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Efficacy and safety profiles of a new S(-)-amlodipine nicotinate formulation versus racemic amlodipine besylate in adult Korean patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group, phase III, noninferiority clinical trial

Authors
 Sung Ai Kim  ;  Sungha Park  ;  Namsik Chung  ;  Do-Sun Lim  ;  Joo-Young Yang  ;  Byung-Hee Oh  ;  Seung-Jea Tahk  ;  Tae-Hoon Ahn 
Citation
 CLINICAL THERAPEUTICS, Vol.30(5) : 845-857, 2008 
Journal Title
CLINICAL THERAPEUTICS
ISSN
 0149-2918 
Issue Date
2008
MeSH
Adult ; Aged ; Amlodipine/adverse effects ; Amlodipine/chemistry ; Amlodipine/therapeutic use* ; Asian Continental Ancestry Group ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Niacin/adverse effects ; Niacin/chemistry ; Niacin/therapeutic use ; Stereoisomerism
Keywords
amlodipine ; hypertension ; nicotinate ; racemic
Abstract
BACKGROUND: "Chiral switching" from an existing racemate to a pure enantiomeric compound is a popular theme in drug development, especially when the enantiomer is found to have better efficacy and safety profiles. Amlodipine is a racemic mixture, composed of the S(-)-enantiomer, which is the pharmacologically active isomer, and the R(+)-enantiomer, which is 1000-fold less active. S(-)-amlodipine nicotinate, a chirally switched form of amlodipine nicotinate, has been developed and found to be bioequivalent to amlodipine besylate in Phase I clinical trials in Korea.

OBJECTIVE: The aim of this study was to compare the efficacy and safety profiles of S(-)-amlodipine nicotinate with those of amlodipine besylate in adult Korean patients with mild to moderate hypertension (diastolic blood pressure [DBP] >or=90 mm Hg and
METHODS: This was an 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group, Phase III, noninferiority clinical trial. After an initial 2-week placebo run-in period, patients aged 18 to 75 years with sitting DBP (SiDBP) >or=90 and or=90 mm Hg). The primary end point was noninferiority of the difference in mean SiDBP from baseline to week 8 for S(-)-amlodipine nicotinate compared with amlodipine besylate. Secondary end points were as follows: (1) noninferiority of the difference in mean sitting systolic blood pressure (SiSBP) from baseline to week 8 between the study groups; and (2) SiDBP response rate (defined as the proportion of patients whose SiDBP was <90 mm Hg or whose SiDBP reduction was >or=10 mm Hg from baseline) after the 8-week treatment. Also, the incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs) were reported. Severe AEs/ADRs were defined as those associated with any of the following: death; an event associated with a high risk of mortality; an event requiring hospitalization; or development of a permanent disability or congenital malformation.

RESULTS: One hundred fifty-seven patients were assessed for inclusion in the study. of these, 124 patients were randomly allocated to receive S(-)-amlodipine nicotinate (42 men, 21 women; mean [SD] age, 52.4 [10.3] years [range, 23-70 years]; weight, 67.7 [10.8] kg [range, 44-92 kg]) or amlodipine besylate (45 men, 16 women; mean [SD] age, 54.5 [10.0] years [range, 30-73]; weight, 68.9 [9.8] kg [range, 49-95 kg]). One hundred sixteen patients completed the study, but 11 patients (8.9%) were dropped from the per-protocol analysis due to violations; therefore, 105 patients were included in the modified intent-to-treat population analysis (S[-]-amlodipine nicotinate, 55 patients; amlodipine besylate, 50 patients). There were no significant between-group differences in the baseline characteristics. Baseline mean (SD) SiSBP and SiDBP were 142.6 (11.3) and 94.9 (4.8) mm Hg in the S(-)-amlodipine nicotinate group, and 141.8 (8.3) and 96.1 (4.9) mm Hg in the amlodipine besylate group. Mean (SD) changes in SiSBP were 17.6 (11.2) mm Hg in the S(-)-amlodipine nicotinate group and 18.6 (12.3) mm Hg in the amlodipine besylate group. The SiDBP response rates were 92.7% in the S(-)-amlodipine nicotinate group and 88.0% in the amlodipine besylate group. There were no significant between-group differences in the prevalence of AEs and ADRs. In the S(-)-amlodipine nicotinate group, 15 patients (23.8%) reported a total of 28 AEs, and 19 patients (31.1%) reported a total of 27 AEs in the amlodipine besylate group. Six patients (9.5%) in the S(-)-amlodipine nicotinate group and 7 patients (11.4%) in the amlodipine besylate group experienced a total of 19 ADRs (11 and 8, respectively). The most common ADRs were liver enzyme elevation (3/63 [4.8%]) in the S(-)-amlodipine nicotinate group and facial flushing (3/61 [4.9%]) in the amlodipine besylate group. No cases of severe AEs or ADRs were reported in either group.

CONCLUSIONS: The reduction of SiDBP after 8 weeks of treatment with S(-)-amlodipine nicotinate was noninferior compared with that of racemic amlodipine besylate in these adult Korean patients with mild to moderate hypertension. The SiDBP response rate and the reduction of SiSBP after 8 weeks of treatment with S(-)-amlodipine nicotinate were not significantly different from those with racemic amlodipine besylate. Both treatments were generally well tolerated.
Full Text
http://www.sciencedirect.com/science/article/pii/S0149291808001835
DOI
10.1016/j.clinthera.2008.05.013
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sung Ai(김성애)
Park, Sung Ha(박성하) ORCID logo https://orcid.org/0000-0001-5362-478X
Chung, Nam Sik(정남식)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/106868
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