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Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers.

ABSTRACT: This study compared the pharmacokinetic (PK) and safety profiles of a fixed-dose combination (FDC) formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs.This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S-amlodipine and were also coadministered the same dose of both drugs given separately. The crossover study design included a 14-day washout period between the two treatments. Blood samples were collected up to 168 h following drug administration. The plasma concentrations of telmisartan and S-amlodipine were determined by liquid chromatography tandem mass spectrometry. PK parameters and plasma concentration-time curves were compared. Safety was assessed by measuring vital signs, clinical laboratory tests, physical examinations, and patient interviews.The geometric mean ratios and 90% CIs for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 0.8782 (0.8167-0.9444) and 0.9662 (0.9210-1.0136) for telmisartan and 1.0069 (0.9723-1.0427) and 1.0324 (0.9969-1.0690) for S-amlodipine, respectively. A total of 36 adverse events (AEs) were reported by 23 subjects, but no statistical differences were observed between the two treatments. The most frequently reported AE was a mild-to-moderate headache that was generally self-limiting.For both telmisartan and S-amlodipine, the Cmax and AUCt 90% CIs were between ln (0.8) and ln (1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile to the coadministration of these drugs.

SUBMITTER: Oh M

PROVIDER: S-EPMC5729885 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers.

Oh Minkyung M Park Sung-Eun SE Ghim Jong-Lyul JL Choi Young-Kyung YK Shim Eon-Jeong EJ Shin Jae-Gook JG Kim Eun-Young EY

Drug design, development and therapy 20171211

<h4>Objective</h4>This study compared the pharmacokinetic (PK) and safety profiles of a fixed-dose combination (FDC) formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs.<h4>Materials and methods</h4>This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S-amlodipine and were also coadministered the same dose of both drugs given separately. The ...[more]

PMID: 29270003

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Project description:Background:A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both hypertension and dyslipidemia. The comparative pharmacokinetic study was performed to compare the profile of an FDC tablet formulation of amlodipine/losartan/rosuvastatin with that of concomitant administration of a currently marketed FDC tablet of amlodipine/losartan with a rosuvastatin tablet. Subjects and Methods:A randomized, open-label, single oral dose, two-way crossover study was conducted in 60 healthy subjects. Subjects were orally administered the FDC tablet of amlodipine/losartan/rosuvastatin and a loose combination (LC) of two tablets comprising an FDC of amlodipine/losartan and rosuvastatin. Blood samples were collected for up to 144 h post dose for pharmacokinetic evaluations. Plasma concentrations of amlodipine, losartan, EXP3174 (an active metabolite of losartan), and rosuvastatin were measured by using liquid chromatography-tandem mass spectrometry. The geometric mean ratio (GMR) and its 90% confidence interval (90% CI) in the FDC treatment to LC treatment for the area under the concentration-time curve from zero to the last quantifiable time point (AUClast) and the maximum plasma concentration (Cmax) were calculated. Safety was monitored throughout the study. Results:The GMR (90% CI) values of AUClast and Cmax were 0.9946 (0.9663-1.0238) and 0.9690 (0.9379-1.0011) for amlodipine, 0.9855 (0.9422-1.0308) and 0.9178 (0.8349-1.0089) for losartan, 0.9814 (0.9501-1.0136) and 0.9756 (0.9313-1.0219) for EXP3174, and 0.9448 (0.8995-0.9923) and 0.9609 (0.8799-1.0494) for rosuvastatin, respectively. No clinically significant changes were observed in any of the safety parameters, including clinical laboratory tests, vital signs, electrocardiograms, and physical examinations, between the FDC treatment and the LC treatment. Conclusion:We confirmed the pharmacokinetic equivalence of the FDC and LC treatments. This triple combination FDC formulation could be a clinically useful replacement for LC therapy.

Project description:A 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.The 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.Forty-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.CKD-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.

