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Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies.

Author(s): Nakashima D, Takama H, Ogasawara Y, Kawakami T, Nishitoba T, Hoshi S, Uchida E, Tanaka H

Affiliation(s): Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd, 26-1 Jingumae 6-chome, Shibuya-ku, Tokyo, 150-8011, Japan. d-nakashima@kirin.co.jp

Publication date & source: 2007-10, J Clin Pharmacol., 47(10):1311-9. Epub 2007 Jul 24.

Publication type: In Vitro; Randomized Controlled Trial

Cinacalcet hydrochloride (cinacalcet) is a positive allosteric modulator of the calcium-sensing receptor indicated for the treatment of secondary hyperparathyroidism in dialysis patients. In vitro study has demonstrated that cinacalcet is a potent inhibitor of cytochrome P450 (CYP) 2D6 with a K(i) value of 0.087 micromol/L, which is comparable to the well-known potent CYP2D6 inhibitor, quinidine (0.064 micromol/L). A clinical study was conducted to assess the inhibitory effect of cinacalcet on CYP2D6 substrates in healthy volunteers. Each subject received 50 mg of cinacalcet or a matched placebo orally once daily for 8 days with 30 mg of dextromethorphan coadministered on day 8. The mean AUC(0-infinity) and C(max) of dextromethorphan increased 11- and 7-fold, respectively, in extensive metabolizers when coadministered with cinacalcet versus placebo. Therefore, during concomitant treatment with cinacalcet, it may be necessary to consider making dose adjustments for drugs with a narrow therapeutic index that are mainly metabolized by CYP2D6.

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