Skip to main content
SpringerLink
Log in

Cinacalcet Does Not Affect the Activity of Cytochrome P450 3A Enzymes, a Metabolic Pathway for Common Immunosuppressive Agents

A Randomized, Open-Label, Crossover, Single-Centre Study in Healthy Volunteers

  • Original Research Article
  • Published:
Drugs in R & D Aims and scope Submit manuscript

Abstract

Background and objective: Cinacalcet HCl (cinacalcet) is approved for the treatment of secondary hyperparathyroidism in subjects receiving dialysis and for the reduction of hypercalcaemia in patients with parathyroid carcinoma. The drug may also be co-administered with medications used in the renal transplantation setting, such as immunosuppressants. Cinacalcet, as well as some immunosuppressants such as ciclosporin, tacrolimus and sirolimus, is partially metabolized by the cytochrome P450 3A enzymes (CYP3A). This study aimed to evaluate the potential inhibitory effects of cinacalcet on CYP3A activity using midazolam as a probe substrate in healthy volunteers.

Methods: In this randomized, open-label, crossover, two-treatment, two-period, single-centre study, 12 healthy volunteers received either oral cinacalcet 90 mg once daily for 5 days plus a single oral dose of midazolam 2 mg on day 5, or a single oral dose of midazolam 2 mg on day 1. Following a 10-day washout period, subjects received the alternate treatment. Blood samples were collected predose and at selected time points up to 24 hours after dosing with midazolam for measurement of midazolam pharmacokinetic parameters.

Results: Eleven subjects completed the study. Mean (standard deviation) midazolam maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) were 9.31 (3.09) ng/mL and 24.1 (7.7) ng • h/mL, respectively, when administered in combination with cinacalcet, compared with 9.76 (2.81) ng/mL and 22.8 (6.1) ng • h/mL when administered alone. The mean geometric ratios (90% confidence interval) were 0.95 (0.84, 1.06) and 1.05 (0.95, 1.16) for Cmax and AUC∞, respectively. All adverse events were mild to moderate in severity, and consistent with the safety profile of cinacalcet.

Conclusion: Once-daily administration of cinacalcet did not alter the pharmacokinetics of midazolam relative to administration of midazolam alone. These data suggest that cinacalcet administration does not affect CYP3A activity, and thus would not have an effect on any drug eliminated via CYP3A, including some commonly used immunosuppressant therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Table I
Table II

Similar content being viewed by others

Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Salem MM. Hyperparathyroidism in the hemodialysis population: a survey of 612 patients. Am J Kidney Dis 1997; 29: 862–5

    Article  PubMed  CAS  Google Scholar 

  2. Heaf J, Tvedegaard E, Kanstrup IL, et al. Hyperparathyroidism and long-term bone loss after renal transplantation. Clin Transplant 2003; 17: 268–74

    Article  PubMed  Google Scholar 

  3. Heaf J, Tvedegaard E, Kanstrup IL, et al. Bone loss after renal transplantation: role of hyperparathyroidism, acidosis, cyclosporine and systemic disease. Clin Transplant 2000; 14: 457–63

    Article  PubMed  CAS  Google Scholar 

  4. Torres A, Lorenzo V, Salido E. Calcium metabolism and skeletal problems after transplantation. J Am Soc Nephrol 2002; 13: 551–8

    PubMed  Google Scholar 

  5. Gwinner W, Suppa S, Mengel M, et al. Early calcification of renal allografts detected by protocol biopsies: causes and clinical implications. Am J Transplant 2005; 5: 1934–41

    Article  PubMed  Google Scholar 

  6. Brandenburg VM, Westenfeld R, Ketteler M. The fate of bone after renal transplantation. J Nephrol 2004; 17: 190–204

    PubMed  Google Scholar 

  7. Nemeth EF, Heaton WH, Miller M, et al. Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. J Pharmacol Exp Ther 2004; 308: 627–35

