of other dihydropyridines remains to be studied. Amlodipine 5 mg (day 28)
DM
No DM
p-value
AUC (hr*ng/ml) Cmax (ng/ml) Tmax (hr) Amlodipine 10 mg (day 42) AUC (hr*ng/ml) Cmax (ng/ml) Tmax (hr)
304.1(165.3) 16.6(9.4) 8.2(2.4)
252.5(121.2) 13.7(7.5) 8.6(5.0)
.40 .41 .79
584.0(244.6) 31.6(13.2) 7.2(2.0)
525.4(234.0) 27.2(11.8) 7.8(4.4)
.59 .45 .67
Grant/Research Support: Pfizer, Inc.
Key Words: Pharmacokinetics, Hypertension in diabetes mellitus, Amlodipine
POSTERS: Antihypertensive Drugs
men and 500 women) with essential hypertension who received monotherapy with one of the following ACEIs. Main data are reported in the table: [table] SE of ACEIs were more often in women (p⬍0.0002) and led them to discontinue their treatment more often (p⫽0.0004). Women had also more often cough (p⫽0.0002) while attenuation of libido was reported in 12 men (1,85%). Exanthema with or without itching had 10 (0.87%) patients, gastric troubles 6 (0.52%) and edema of the lips 4 (0.35%). It is concluded that antihypertensive treatment with ACEIs often has SE which lead patients to discontinue their drugs, while cough is the most common SE mainly in women. ACEIs
n
CAPTOPRIL CILAZAPRIL ENALAPRIL FOSINOPRIL LISINOPRIL PERINDOPRIL QUINAPRIL TRANDOLAPRIL Men Women Total
110 87 304 124 191 152 125 58 650 500 1150
SE n
%
discontinuation n %
cough n %
16 13 50 10 35 27 23 10 81 103 184
14,5 14,9 16,4 8,1 18,3 17,8 18,4 17,2 12,5 20,6 16
13 10 35 9 26 20 19 7 59 80 139
10 9 44 10 28 20 15 8 61 83 144
11,8 11,5 11,5 7,3 13,6 13,2 15,2 12,1 9,1 16 12,1
9,1 10,3 14,5 8,1 14,7 13,2 12,0 13,8 9,4 16,6 12,5
Key Words: Side effects, ACE inhibitors, Antihypertensive therapy
P-258 THE REASON PROJECT: BLOOD PRESSURE EVALUATION R. Asmar, G. London, A. Be´ne´tos, J. M. Mallion, N. De Luca, J. P. Ollivier, M. O’Rourke, M. Safar. 1Hoˆpital Broussais, Paris, France The aim of the REASON (REgression of Arterial Stiffness with perindOpril/iNdapamide fixed low-dose combination) project was to compare the antihypertensive effects of a fixed low-dose combination of perindopril 2 mg/indapamide 0.625 mg (Per/Ind), versus atenolol 50 mg (ATE) in patients with essential mild-to-moderate and uncomplicated hypertension, as well as effects on arterial stiffness through tonometry and pulse wave velocity evaluation and carotid ultrasonography. The projects included also 24-h ABPM, echocardiography, 24-h ECG holter, and genotypes identification. The REASON project was a 12-month international (13 countries) multicentre, randomized, parallel groups double-blind study. Treatment was given OD over one year and dosage doubled if uncontrolled casual BP. At intermediary visits (M0, M1, M3, M6, M9, M12) BP was measured at rest in a supine position using sphygmomanometer 24-h after the last drug intake. Enrolled patients were aged between 18 and 85 years with uncomplicated essential hypertension defined as 95ⱕ DBP⬍ 110 mm Hg and 160 mm Hgⱕ SBP⬍ 210 mm Hg. Evaluation criteria were change (⌬) in SBP, DBP, PP, MBP and percentage of responders. Enrolled patients: 562; randomized : 471 ; treatment duration:11.7 ⫾ 2.0 months, age: 54.2 ⫾ 12.3 years, men: 66.7%. Preliminary results from 469 patients (ITT) are shown: Brachial BP (mm Hg) N⫽ 235 SBP
Per/Ind
ATE
N⫽ 234
[95%]
Baseline ⱖ⌬ DBP Baseline ⱖ⌬ MBP Baseline ⱖ⌬ PP Baseline ⱖ⌬ HR Baseline ⱖ⌬ Responder N (%)
163.1 ⫾ 13.4 -22.0 ⫾ 15.6 98.6 ⫾ 6.8 -12.6 ⫾ 8.9 120.1 ⫾ 6.4 -15.7 ⫾ 10.1 64.5 ⫾ 14.9 -9.4 ⫾ 12.2 72.2 ⫾ 9.7 -1.1 ⫾ 9.0 180 (77.9%)
