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Effect of Cinacalcet Hydrochloride, a New Calcimimetic Agent, on the Pharmacokinetics of Dextromethorphan: In Vitro and Clinical Studies

From the Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd, Tokyo, Japan (D. Nakashima, Dr Takama, Y. Ogasawara, T. Kawakami, Dr Nishitoba, Dr Tanaka); Department of Allergy and Respiratory Medicine, Doai Memorial Hospital, Tokyo, Japan (Dr Hoshi); and Second Department of Pharmacology, Showa University School of Medicine, Tokyo, Japan (Dr Uchida).

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 µmol/L, which is comparable to the well-known potent CYP2D6 inhibitor, quinidine (0.064 µmol/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- 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.

Key Words: Cinacalcet • CYP2D6 • dextromethorphan • drug interaction • pharmacokinetics

Address for correspondence: Daisuke Nakashima, Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd, 26-1 Jingumae 6-chome, Shibuya-ku, Tokyo, 150-8011, Japan; e-mail: d-nakashima{at}kirin.co.jp.

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