    Article  PubMed  CAS  Google Scholar 

  8. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993; 366: 575–80

    Article  PubMed  CAS  Google Scholar 

  9. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004; 350: 1516–25

    Article  PubMed  CAS  Google Scholar 

  10. Lindberg JS, Culleton B, Wong G, et al. 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 2005; 16: 800–7

    Article  PubMed  CAS  Google Scholar 

  11. El-Amm JM, Doshi MD, Singh A, et al. Preliminary experience with cinacalcet use in persistent secondary hyperparathyroidism after kidney transplantation. Transplantation 2007; 83: 546–9

    Article  PubMed  CAS  Google Scholar 

  12. Szwarc I, Argiles A, Garrigue V, et al. Cinacalcet chloride is efficient and safe in renal transplant recipients with posttransplant hyperparathyroidism. Transplantation 2006; 82: 675–80

    Article  PubMed  CAS  Google Scholar 

  13. Serra AL, Schwarz AA, Wick FH, et al. Successful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 2005; 20: 1315–9

    Article  PubMed  CAS  Google Scholar 

  14. Apostolou T, Damianou L, Kotsiev V, et al. Treatment of severe hypercalcemia due to refractory hyperparathyroidism in renal transplant patients with the calcimimetic agent cinacalcet. Clin Nephrol 2006; 65: 374–7

    PubMed  CAS  Google Scholar 

  15. Apostolou T, Kollia K, Damianou L, et al. Hypercalcemia due to resistant hyperparathyroidism in renal transplant patients treated with the calcimimetic agent cinacalcet. Transplant Proc 2006; 38: 3514–6

    Article  PubMed  CAS  Google Scholar 

  16. Kruse AE, Eisenberger U, Frey FJ, et al. The calcimimetic cinacalcet normalizes serum calcium in renal transplant patients with persistent hyperparathyroidism. Nephrol Dial Transplant 2005; 20: 1311–4

    Article  PubMed  CAS  Google Scholar 

  17. Leca N, Laftavi M, Gundroo A, et al. Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet. Am J Transplant 2006; 6: 2391–5

    Article  PubMed  CAS  Google Scholar 

  18. Serra AL, Savoca R, Huber AR, et al. Effective control of persistent hyperparathyroidism with cinacalcet in renal allograft recipients. Nephrol Dial Transplant 2007; 22: 577–83

    Article  PubMed  CAS  Google Scholar 

  19. Amgen Inc. Sensipar® (cinacalcet HCl) tablets prescribing information [online]. Available from URL: http://www.sensipar.com/professional/prescribing_information/prescribing_information.jsp [Accessed 2007 Dec 11]

    Google Scholar 

  20. Eichelbaum M, Burk O. CYP3A genetics in drug metabolism. Nat Med 2001; 7: 285–7

    Article  PubMed  CAS  Google Scholar 

  21. Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 2003; 31: 815–32

    Article  PubMed  CAS  Google Scholar 

  22. Arellano C, Philibert C, Vachoux C, et al. The metabolism of midazolam and comparison with other CYP enzyme substrates during intestinal absorption: in vitro studies with rat everted gut sacs. J Pharm Pharm Sci 2007; 10: 26–36

    PubMed  CAS  Google Scholar 

  23. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for industry: in vivo drug metabolism/drug interaction studies — study design, data analysis, and recommendations for dosing and labeling; November 1999 [online]. Available from URL: http://www.fda.gov/cder/guidance/index.htm [Accessed 2008 Jul 27]

    Google Scholar 

  24. Messa P, Sindici C, Cannella G, et al. Persistent secondary hyperparathyroidism after renal transplantation. Kidney Int 1998; 54: 1704–13

    Article  PubMed  CAS  Google Scholar 

  25. Julian BA, Laskow DA, Dubovsky J, et al. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991; 325: 544–50

    Article  PubMed  CAS  Google Scholar 

  26. Mikuls TR, Julian BA, Bartolucci A, et al. Bone mineral density changes within six months of renal transplantation. Transplantation 2003; 75: 49–54

