J Korean Soc Clin Pharmacol Ther.  2012 Jun;20(1):42-50.

Comparison of Pharmacokinetic Characteristics and the Safety between Amlodipine Maleate Tablet 5 mg and Amlodipine Besylate Tablet 5 mg

• Choi HY
• Kim JW
• Lim HS
• Cho SH
• Ghim JL
• Choe S
• Jung JA
• Lim J
• Bae KS

Abstract

BACKGROUND
Amlodipine is a third-generation dihydropyridine calcium channel blocker for treating hypertension. Though marketed primarily as a besylate salt, there have been some efforts to find other comparable salts. Among them, maleate is the salt that has been considered favorable for many drugs. The aim of this study was to compare the pharmacokinetics, as well as safety and tolerability of amlodipine maleate with amlodipine besylate.
METHODS
This study was open, randomized, two-period crossover design investigated in twelve healthy male volunteers over a 144 h period after administrating two forms of amlodipine 5 mg, respectively. Each period was separated with 2 weeks. Plasma concentrations of amlodipine were determined by liquid chromatography-tandem mass spectrometry. Safety profiles were assessed by vital signs, physical examinations, electrocardiograms, laboratory testing and adverse events monitoring.
RESULTS
All subjects were completed this study. Geometric mean ratios (GMRs) of amlodipine maleate/amlodipine besylate of Cmax and AUClast for amlodipine were 0.92 (90 % confidence interval, 0.81 ~ 1.05) and 1.05 (0.96 ~ 1.16), respectively. No serious adverse events were reported, and no clinically relevant changes were observed in safety profiles during this trial.
CONCLUSION
Pharmacokinetics, tolerability and the safety were comparable between amlodipine maleate and amlodipine besylate in healthy individuals.

Keyword

Amlodipine maleate; Amlodipine besylate; Pharmacokinetics

MeSH Terms

Amlodipine
Calcium Channels
Cross-Over Studies
Dihydropyridines
Electrocardiography
gamma-Aminobutyric Acid
Humans
Hypertension
Male
Maleates
Mass Spectrometry
Physical Examination
Plasma
Salts
Vital Signs
Amlodipine
Calcium Channels
Dihydropyridines
Maleates
Salts
gamma-Aminobutyric Acid

Figure

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  Figure 1 Mean plasma amlodipine concentration-time curves.

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  Figure 2 Systolic blood pressure (upper), diastolic blood pressure (middle), pulse rate (low). Data are presented as mean ± SD.

Reference

1. Benetos A, Consoli S, Safavian A, Dubanchet A, Safar M. Efficacy, safety, and effects on quality of life of bisoprolol/hydrochlorothiazide versus amlodipine in elderly patients with systolic hypertension. Am Heart J. 2000. 140(4):E11.

2. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005. 365(9455):217–223.

3. Franco OH, Peeters A, Bonneux L, de Laet C. Blood pressure in adulthood and life expectancy with cardiovascular disease in men and women: life course analysis. Hypertension. 2005. 46(2):280–286.

4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003. 289(19):2560–2572.

5. Mason RP, Marche P, Hintze TH. Novel vascular biology of third-generation L-type calcium channel antagonists: ancillary actions of amlodipine. Arterioscler Thromb Vasc Biol. 2003. 23(12):2155–2163.

6. Beresford AP, McGibney D, Humphrey MJ, Macrae PV, Stopher DA. Metabolism and kinetics of amlodipine in man. Xenobiotica. 1988. 18(2):245–254.

7. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, Wester PO, Hedner T, de Faire U. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999. 354(9192):1751–1756.

8. Burges R, Moisey D. Unique pharmacologic properties of amlodipine. Am J Cardiol. 1994. 73(3):2A–9A.

9. van Zwieten PA. Amlodipine: an overview of its pharmacodynamic and pharmacokinetic properties. Clin Cardiol. 1994. 17:9 Suppl 3. III3–III6.

10. Park JY, Kim KA, Lee GS, Park PW, Kim SL, Lee YS, Lee YW, Shin EK. Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects. Clin Ther. 2004. 26(5):715–723.

11. New amlodipine (Amloc) product available in South Africa. Cardiovasc J S Afr. 2005. 16(1):61.

12. Lee HY, Kang HJ, Koo BK, Oh BH, Heung-Sun K, Kim KS, Seo HS, RO YM, Kang JH, Woong CJ, Joo SJ, Kim MH, Joon-Han S, Yoon J, Park SH, Jin-Ok J, Ju AK, Chong-Yun R, Yeon KJ, Park KM, Lim DK, Park SY. Clinic blood pressure responses to two amlodipine salt formulations, adipate and besylate, in adult Korean patients with mild to moderate hypertension: a multicenter, randomized, double-blind, parallel-group, 8-week comparison. Clin Ther. 2005. 27(6):728–739.

13. Park S, Chung N, Kwon J, Yoon JH, Kim YJ, Han DS, Kim HS. Results of a multicenter, 8-week, parallel-group, randomized,double-blind, double-dummy, Phase III clinical trial to evaluate the efficacy and tolerability of amlodipine maleate versus amlodipine besylate in Korean patients with mild to moderate hypertension. Clin Ther. 2005. 27(4):441–450.

14. Carvalho M, Oliveira CH, Mendes GD, Sucupira M, Moraes ME, De Nucci G. Amlodipine bioequivalence study: quantification by liquid chromatography coupled to tandem mass spectrometry. Biopharm Drug Dispos. 2001. 22(9):383–390.

15. Hong SJ, Ahn TH, Baek SH, Cho WH, Jeon HK, Kwan J, Yoon MH, Lee KJ, Lim DS. Comparison of efficacy and tolerability of amlodipine orotate versus amlodipine besylate in adult patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 8-week follow-up, noninferiority trial. Clin Ther. 2006. 28(4):537–551.

16. Kes S, Caglar N, Canberk A, Deger N, Demirtas M, Dortlemez H, Kiliccioglu B, Kozan O, Ovunc K, Turkoglu C. Treatment of mild-to-moderate hypertension with calcium channel blockers: a multicentre comparison of once-daily nifedipine GITS with once-daily amlodipine. Curr Med Res Opin. 2003. 19(3):226–237.

17. Meredith PA. Potential concerns about generic substitution: bioequivalence versus therapeutic equivalence of different amlodipine salt forms. Curr Med Res Opin. 2009. 25(9):2179–2189.

18. Mignini F, Tomassoni D, Traini E, Amenta F. Single-dose, randomized, crossover bioequivalence study of amlodipine maleate versus amlodipine besylate in healthy volunteers. Clin Exp Hypertens. 2007. 29(8):539–552.

19. Jeon JY, Kim JR, Chung JY, Oh DS, Cho JY, Yu KS, Jang IJ, Shin SG. Pharmacokinetic and pharmacodynamic comparative study of amlodipine adipate and amlodipine besylate. J Korean Soc Clin Pharmacol Ther. 2006. 14(2):106–115.