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.
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 (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) 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 C(max) and AUC(infinity), respectively. All adverse events were mild to moderate in severity, and consistent with the safety profile of cinacalcet.


CONCLUSIONS
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.
Padhi
Desmond
D
Department of Medical Sciences, Amgen Inc., Thousand Oaks, California 91320, USA. dpadhi@amgen.com
Salfi
Maggi
M
Emery
Maurice
M
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002118:Calcium / Q000097:blood; D002120:Calcium Channel Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069449:Cinacalcet; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D005260:Female; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007166:Immunosuppressive Agents / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009325:Nausea / Q000139:chemically induced; D010292:Paresthesia / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
D002120:Calcium Channel Agonists; D006993:Hypnotics and Sedatives; D007166:Immunosuppressive Agents; D009281:Naphthalenes; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D002118:Calcium; D000069449:Cinacalcet