Difference (Per/Ind-ATE) 161.4 ⫾ 14.8 -15.0 ⫾ 16.3 98.6 ⫾ 7.0 -12.0 ⫾ 9.7 119.5 ⫾ 7.0 -13.0 ⫾ 10.6 62.9 ⫾ 16.0 -3.1 ⫾ 13.2 72.4 ⫾ 9.5 -7.2 ⫾ 9.5 166 (72.8%)
mean ⴞ sd
-6.4[-9.2,-3.6] -0.6[-2.2,1.0] -2.7[-4.6,-0.9] -6.5[-9.1,-4.0] 6.1(4.4,7.8]
The 95% confidential interval shows a statistical superiority of the fixed low-dose combination of Per 2 mg/ Ind 0.625 mg treatment group
115A
on SBP, PP and MBP versus atenolol. This observation is of importance when considering the prognosis value of SBP and PP. Heart rate was significantly decrease with Atenolol but not with Per/Ind. These results confirm the efficacy of the fixed low-dose combination Per 2 mg/Ind 0.625 mg as first line therapy in Hypertension. Key Words: ACE-inhibitor, Diuretic, Pulse pressure
P-259 EFFECTS OF TYPE II DIABETES MELLITUS ON THE COMPARATIVE PHARMACOKINETICS AND PHARMACODYNAMICS OF AMLODIPINE IN HYPERTENSIVE PATIENTS Richard A. Preston, Menger Chung, Michael Gaffney, Alberto Alonso, Neyton M. Baltodano, Murray Epstein. 1Division of Clinical Pharmacology, Department of Medicine, University of Miami School of Medicine, Miami, FL, United States, 2Global Research and Development, Pfizer, Inc., New York, NY, United States Introduction: Recent clinical trials aimed at attenuating complications in diabetes mellitus have generated interest in the impact of drug formulation on altered pharmacokinetics (PK) and pharmacodynamics (PD) in diabetes. This study investigates the PK and PD of amlodipine in hypertensive subjects with and without diabetes mellitus to determine whether the diabetic state alters these parameters. Methods: Two-week placebo wash-out phase, two week titration phase, and two-week maintenance phases. Patients included 18 hypertensive patients with Type II diabetes mellitus and 10 nondiabetic hypertensive patients. Patients were admitted to the University of Miami Division of Clinical Pharmacology Research Center for 24-hour PK and PD studies. AUC, Cmax, and Tmax were analyzed for differences between hypertensive patients with and without diabetes on day 28 when all 28 subjects received amlodipine 5 mg and at day 42 for the 21 subjects who received amlodpine 10mg. The acute PD response to amlodipine was assessed by systolic and diastolic blood pressure changes and by telemetric heart rate monitoring. Results: There were no significant differences for either amlodipine 5 or 10 mg in AUC, Cmax, and Tmax between diabetic and non-diabetic hypertensive subjects. The 24-hour pharmacodynamic effects of amlodipine on systolic blood pressure, diastolic blood pressure, and telemetric heart rate did not differ between diabetic and nondiabetic subjects as assessed by repeated measures analysis of variance. Conclusion: Because of the theoretical basis for anticipating that diabetes mellitus may provoke important pharmacokinetic and pharmacodynamic alterations, our study provides an important data base in clearly demonstrating that the diabetic milieu did not alter the pharmacokinetics or pharmacodynamics of amlodipine. Whether diabetes mellitus alters the PK or PD of other dihydropyridines remains to be studied. Amlodipine 5 mg (day 28)
DM
No DM
p-value
AUC (hr*ng/ml) Cmax (ng/ml) Tmax (hr) Amlodipine 10 mg (day 42) AUC (hr*ng/ml) Cmax (ng/ml) Tmax (hr)
304.1(165.3) 16.6(9.4) 8.2(2.4)
252.5(121.2) 13.7(7.5) 8.6(5.0)
.40 .41 .79
584.0(244.6) 31.6(13.2) 7.2(2.0)
525.4(234.0) 27.2(11.8) 7.8(4.4)
.59 .45 .67
Grant/Research Support: Pfizer, Inc.
Key Words: Pharmacokinetics, Hypertension in diabetes mellitus, Amlodipine