Pharmacokinetics of cinacalcet hydrochloride when administered with ketoconazole.
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.


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.
Harris
Robert Z
RZ
Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA. harrisr@amgen.com
Salfi
Margaret
M
Sullivan
John T
JT
Padhi
Desmond
D
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000009:adverse effects / Q000494:pharmacology*; D019540:Area Under Curve; D002118:Calcium / Q000378:metabolism; D000069449:Cinacalcet; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy; D007654:Ketoconazole / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy
D000935:Antifungal Agents; D009281:Naphthalenes; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D002118:Calcium; D000069449:Cinacalcet