Hongzhong Liu1, Hongyun Wang1, Tao Liu1, Ji Jiang1, Xia Chen1, Feng Gao2, Pei Hu3. 1. Clinical Pharmacology Research Centre, Peking Union Medical College Hospital, Beijing, China. 2. Kyowa Hakko Kirin China Pharmaceutical Co, Ltd, Shanghai, China. 3. Clinical Pharmacology Research Centre, Peking Union Medical College Hospital, Beijing, China. Electronic address: hubei@pumch.cn.
Abstract
PURPOSE: The aim of this study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety of single and multiple doses of cinacalcet in Chinese healthy volunteers (HVs) for the purposes of a New Drug Application package for the Chinese Food and Drug Administration. METHODS: In this randomized, open-label, single ascending-dose and multiple-dose, parallel-group study, 42 Chinese HVs were randomized to receive a single oral dose of 25, 50, or 100 mg of cinacalcet and multiple doses of 50 mg of cinacalcet once daily for 7 days. Plasma cinacalcet concentrations were analyzed by HPLC-MS/MS. The PK parameters were assessed with noncompartmental analysis. Plasma intact parathyroid hormone, serum calcium, and phosphorus concentrations were measured for PD evaluation. The safety profile was also assessed. Adverse events (AEs) were noted during the study. FINDINGS: Of the 42 randomized HVs, 41 completed the study per protocol; 1 prematurely discontinued the study because of AEs. Cinacalcet has nonlinear PK properties over a dose range of 25 to 100 mg after a single dose. Mean (SD) Cmax values were 7.68 (4.25), 17 (6.33), and 31.3 (16.42) ng/mL with single doses of 25, 50, and 100 mg of cinacalcet, respectively. Mean (SD) AUC0- last values were 58.4 (25.38), 187 (70.7), and 367 (180.03) hr∙ng/mL with single doses of 25, 50, and 100 mg of cinacalcet, respectively. Steady state was attained within 7 doses of successive daily administration of 50 mg of cinacalcet. At steady state, the mean (SD) Cmax and AUC0-last values were 20.6 (9.63) ng/mL and 297 (146.15) ng∙h/mL. The accumulation ratios of Cmax and AUC (AUCτ/AUC0-24) were 1.21 and 1.32. Plasma intactparathyroid hormone and serum calcium concentrations had similar patterns, both decreased after administration of cinacalcet, whether after single dose or multiple doses. A total of 52 AEs were reported in 20 HVs (47.6%). The most frequently reported AEs after single-dose and multiple-dose cinacalcet administration were hypocalcemia, numbness, dizziness, and muscle soreness. No serious AEs were reported. IMPLICATIONS: Cinacalcet was well tolerated and effective after administration of a single oral dose up to 100 mg and multiple doses of 50 mg of cinacalcet once daily for 7 days. Cinacalcet has nonlinear PK properties over a dose range of 25 to 100 mg after a single dose. PK profiles after multiple doses were similar to those after a single dose with no accumulation. Cinacalcet had similar PK and safety profiles between Chinese and Western HVs at the same dose levels.
RCT Entities:
PURPOSE: The aim of this study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety of single and multiple doses of cinacalcet in Chinese healthy volunteers (HVs) for the purposes of a New Drug Application package for the Chinese Food and Drug Administration. METHODS: In this randomized, open-label, single ascending-dose and multiple-dose, parallel-group study, 42 Chinese HVs were randomized to receive a single oral dose of 25, 50, or 100 mg of cinacalcet and multiple doses of 50 mg of cinacalcet once daily for 7 days. Plasma cinacalcet concentrations were analyzed by HPLC-MS/MS. The PK parameters were assessed with noncompartmental analysis. Plasma intact parathyroid hormone, serum calcium, and phosphorus concentrations were measured for PD evaluation. The safety profile was also assessed. Adverse events (AEs) were noted during the study. FINDINGS: Of the 42 randomized HVs, 41 completed the study per protocol; 1 prematurely discontinued the study because of AEs. Cinacalcet has nonlinear PK properties over a dose range of 25 to 100 mg after a single dose. Mean (SD) Cmax values were 7.68 (4.25), 17 (6.33), and 31.3 (16.42) ng/mL with single doses of 25, 50, and 100 mg of cinacalcet, respectively. Mean (SD) AUC0- last values were 58.4 (25.38), 187 (70.7), and 367 (180.03) hr∙ng/mL with single doses of 25, 50, and 100 mg of cinacalcet, respectively. Steady state was attained within 7 doses of successive daily administration of 50 mg of cinacalcet. At steady state, the mean (SD) Cmax and AUC0-last values were 20.6 (9.63) ng/mL and 297 (146.15) ng∙h/mL. The accumulation ratios of Cmax and AUC (AUCτ/AUC0-24) were 1.21 and 1.32. Plasma intact parathyroid hormone and serum calcium concentrations had similar patterns, both decreased after administration of cinacalcet, whether after single dose or multiple doses. A total of 52 AEs were reported in 20 HVs (47.6%). The most frequently reported AEs after single-dose and multiple-dose cinacalcet administration were hypocalcemia, numbness, dizziness, and muscle soreness. No serious AEs were reported. IMPLICATIONS: Cinacalcet was well tolerated and effective after administration of a single oral dose up to 100 mg and multiple doses of 50 mg of cinacalcet once daily for 7 days. Cinacalcet has nonlinear PK properties over a dose range of 25 to 100 mg after a single dose. PK profiles after multiple doses were similar to those after a single dose with no accumulation. Cinacalcet had similar PK and safety profiles between Chinese and Western HVs at the same dose levels.