    Article  PubMed  CAS  Google Scholar 

  27. Rubello D, Giannini S, D’Angelo A, et al. Secondary hyperparathyroidism is associated with vitamin D receptor polymorphism and bone density after renal transplantation. Biomed Pharmacother 2005; 59: 402–7

    Article  PubMed  CAS  Google Scholar 

  28. Giannini S, D’Angelo A, Carraro G, et al. Persistently increased bone turnover and low bone density in long-term survivors to kidney transplantation. Clin Nephrol 2001; 56: 353–63

    PubMed  CAS  Google Scholar 

  29. Vautour LM, Melton 3rd LJ, Clarke BL, et al. Long-term fracture risk following renal transplantation: a population-based study. Osteoporos Int 2004; 15: 160–7

    Article  PubMed  Google Scholar 

  30. Suwelack B, Gerhardt U, Witta J, et al. Effect of parathyroid hormone levels on carotid intima-media thickness after renal transplantation. Am J Hypertens 2001; 14: 1012–8

    Article  PubMed  CAS  Google Scholar 

  31. Palmer S, McGregor DO, Strippoli GF. Interventions for preventing bone disease in kidney transplant recipients. Cochrane Database Syst Rev 2005; (2): CD005015

    PubMed  Google Scholar 

  32. Evenepoel P, Claes K, Kuypers D, et al. Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study. Nephrol Dial Transplant 2005; 20: 1714–20

    Article  PubMed  CAS  Google Scholar 

  33. Harris RZ, Salfi M, Sullivan JT, et al. Pharmacokinetics of cinacalcet hydrochloride when administered with ketoconazole. Clin Pharmacokinet 2007; 46: 495–501

    Article  PubMed  CAS  Google Scholar 

  34. Padhi D, Harris RZ, Salfi M, et al. No effect of renal function or dialysis on pharmacokinetics of cinacalcet (Sensipar®/Mimpara). Clin Pharmacokinet 2005; 44: 509–16

    Article  PubMed  CAS  Google Scholar 

  35. Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol 2007; 2: 374–84

    Article  PubMed  CAS  Google Scholar 

  36. Falck P, Vethe NT, Asberg A, et al. Cinacalcet’s effect on the pharmacokinetics of tacrolimus, cyclosporine and mycophenolate in renal transplant recipients. Nephrol Dial Transplant 2008; 23: 1048–53

    Article  PubMed  CAS  Google Scholar 

  37. Kruse AE, Eisenberger U, Frey FJ, et al. Effect of cinacalcet cessation in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 2007; 22: 2362–5

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Funding for this study (Amgen Study 20050226), as well as for manuscript preparation, was provided by Amgen, Inc. (Thousand Oaks, CA, USA). The authors would like to thank Niall Harrison, Jackie Bannister and Jane Mannion for their assistance with the writing of this manuscript. Drs Padhi and Emery, along with Ms Salfi and Ms Mannion, are employees of, and stockholders in, Amgen, Inc.

Author information

Authors and Affiliations

  1. Department of Medical Sciences, Amgen Inc., Thousand Oaks, California, USA

    Desmond Padhi

  2. Department of Biostatistics, Amgen Inc., Thousand Oaks, California, USA

    Maggi Salfi

  3. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington, USA

    Maurice Emery

Authors
  1. Desmond Padhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maggi Salfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maurice Emery
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Desmond Padhi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Padhi, D., Salfi, M. & Emery, M. Cinacalcet Does Not Affect the Activity of Cytochrome P450 3A Enzymes, a Metabolic Pathway for Common Immunosuppressive Agents. Drugs R D 9, 335–343 (2008). https://doi.org/10.2165/00126839-200809050-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00126839-200809050-00004

Keywords

Search

Navigation