Pharmacokinetics, pharmacodynamics, and safety of cinacalcet hydrochloride in hemodialysis patients at doses up to 200 mg once daily.
BACKGROUND
Cinacalcet hydrochloride (HCl) can be used to manage the secondary hyperparathyroidism of patients with chronic kidney disease. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of cinacalcet HCl over a dose range of 25 to 300 mg/d in patients receiving dialysis.


METHODS
Hemodialysis patients were randomly assigned 4:1 to receive cinacalcet HCl or placebo in this double-blind study. Cinacalcet HCl doses were escalated weekly in 25-mg increments from 25 to 300 mg/d. Noncompartmental methods were used to analyze the pharmacokinetic parameters of cinacalcet (the free-base). The effects of cinacalcet concentration on plasma parathyroid hormone (PTH) and serum calcium levels were evaluated.


RESULTS
Of 23 patients enrolled (17 patients, cinacalcet HCl; 6 patients, placebo), 10 patients (8 patients, cinacalcet HCl; 2 patients, placebo) completed the study. Plasma concentration, median area under the plasma concentration-time curve from time 0 to 24 hours after dosing, and maximal plasma concentration (Cmax ) of cinacalcet increased with doses up to 200 mg once daily. Median oral clearance ranged from 222 to 599 L/h, and median time after dosing when C max occurred ranged from 2 to 3 hours across all doses. The pharmacokinetics were linear over the 25- to 200-mg once-daily dose range, with no substantial increase in exposure at greater than 200 mg. Changes in plasma PTH concentrations correlated inversely with cinacalcet concentration. The concentration-effect relationship was well described by an inhibitory maximal effect model. Cinacalcet HCl was reasonably tolerated, and the incidence of adverse events was similar between groups (76%, cinacalcet; 80%, placebo). Gastrointestinal events were noted at greater doses and may be dose related.


CONCLUSIONS
Cinacalcet HCl shows a dose-proportional increase in exposure over the range of 25 to 200 mg once daily in patients on hemodialysis therapy, and kinetics were linear up to 200 mg once daily. The incidence of adverse events was similar between groups.
Harris
Robert Z
RZ
Department of Pharmacokinetics and Drug Metabolism, Amgen Inc, Thousand Oaks, CA 91360, USA. harrisr@amgen.com
Padhi
Desmond
D
Marbury
Thomas C
TC
Noveck
Robert J
RJ
Salfi
Margaret
M
Sullivan
John T
JT
D000293:Adolescent; D000328:Adult; D000368:Aged; D000069449:Cinacalcet; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006435:Renal Dialysis / Q000379:methods*
D009281:Naphthalenes; D000069449:Cinacalcet