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      Evaluation of the pharmacokinetic and pharmacodynamic drug interactions between cilnidipine and valsartan, in healthy volunteers

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          Although cilnidipine and valsartan are widely coadministered to patients with hypertension, their drug–drug interaction potential has not been investigated. This study compared the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of cilnidipine and valsartan, both alone and in combination, in healthy male subjects.

          Patients and methods

          Fifty-four subjects, enrolled into an open-label, single-dose, three-treatment, three-period crossover study, randomly received cilnidipine (10 mg), valsartan (160 mg), or both according to one of six sequences. Blood samples were collected at baseline and up to 24 hours after drug administration in each period. Plasma concentrations of cilnidipine and valsartan were determined by liquid chromatography with tandem mass spectrometry. Maximum plasma concentration (C max) and area under the concentration-time curve from 0 to the last measurable time (AUC last) were estimated using a noncompartmental method. Tolerability was evaluated by assessing adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory tests. Blood pressure was also measured for PD assessment.


          A total of 51 subjects completed the study. The PK profile of cilnidipine was not significantly affected by coadministered valsartan; the geometric mean ratio and 90% confidence interval (90% CI) of AUC last for cilnidipine with and without valsartan was 1.04 (0.98–1.10). Likewise, cilnidipine did not affect the PK of valsartan; the geometric mean ratio (90% CI) of AUC last for valsartan with and without cilnidipine was 0.94 (0.83–1.07). Coadministration of cilnidipine and valsartan reduced blood pressure in an additive way. No serious AEs were reported, and both cilnidipine and valsartan were well tolerated.


          Coadministered cilnidipine and valsartan do not cause a significant PK or PD interaction, and they are well tolerated.

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          Most cited references 22

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          Revising the declaration of Helsinki

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            Cilnidipine: a new generation Ca channel blocker with inhibitory action on sympathetic neurotransmitter release.

            Cilnidipine is a unique Ca(2+) channel blocker with an inhibitory action on the sympathetic N-type Ca(2+) channels, which is used for patients with hypertension in Japan. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca(2+) channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine as an antihypertensive drug, many Ca(2+) channel blockers with long-lasting action for blood pressure have been developed to minimize sympathetic reflex during antihypertensive therapy, which have been divided into three groups; namely, first, second, and third generation based on their pharmacokinetic profiles. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N-type Ca(2+) channel-blocking property, the drug can be expected as fourth generation, providing an effective strategy for the treatment of cardiovascular diseases.
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              Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension.

              Fimasartan, a selective angiotensin II type 1 receptor blocker, was approved in Korea for the treatment of patients with mild to moderate hypertension.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                08 October 2014
                : 8
                : 1781-1788
                [1 ]Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
                [2 ]Clinical Trials Center, Seoul National University Hospital, Seoul, Republic of Korea
                [3 ]Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, Republic of Korea
                Author notes
                Correspondence: Kyung-Sang Yu, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-799, Korea, Tel +82 2 2072 1920, Fax +82 2 742 9252, Email ksyu@ 123456snu.ac.kr

                *These authors contributed equally to this work

                © 2014 Lee et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine

                antihypertensive drugs


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