Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects

Oh, Mi Jin; Hwang, Hyun Hwan; Kim, Hyun Gyu; Lee, Geun Hyeog; Cho, Yun-Seok; Lee, Sun Young; Kang, Soo Yeon; Cho, Kyung Hee; Lee, Yun Young; Lee, Yun Jeong; Jang, Choon‐Gon; Lee, Seok‐Yong

doi:10.1016/j.clinthera.2017.05.355

Cited by 5 publications

(10 citation statements)

References 13 publications

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“…In the drug label and a previous related study by Kim et al,12 headache was the most frequently reported AE (2 cases in 2 volunteers [8.3%] in the pharmacodynamic study, and 18 cases in 11 volunteers [45.8%] in the PK study). 13 However, instead of headache and dizziness, more sinus bradycardia occurred in this study, which is similar to the study of Oh et al 14 The lowest heart rate was 52, which occurred in subject 125 24 hours after administration of the second cycle of test formulation without medical intervention, for a duration of 1.5 hours and spontaneous remission.…”

Section: Discussionsupporting

confidence: 89%

Pharmacokinetics, Bioequivalence, and Safety Studies of Amlodipine Besylate in Healthy Subjects

Chen

Chen²,

et al. 2022

Clinical Pharm in Drug Dev

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This study aimed to evaluate the bioequivalence of 2 amlodipine besylate tablet formulations, a generic formulation and an original formulation, and to investigate their pharmacokinetic and safety profiles. This study was designed as a randomized, open-label, single-dose, crossover, dual-period study and was divided into fasting and postprandial human bioequivalence trials. In the first trial after overnight fasting, 28 subjects were given 5-mg amlodipine besylate tablets via oral administration, and blood specimens were obtained up to 144 hours after dosing; another 28 subjects had a high-fat meal 1 hour before drug administration and proceeded the same as the fasting trial. Bioequivalence was evaluated using 90%CIs for the ratio test/reference of log area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration, log AUC from time 0 to infinity, and log peak concentration. The plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. The safety was assessed throughout the study. The results show that no significant differences were observed between the pharmacokinetic profiles of the test and reference amlodipine besylate tablets in the fasting and postprandial trials.The 90%CIs of the peak concentration, AUC from time 0 to the last quantifiable concentration and AUC from time 0 to infinity of amlodipine in the 2 trials were within the commonly accepted bioequivalence criteria of 80% to 125%. Compared with the pharmacokinetic parameters of the fasting and postprandial trials, food had no significant effect on exposure of amlodipine besylate. There was no significant difference in safety statistical results between the 2 groups. The results suggest that generic and original amlodipine besylate tablets are bioequivalent with similar safety profiles.

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Section: Discussionsupporting

confidence: 89%

Pharmacokinetics, Bioequivalence, and Safety Studies of Amlodipine Besylate in Healthy Subjects

Chen

Chen²,

et al. 2022

Clinical Pharm in Drug Dev

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“…Since a significant reduction in BP can be seen in 2 weeks, the first use of the 20/5 mg/day dose of olmesartan/amlodipine is recommended. If the low dose does not effectively control the BP in the normal range, consider adjusting to the 40‐mg dose 7–16 …”

Section: Discussionmentioning

confidence: 99%

“…A study comparing olmesartan with captopril and losartan found that olmesartan had a similar or better antihypertensive efficacy than other 2 drugs 7 . The time to maximum concentration (t max ) was 1 to 4 hours, and the mean half‐life at terminal phase was between 14 and 16 hours, which allows once‐daily administration 8 . It is generally well tolerated, with an adverse effect profile comparable to that of other ARBs 7 …”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have shown no pharmacokinetic (PK) interaction between olmesartan and amlodipine. In the fixed‐dose combination, olmesartan and amlodipine have synergistic antihypertensive effects, which can be used for preliminary treatment of hypertension 8,12,13 . The brand‐named preparation made by Daiichi Sankyo Europe GmbH was widely used in 30 countries around the world.…”

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetics and Bioequivalence Evaluation of 2 Olmesartan Medoxomil and Amlodipine Besylate Fixed‐Dose Combination Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions

