title: Pharmacokinetic and pharmacodynamic properties of the calcimimetic agent cinacalcet (KRN1493) in healthy male Korean subjects: a randomized, open-label, single ascending-dose, parallel-group study.
abstract: BACKGROUND
  Cinacalcet (KRN1493) was developed to manage secondary hyperparathyroidism in patients with chronic kidney disease. The characteristics of cinacalcet have not been studied in the Korean population.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose cinacalcet 50 to 100 mg in healthy male Korean subjects for the purposes of a New Drug Application package for the Korean Food and Drug Administration.
  
  
  METHODS
  A randomized, open-label, single ascending-dose, parallel-group study was conducted in healthy male Korean subjects. Subjects were randomly assigned to receive a single oral dose of cinacalcet 50, 75, or 100 mg. Serial blood samples for PK/PD analysis were taken for up to 96 hours after administration. Plasma cinacalcet concentrations were analyzed by HPLC-MS/MS. PK parameters were determined using noncompartmental methods. Plasma intact parathyroid hormone (iPTH) concentrations, albumin-corrected serum calcium concentrations, and serum phosphorus concentrations were measured for PD evaluation. For the evaluation of tolerability, adverse events (AEs) were collected using investigators' questionnaires, subjects' spontaneous reports, clinical laboratory tests, ECG, and physical examinations including vital sign measurements.
  
  
  RESULTS
  Sixteen subjects in the 50-mg group, 16 in the 75-mg group, and 6 in the 100-mg group completed the study and were included in the PK/PD analysis. The mean (SD) age, height, and weight of the study population were 4.3 (3.0) years, 174.8 (4.9) cm, and 68.2 (7.5) kg, respectively. The median T(max) value in each of the 3 dose groups was 6.0 hours. Mean C(max) values in the 50-, 75-, and 100-mg dose groups were 12.0 (5.5), 17.2 (14.9), and 43.1 (15.5) μg/L; mean AUC(0-∞) values were 126.6 (56.4), 184.3 (87.9), and 417.4 (169.9) μg · h/L. Characteristics were not linear, based on the data over the dose range of 50 to 100 mg. Mean plasma iPTH concentrations in the 50-, 75-, and 100-mg dose groups were decreased from baseline by 64.0% (11.7%), 63.1% (14.6%), and 70.6% (6.3%). Albumin-corrected serum calcium concentrations displayed patterns similar to those of the plasma iPTH concentrations. Sixteen AEs were reported in 11 subjects. No clinically significant abnormalities were observed in the tolerability assessments.
  
  
  CONCLUSIONS
  A single oral dose of cinacalcet was well-tolerated up to 100 mg in this small, selected population of healthy male Korean subjects. In addition, the PK characteristics of cinacalcet and its accompanying PD changes-the decreases in the concentrations of plasma iPTH and albumin corrected serum calcium-were demonstrated in the same population. ClinicalTrials.gov identifier: NCT00942773.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: SeungHwan
authors.initials: S
authors.lastname: Lee
authors.forename: Namyi
authors.initials: N
authors.lastname: Gu
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002118:Calcium / Q000097:blood*; D002851:Chromatography, High Pressure Liquid; D000069449:Cinacalcet; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000097:blood*; D010758:Phosphorus / Q000097:blood*; D056910:Republic of Korea; D012709:Serum Albumin / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D009281:Naphthalenes; D010281:Parathyroid Hormone; D012709:Serum Albumin; D010758:Phosphorus; D002118:Calcium; D000069449:Cinacalcet