Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies
Comment from Dr. Oesterheld: Cinacalcet is a calcium- reducing drug commonly used in patients with chromic renal failure/dialysis. Although it was known that cinacalcet is a CYP2D6 inhibitor, and desipramine levels were increased when co-administered with this drug, the Ki of cinacalcet was not known to be similar to quinidine and thus amongst the most potent CYP2D6 inhibitors (comparable to fluoxetine or paroxetine).
Clinicians should be aware of this new finding so that they can anticipate drug interactions with CYP2D6 substrates.
J Clin Pharmacol. 2007 Oct;47(10):1311-9. Epub 2007 Jul 24.
Effect of cinacalcet hydrochloride, a new calcimimetic agent, on the pharmacokinetics of dextromethorphan: in vitro and clinical studies.
Nakashima D, Takama H, Ogasawara Y, Kawakami T, Nishitoba T, Hoshi S, Uchida E, Tanaka H.
Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd, 26-1 Jingumae 6-chome, Shibuya-ku, Tokyo, 150-8011, Japan. firstname.lastname@example.org
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.