Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl
- 210 Downloads
In vitro work has demonstrated that cinacalcet is a strong inhibitor of cytochrome P450 isoenzyme (CYP) 2D6. The purpose of this study was to evaluate the effect of cinacalcet on CYP2D6 activity, using desipramine as a probe substrate, in healthy subjects.
Seventeen subjects who were genotyped as CYP2D6 extensive metabolizers were enrolled in this randomized, open-label, crossover study to receive a single oral dose of desipramine (50 mg) on two separate occasions, once alone and once after multiple doses of cinacalcet (90 mg for 7 days). Blood samples were obtained predose and up to 72 h postdose.
Fourteen subjects completed both treatment arms. Relative to desipramine alone, mean AUC and Cmax of desipramine increased 3.6- and 1.8-fold when coadministered with cinacalcet. The t 1/2,z of desipramine was longer when desipramine was coadministered with cinacalcet (21.0 versus 43.3 hs). The t max was similar between the regimens. Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33 versus 86%), the most frequent of which (nausea and headache) have been reported for patients treated with either desipramine or cinacalcet.
This study demonstrates that cinacalcet is a strong inhibitor of CYP2D6. These data suggest that during concomitant treatment with cinacalcet, dose adjustment may be necessary for drugs that demonstrate a narrow therapeutic index and are metabolized by CYP2D6.
KeywordsCinacalcet CYP2D6 Desipramine Drug interaction Pharmacokinetics
Amgen, Inc. supported this study (Study 20040151). The study was conducted at PPD Development, LP, Austin, Texas. Drs. Padhi, Posvar, and Harris and Ms. Salfi are employees and stockholders of Amgen, Inc. Dr. William Stark, an employee and stockholder of Amgen, Inc., contributed to the writing of this manuscript. This study complied with Good Clinical Practice guidelines and ethics regulations put forth by the United States of America.
- 4.Silverberg SJ, Faiman C, Bilezikian JP, Shoback D, Rubin MR, Smallridge R et al (2004) Cinacalcet HCl effectively treats hypercalcemia in patients with parathyroid carcinoma. J Bone Miner Res 19(S1):S103Google Scholar
- 5.Bajpai M, Esmay J, Chi V, Hayashi M, Poppe L, Kumar G (2005) In vitro metabolism and prediction of drug-drug interactions of the calcimimetic agent cinacalcet HCl. Drug Metab Rev 37(Suppl 2):124Google Scholar
- 12.Hamelin BA, Bouayad A, Methot J, Jobin J, Desgagnes P, Poirier P et al (2000) Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 67(5):466–477PubMedCrossRefGoogle Scholar
- 18.Amgen Inc. (2004) Sensipar (cinacalcet HCl) prescribing information. Retrieved 11 January 2006 from http://www.sensipar.com/prescribingInfo.jsp
- 19.Lindberg JS, Culleton B, Wong G, Borah MF, Clark RV, Shapiro WB et al (2005) Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study. J Am Soc Nephrol 16(3):800–807PubMedCrossRefGoogle Scholar