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

¹ Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd
² Department of Allergy and Respiratory Medicine, Doai Memorial Hospital
³ Second Department of Pharmacology, Showa University School of Medicine

^* To whom correspondence should be addressed. E-mail: d-nakashima{at}kirin.co.jp.

	Abstract

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 cincalcet 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.
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