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European Journal of Clinical Pharmacology

, Volume 63, Issue 2, pp 159–163 | Cite as

Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl

  • Robert Z. Harris
  • Margaret Salfi
  • Ed Posvar
  • David Hoelscher
  • Desmond Padhi
Pharmacokinetics and Disposition

Abstract

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

Cinacalcet CYP2D6 Desipramine Drug interaction Pharmacokinetics 

Notes

Acknowledgements

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.

References

  1. 1.
    Block GA, Martin KJ, de Francisco AL, Turner SA, Avram MM, Suranyi MG et al (2004) Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 350(15):1516–1525PubMedCrossRefGoogle Scholar
  2. 2.
    Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D (2005) Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 90(1):135–141PubMedCrossRefGoogle Scholar
  3. 3.
    Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M (2003) The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 88(12):5644–5649PubMedCrossRefGoogle Scholar
  4. 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. 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
  6. 6.
    Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000) Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 38(2):111–180PubMedCrossRefGoogle Scholar
  7. 7.
    Preskorn SH, Beber JH, Faul JC, Hirschfeld RM (1990) Serious adverse effects of combining fluoxetine and tricyclic antidepressants. Am J Psychiatry 147(4):532PubMedGoogle Scholar
  8. 8.
    Bell IR, Cole JO (1988) Fluoxetine induces elevation of desipramine level and exacerbation of geriatric nonpsychotic depression. J Clin Psychopharmacol 8(6):447–448CrossRefGoogle Scholar
  9. 9.
    Westermeyer J (1991) Fluoxetine-induced tricyclic toxicity: extent and duration. J Clin Pharmacol 31(4):388–392PubMedGoogle Scholar
  10. 10.
    Alderman J, Preskorn SH, Greenblatt DJ, Harrison W, Penenberg D, Allison J et al (1997) Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. J Clin Psychopharmacol 17(4):284–291PubMedCrossRefGoogle Scholar
  11. 11.
    Madani S, Barilla D, Cramer J, Wang Y, Paul C (2002) Effect of terbinafine on the pharmacokinetics and pharmacodynamics of desipramine in healthy volunteers identified as cytochrome P450 2D6 (CYP2D6) extensive metabolizers. J Clin Pharmacol 42(11):1211–1218PubMedCrossRefGoogle Scholar
  12. 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
  13. 13.
    Laine K, De Bruyn S, Bjorklund H, Rouru J, Hanninen J, Scheinin H et al (2004) Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics. Eur J Clin Pharmacol 59(12):893–898PubMedCrossRefGoogle Scholar
  14. 14.
    Skinner MH, Kuan HY, Pan A, Sathirakul K, Knadler MP, Gonzales CR et al (2003) Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 73(3):170–177PubMedCrossRefGoogle Scholar
  15. 15.
    Brøsen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF (1993) Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44(4):349–355PubMedCrossRefGoogle Scholar
  16. 16.
    Preskorn SH, Alderman J, Chung M, Harrison W, Messig M, Harris S (1994) Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 14(2):90–98PubMedCrossRefGoogle Scholar
  17. 17.
    Spina E, Gitto C, Avenoso A, Campo GM, Caputi AP, Perucca E (1997) Relationship between plasma desipramine levels, CYP2D6 phenotype and clinical response to desipramine: a prospective study. Eur J Clin Pharmacol 51(5):395–398PubMedCrossRefGoogle Scholar
  18. 18.
    Amgen Inc. (2004) Sensipar (cinacalcet HCl) prescribing information. Retrieved 11 January 2006 from http://www.sensipar.com/prescribingInfo.jsp
  19. 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
  20. 20.
    Charytan C, Coburn JW, Chonchol M, Herman J, Lien YH, Liu W et al (2005) Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis. Am J Kidney Dis 46(1):58–67PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Robert Z. Harris
    • 1
  • Margaret Salfi
    • 2
  • Ed Posvar
    • 3
  • David Hoelscher
    • 4
  • Desmond Padhi
    • 3
  1. 1.Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc.Thousand OaksUSA
  2. 2.Department of Biostatistics, Amgen, Inc.Thousand OaksUSA
  3. 3.Department of Early Development/Medical Sciences, Amgen, Inc.Thousand OaksUSA
  4. 4.PPD Development, Inc.AustinUSA

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