Chen

2022

Clinical Pharm in Drug Dev

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Combined antihypertensive drugs have become the basic method of treating hypertension. Olmesartan and amlodipine, as representative drugs of angiotensin receptor blockers and calcium channel blockers, were developed as a compound formulation for antihypertensive treatment. The purpose of this study was to evaluate the bioequivalence of olmesartan medoxomil/amlodipine besylate tablet (20 mg/5 mg) under fasting and fed conditions in healthy Chinese volunteers. A phase 1 randomized, open-label, 2-period, single-dose crossover study (n = 56) was designed, with subjects under fasting (n = 28) or fed (n = 28) conditions. Of the 56 enrolled participants, 55 healthy volunteers completed the study. Blood samples for pharmacokinetic analysis were collected from 1.5 hours before dosing to 168 hours after dosing. The 90%CIs for the geometric mean ratios of maximum plasma drug concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration and AUC from time 0 to infinity of the test/reference were all within the acceptance range for bioequivalence (80%-125%). The data showed that the absorption of amlodipine is not affected by food, but the exposure of olmesartan (both AUC from time 0 to the last measurable concentration and AUC from time 0 to infinity were P < .05) reduced significantly after consuming a high-fat meal, which indicates that the effects of food on olmesartan exposure in healthy Chinese were clinically relevant. During the study, there were no suspected serious adverse reactions or serious adverse events. All adverse events were determined to be mild after Common Terminology Criteria for Adverse Events 5.0 evaluation. These results indicated that both the test and reference formulations were bioequivalent with similar safety profiles.

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“… 25 The antihypertensive effect of amlodipine through calcium-channel blocking properties is ascribed to S-amlodipine, while R-amlodipine may be responsible for the side effects of racemic amlodipine, as it has 1,000-fold lower CCB activity. 26 , 27 Accordingly, an amlodipine formulation containing only S-amlodipine is more favorable, with fewer side effects than racemic amlodipine. 27 , 28 Following oral administration, amlodipine shows different pharmacokinetic (PK) characteristics (high oral bioavailability of 60%–65%, a longer time to C max [t max ] of 6–12 hours, and a longer t 1/2 of 30–50 hours) compared to other dihydropyridine CCBs.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and bioequivalence study of a telmisartan/S-amlodipine fixed-dose combination (CKD-828) formulation and coadministered telmisartan and S-amlodipine in healthy subjects

Kang

Seong

Ohk

et al. 2018

DDDT

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PurposeA new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance.MethodsThe pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography–tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period.ResultsForty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (Cmax) and the area under the plasma concentration–time curve from time 0 to the last measurement (AUC0–t) values of telmisartan were 522.29 ng/mL and 2,475.16 ng·h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng·h/mL for the individual agents concomitantly administered, respectively. The mean Cmax and AUC0–t values of S-amlodipine were 2.71 ng/mL and 130.69 ng·h/mL for the FDC, and 2.74 ng/mL and 129.81 ng·h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan Cmax and AUC0–t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353–0.9846) and 0.9431 (0.8698–1.0226), respectively. The GMR and 90% CI for the S-amlodipine Cmax and AUC0–t (FDC/concomitant administration) were 0.9829 (0.9143–1.0567) and 0.9632 (0.8798–1.0546), respectively. As the intrasubject variability of the Cmax for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study.ConclusionCKD-828 FDC tablets were shown to be bioequivalent to coadministration of the individual agents with the respective strength, in healthy subjects under fasting conditions. There was no significant difference in safety profile between the two treatments.

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Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects

Cited by 5 publications

References 13 publications

Pharmacokinetics, Bioequivalence, and Safety Studies of Amlodipine Besylate in Healthy Subjects

Pharmacokinetics, Bioequivalence, and Safety Studies of Amlodipine Besylate in Healthy Subjects

Pharmacokinetics and Bioequivalence Evaluation of 2 Olmesartan Medoxomil and Amlodipine Besylate Fixed‐Dose Combination Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions

Pharmacokinetic and bioequivalence study of a telmisartan/S-amlodipine fixed-dose combination (CKD-828) formulation and coadministered telmisartan and S-amlodipine in healthy subjects

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