Project description:Objective:The aim of this study was to compare the pharmacokinetics (PK) and safety profiles of a fixed-dose combination (FDC) formulation of fimasartan, amlodipine, and rosuvastatin with the co-administration of the two products by using a replicated crossover study design in healthy male subjects. Results:This was an open-label, randomized, three-sequence, three-period replicated crossover study in healthy male subjects. The replicated crossover design was done because of high coefficient of variation of PK parameter for fimasartan, that is, >30%. With a 14 days washout period, an FDC tablet containing 60 mg fimasartan, 10 mg amlodipine, and 20 mg rosuvastatin was administered only once, and separate formulations of fimasartan/amlodipine 60 mg/10 mg FDC tablet and 20 mg rosuvastatin tablet administered twice. Blood samples were collected up to 72 hours following drug administration. The plasma concentrations of fimasartan, amlodipine, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was assessed by evaluating vital signs, clinical laboratory parameters, physical examinations, and medical interviews. Results:The geometric mean ratios and 90% confidence intervals (CIs) for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last measurable sampling time (AUCt) were 1.0776 (0.9201-1.2622) and 0.9978 (0.9538-1.0439) for fimasartan, 1.0038 (0.9782-1.0301) and 1.0055 (0.9828-1.0288) for amlodipine, and 1.0006 (0.9290-1.0776) and 0.9986 (0.9532-1.0461) for rosuvastatin, respectively. A total of 22 adverse events (AEs) were reported by 60 subjects; there were no significant differences in the incidence of AEs between the two groups. Conclusion:The 90% CI of the Cmax of fimasartan was within the widened acceptance limit, ln(0.6984)-ln(1.4319). The 90% CIs of the other PK parameters for drugs were between ln(0.8) and ln(1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile, to the co-administration of its three constituent drugs.

Project description:HCP1004 is a newly developed fixed-dose combination of naproxen (500 mg) and esomeprazole strontium (20 mg) that is used in the treatment of rheumatic diseases and can reduce the risk of nonsteroidal anti-inflammatory drug-associated ulcers. The aim of this study was to evaluate the pharmacokinetics (PK) and safety of HCP1004 compared to VIMOVO(®) (a marketed fixed-dose combination of naproxen and esomeprazole magnesium).An open-label, randomized, two-treatment, two-sequence crossover, single-dose clinical study was conducted in 70 healthy volunteers. In each period, a reference (VIMOVO(®)) or test (HCP1004) drug was administered orally, and serial blood samples for PK analysis were collected up to 72 hours after dosing. To evaluate the PK profiles, the maximum plasma concentration (Cmax) and the area under the concentration-time curve from 0 to the last measurable time (AUC0-t) were estimated using a noncompartmental method. Safety profiles were evaluated throughout the study.Sixty-six of the 70 subjects completed the study. The Cmax (mean ± standard deviation) and AUC0-t (mean ± standard deviation) for naproxen in HCP1004 were 61.67 ± 15.16 µg/mL and 1,206.52 ± 166.46 h · µg/mL, respectively; in VIMOVO(®); these values were 61.85 ± 14.54 µg/mL and 1,211.44 ± 170.01 h · µg/mL, respectively. The Cmax and AUC0-t for esomeprazole in HCP1004 were 658.21 ± 510.91 ng/mL and 1,109.11 ± 1,111.59 h · ng/mL, respectively; for VIMOVO(®), these values were 595.09 ± 364.23 ng/mL and 1,015.12 ± 952.98 h · ng/mL, respectively. The geometric mean ratios and 90% confidence intervals (CIs) (HCP1004 to VIMOVO(®)) of the Cmax and AUC0-t of naproxen were 0.99 (0.94-1.06) and 1.00 (0.98-1.01), respectively. For esomeprazole, the geometric mean ratios (90% CI) for the Cmax and AUC0-t were 0.99 (0.82-1.18) and 1.04 (0.91-1.18), respectively. The overall results of the safety assessment showed no clinically significant issues for either treatment.The PK of HCP1004 500/20 mg was comparable to that of VIMOVO(®) 500/20 mg for both naproxen and esomeprazole after a single oral dose. Both drugs were well-tolerated without any safety issues.

Dataset Information

Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers.

Publications

Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers.

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