Transl Clin Pharmacol.  2019 Dec;27(4):134-140. 10.12793/tcp.2019.27.4.134.

Pharmacokinetic comparison between fixed-dose combination of fimasartan/amlodipine 60/10 mg and the corresponding loose combination through partial replicated crossover study in healthy subjects

• Yang E
• Lee S
• Lee H
• Hwang I
• Jang IJ
• Yu KS
• Lee S

• KMID: 2467967
• DOI: http://doi.org/10.12793/tcp.2019.27.4.134

Abstract

Combination therapies of antihypertensive drugs are recommended in cases where hypertension is not controlled by monotherapy. This study aimed to compare the pharmacokinetics (PKs) between fixed-dose combination (FDC) of fimasartan/amlodipine 60/10 mg and the corresponding loose combination. Because of the high intra-subject variability for maximum plasma concentration (C(max)) of fimasartan, a randomized, open-label, 3×3 partial replicated crossover design was adopted. Subjects received a single dose of FDC of fimasartan/amlodipine 60/10 mg or the corresponding loose combination in each period. Blood samples for PK analysis were collected up to 48 hours for fimasartan and 144 hours for amlodipine, respectively. Geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) of the FDC to the loose combination for C(max) and area under the concentration-time curve from time 0 to the last quantifiable time point (AUC(last)) were calculated. Sixty healthy subjects were randomized, and 57 subjects completed the study. The concentration-time profiles of fimasartan and amlodipine were similar between the FDC and loose combination. The GMRs (90% CIs) of the FDC to the loose combination for C(max) and AUC(last) were 1.0440 (0.9202-1.1844) and 1.0412 (0.9775-1.1090) for fimasartan, and 1.0430 (1.0156-1.0711) and 1.0339 (1.0055-1.0631) for amlodipine, respectively. The GMRs and its 90% CIs for C(max) and AUC(last) of fimasartan and amlodipine were included not only in the scaled bioequivalence criteria but also in the conventional bioequivalence criteria. In conclusion, FDC of fimasartan/amlodipine 60/10 mg showed comparable PK profiles with the corresponding loose combination, which suggests their bioequivalence.

Keyword

Amlodipine; Fimasartan; Fixed-dose combination; Scaled bioequivalence; Partial replicated crossover

MeSH Terms

Amlodipine
Antihypertensive Agents
Cross-Over Studies*
Healthy Volunteers*
Hypertension
Pharmacokinetics
Plasma
Therapeutic Equivalency
Amlodipine
Antihypertensive Agents

Figure

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  Figure 1 Mean plasma concentration-time profiles of (A) fimasartan and (B) amlodipine following a single administration of fixed-dose combination (FDC) of fimasartan/amlodipine 60/10 mg or the corresponding loose combination with a linear scale.

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  Figure 2 Individual comparison of (A) Cmax and (B) AUClast of fimasartan, and (C) Cmax and (D) AUClast of amlodipine following a single administration of fixed-dose combination (FDC) of fimasartan/amlodipine 60/10 mg or the corresponding loose combination.

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  Figure 3 Mean (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) following a single administration of fixed-dose combination (FDC) of fimasartan/amlodipine 60/10 mg or the corresponding loose combination.

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