Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies.
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.
Nakashima
Daisuke
D
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
Takama
Hirotaka
H
Ogasawara
Yuko
Y
Kawakami
Tetsuyoshi
T
Nishitoba
Tsuyoshi
T
Hoshi
Sakuo
S
Uchida
Eiji
E
Tanaka
Hideji
H
D000328:Adult; D000494:Allosteric Regulation; D000704:Analysis of Variance; D019540:Area Under Curve; D000069449:Cinacalcet; D018592:Cross-Over Studies; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003600:Cytosol / Q000378:metabolism; D003915:Dextromethorphan / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D003917:Dextrorphan / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D044169:Receptors, Calcium-Sensing / Q000502:physiology
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D009281:Naphthalenes; D044169:Receptors, Calcium-Sensing; D003917:Dextrorphan; D003915:Dextromethorphan; D000069449:Cinacalcet