Padhi Desmond, Sullivan John T
Department of Early Development/Medical Sciences, Amgen Inc., Thousand Oaks, California 91320, USA.
Drugs R D. 2007;8(2):79-87. doi: 10.2165/00126839-200708020-00002.
Cinacalcet HCl (cinacalcet), approved for secondary hyperparathyroidism and parathyroid carcinoma-associated hypercalcaemia, may be coadministered with warfarin. The purpose of this study was to determine the pharmacokinetics/pharmacodynamics and tolerability of warfarin during cinacalcet coadministration.
In this phase 1, randomised, double-blind, placebo-controlled, two-treatment, two-period crossover study, 21 healthy subjects received oral cinacalcet (30 mg) or placebo twice a day for 7 days and once on day 8, with a single warfarin dose (25mg) on day 5. After a 3-week washout, subjects received the alternative treatment. Samples for warfarin pharmacokinetics/pharmacodynamics were obtained until 144 hours post-dose.
Single-dose administration of warfarin to subjects receiving cinacalcet did not demonstrate altered pharmacodynamics of either the R- or S-enantiomer. Geometric means ratio (90% CIs) for R- and S-warfarin were 1.01 (0.95, 1.07) and 1.00 (0.94, 1.04), respectively, for the area under the plasma concentration-time curve from time 0 to infinity (AUC(infinity)) and 0.90 (0.84, 0.96) and 0.88 (0.83, 0.94), respectively, for observed maximum plasma concentrations (C(max)). Additionally, the pharmacokinetic profiles of R- or S-warfarin were similar for all subjects. The ratio for the AUC from time 0 to the last measurable concentration (AUC(t)) for prothrombin time and factor VII were 1.03 (1.01, 1.04) and 0.97 (0.93, 1.01), respectively. The maximum rise (R(max)) and maximum change (Delta(max)) were 1.04 (1.02, 1.05) and 1.00 (0.96, 1.03), respectively. All treatment-emergent and treatment-related adverse events were mild to moderate in severity. There were no obvious differences in adverse events according to treatment.
Warfarin pharmacokinetics/pharmacodynamics were not affected in subjects treated with warfarin 25mg who received cinacalcet 30 mg twice daily, thus suggesting that dose adjustment is not required.
盐酸西那卡塞（西那卡塞）已被批准用于治疗继发性甲状旁腺功能亢进和甲状旁腺癌相关的高钙血症，它可能与华法林联合使用。本研究的目的是确定西那卡塞联合使用期间华法林的药代动力学/药效学及耐受性。
在这项1期随机、双盲、安慰剂对照、双治疗、两周期交叉研究中，21名健康受试者每天口服西那卡塞（30毫克）或安慰剂两次，共7天，并在第8天服用一次，在第5天服用单剂量华法林（25毫克）。经过3周的洗脱期后，受试者接受替代治疗。在给药后144小时内采集华法林药代动力学/药效学样本。
接受西那卡塞的受试者单剂量服用华法林后，R型或S型对映体的药效学均未显示改变。从时间0至无穷大的血浆浓度-时间曲线下面积（AUC(∞)）方面，R-华法林和S-华法林的几何均值比（90%置信区间）分别为1.01（0.95，1.0七）和1.00（0.94，1.04）；观察到的最大血浆浓度（C(max)）方面，分别为0.90（0.84，0.96）和0.88（0.83，0.94）。此外，所有受试者的R型或S型华法林药代动力学曲线相似。凝血酶原时间和因子VII从时间0至最后可测量浓度的曲线下面积（AUC(t)）之比分别为1.03（1.01，1.04）和0.97（0.93，1.01）。最大上升幅度（R(max)）和最大变化幅度（Delta(max)）分别为1.04（1.02，1.05）和1.00（0.96，1.03）。所有治疗中出现的和与治疗相关的不良事件严重程度均为轻度至中度。根据治疗情况，不良事件无明显差异。
每日两次服用30毫克西那卡塞的25毫克华法林治疗受试者中，华法林的药代动力学/药效学未受影响，因此表明无需调整剂量。
