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Pharmacokinetics of cinacalcet hydrochloride when administered with ketoconazole.
Clin Pharmacokinet. 2007; 46(6):495-501.CP

Abstract

BACKGROUND AND OBJECTIVE

The calcimimetic cinacalcet hydrochloride (cinacalcet) is used for treatment of patients with chronic kidney disease with secondary hyperparathyroidism, a population that commonly receives multiple concurrent medications. Cinacalcet is eliminated primarily via oxidative metabolism mediated, in part, through cytochrome P450 (CYP) 3A4. Thus, the potential for an inhibitor of CYP3A4 to alter the pharmacokinetics of cinacalcet is of clinical importance. The objective of this study was to evaluate the pharmacokinetics of cinacalcet during treatment with a potent CYP3A4 inhibitor, ketoconazole.

SUBJECTS AND METHODS

Twenty-four healthy subjects were enrolled in an open-label, crossover, phase I study to receive a single oral dose of cinacalcet (90 mg) alone and with 7 days of ketoconazole (200mg twice daily). Blood samples for pharmacokinetics were collected for up to 72 hours postdose. Cinacalcet plasma concentration-time data were analysed by noncompartmental methods. Pharmacokinetic parameters were analysed using a crossover ANOVA model that included subjects who completed both treatment arms.

RESULTS

Twenty subjects completed both treatment arms. The mean area under the plasma concentration-time curve of cinacalcet increased 2.3-fold (90% CI 1.92, 2.67) [range 1.15- to 7.12-fold] and the mean maximum plasma concentration increased 2.2-fold (90% CI 1.67, 2.78) [range 0.904- to 10.8-fold] when administered with ketoconazole, relative to when administered alone. The time to reach the maximum plasma concentration was not significantly affected, and the terminal elimination half-lives were similar between treatments.

CONCLUSIONS

Co-administration of a potent CYP3A4 inhibitor moderately increased cinacalcet exposure in study subjects. This suggests that clinicians should monitor parathyroid hormone and calcium concentrations when a patient receiving cinacalcet initiates or discontinues therapy with a strong CYP3A4 inhibitor.

Authors+Show Affiliations

Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA. harrisr@amgen.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17518508

Citation

Harris, Robert Z., et al. "Pharmacokinetics of Cinacalcet Hydrochloride when Administered With Ketoconazole." Clinical Pharmacokinetics, vol. 46, no. 6, 2007, pp. 495-501.
Harris RZ, Salfi M, Sullivan JT, et al. Pharmacokinetics of cinacalcet hydrochloride when administered with ketoconazole. Clin Pharmacokinet. 2007;46(6):495-501.
Harris, R. Z., Salfi, M., Sullivan, J. T., & Padhi, D. (2007). Pharmacokinetics of cinacalcet hydrochloride when administered with ketoconazole. Clinical Pharmacokinetics, 46(6), 495-501.
Harris RZ, et al. Pharmacokinetics of Cinacalcet Hydrochloride when Administered With Ketoconazole. Clin Pharmacokinet. 2007;46(6):495-501. PubMed PMID: 17518508.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics of cinacalcet hydrochloride when administered with ketoconazole. AU - Harris,Robert Z, AU - Salfi,Margaret, AU - Sullivan,John T, AU - Padhi,Desmond, PY - 2007/5/24/pubmed PY - 2007/9/27/medline PY - 2007/5/24/entrez SP - 495 EP - 501 JF - Clinical pharmacokinetics JO - Clin Pharmacokinet VL - 46 IS - 6 N2 - BACKGROUND AND OBJECTIVE: The calcimimetic cinacalcet hydrochloride (cinacalcet) is used for treatment of patients with chronic kidney disease with secondary hyperparathyroidism, a population that commonly receives multiple concurrent medications. Cinacalcet is eliminated primarily via oxidative metabolism mediated, in part, through cytochrome P450 (CYP) 3A4. Thus, the potential for an inhibitor of CYP3A4 to alter the pharmacokinetics of cinacalcet is of clinical importance. The objective of this study was to evaluate the pharmacokinetics of cinacalcet during treatment with a potent CYP3A4 inhibitor, ketoconazole. SUBJECTS AND METHODS: Twenty-four healthy subjects were enrolled in an open-label, crossover, phase I study to receive a single oral dose of cinacalcet (90 mg) alone and with 7 days of ketoconazole (200mg twice daily). Blood samples for pharmacokinetics were collected for up to 72 hours postdose. Cinacalcet plasma concentration-time data were analysed by noncompartmental methods. Pharmacokinetic parameters were analysed using a crossover ANOVA model that included subjects who completed both treatment arms. RESULTS: Twenty subjects completed both treatment arms. The mean area under the plasma concentration-time curve of cinacalcet increased 2.3-fold (90% CI 1.92, 2.67) [range 1.15- to 7.12-fold] and the mean maximum plasma concentration increased 2.2-fold (90% CI 1.67, 2.78) [range 0.904- to 10.8-fold] when administered with ketoconazole, relative to when administered alone. The time to reach the maximum plasma concentration was not significantly affected, and the terminal elimination half-lives were similar between treatments. CONCLUSIONS: Co-administration of a potent CYP3A4 inhibitor moderately increased cinacalcet exposure in study subjects. This suggests that clinicians should monitor parathyroid hormone and calcium concentrations when a patient receiving cinacalcet initiates or discontinues therapy with a strong CYP3A4 inhibitor. SN - 0312-5963 UR - https://www.unboundmedicine.com/medline/citation/17518508/Pharmacokinetics_of_cinacalcet_hydrochloride_when_administered_with_ketoconazole_ L2 - https://dx.doi.org/10.2165/00003088-200746060-00003 DB - PRIME DP - Unbound Medicine ER -