帕立骨化醇 Paricalcitol
【其它名称】zemplar
规格
帕立骨化醇胶囊(1)1μg。(2)2μg。(3)4μg。
药品简介
雅培公司（Abbott）5月27日宣布，FDA批准其活性维生素D治疗药物帕立骨化醇（paricalcitol，Zemplar）1、2和4 mcg胶囊剂用于预防和治疗继发性甲状旁腺功能亢进症（SHPT）。本品对接受透析和移植手术前的Ⅲ及Ⅳ期慢性肾脏疾病（CKD）患者的SHPT显示预防及治疗疗效。
本品为口服制剂，其活性成份帕立骨化醇的注射制剂于1998年上市，并已成为透析患者最广泛使用的SHPT预防及治疗药物。本品通过更为便利的口服途径给药降低甲状旁腺激素（PTH）水平，同时对血钙及血磷水平具有最小影响。PTH降低是SHPT治疗疗效的一个关键性指标。
3项Ⅲ期临床研究结果表明，本品能安全、有效地降低并发SHPT 的Ⅲ及Ⅳ期CKD患者PTH水平。在24周的治疗后，本品组91%的患者PTH水平明显且持续降低，而安慰剂组这一比例仅为13%。PTH水平明显且持续降低是指PTH至少连续2次降低30%以上（包括30%），并且在治疗第9周患者PTH平均降低30%以上。
本品常见的不良反应发生情况与安慰剂类似。另外，偶见治疗不当引发的维生素D中毒、血钙过多以及对本品成份过敏。
药理作用
药效学
本药为19-去甲-1，25-二羟基维生素D2，是骨化三醇的类似物，属维生素D类抗甲状旁腺药，供静脉或口服用。本药通过选择性激活维生素D的反应途径，抑制甲状旁腺素(PTH)的合成和释放，从而降低PTH水平。其抑制血PTH的疗效与均等剂量的骨化三醇同样有效。在安慰剂对照的研究中，本药诱导高钙血症和高磷血症的倾向降低。
药动学
健康受试者静脉弹丸式注射单剂0.04μg／kg、0.08μg／kg和0.16μg／kg，注射结束时达血药峰浓度，分别为256pg/ml、664pg／m1．和1242pg／ml。帕立骨化醇吸收良好，健康受试者口服0.24μg/g，3小时达血药峰浓度0.63ng／ml，平均绝对生物利用度约为72％，曲线下面积(AUC0-∞)为5.25(ng.h)／ml，食物对全身生物利用度无影响，但与饮食同服组达峰时间延迟约2小时。静脉给药的曲线下面积(AUC)14.51(ng.h)／ml。99％以上的药物与蛋白结合，稳态分布容积为17～34L。本药经线粒体细胞色素P450(CYP)24、CYP3A4和尿苷二磷酸葡萄糖醛酸转移酶(UGT)1A4广泛代谢，检测到的代谢物为有活性的24(R)-羟基帕立骨化醇。健康受试者中总体清除率为2.5～4L／h，经肾和粪便的排泄率分别为18％～19％和63％～74％，其母体化合物的消除半衰期为4～7小时，血液透析不能清除本药。
适应症
用于预防和治疗由3期和4期慢性肾衰竭引起的继发性甲状旁腺功能亢进。(国外资料)
用法用量
[国外用法用量参考]
•常规剂量
*静脉注射
推荐的初始剂量是一次0.04～0.1μg／kg(2.8～7μg），静脉弹丸式注射；在血液透析过程中，不得超过每2日1次的给药频率。有资料显示，一次0.24μg／kg(16.8μg)的剂量可安全给药。剂量调整应根据PTH水平，间隔2～4周可增加剂量2～4μg。
**根据PTH剂量调整表
PTH水平——本药剂量调整:
不变、升高及降低幅度小于30％——增加剂量
降低30％～60％——维持当前剂量
降低幅度大于60％——减少剂量
*口服给药
(1)初始剂量根据基础iPTH水平而定。
①一日1次给药。如基础iPTH不超过500pg／ml，则初始剂量为一次1μg；如基础iPTH超过500pg／ml，则初始剂量为一次2μg。
②一周3次给药，不超过每2日1次的给药频率。如基础iPTH不超过500pg/ml，则初始剂量为一次2μg；如基础iPTH超过500pg／ml，则初始剂量为一次4μg。
(2)间隔2-4周调整剂量。
**一日1次给药的剂量调整表:
iPTH相对于基础值的水平——本药剂量调整:
不变、升高及降低幅度小于30％——增加剂量1μg
降低幅度30％～60％——维持当前剂量
降低幅度超过60％或iPTH低于60pg／ml——减少剂量1μg
**一周3次给药的剂量调整表:
iPTH相对于基础值的水平——本药剂量调整:
不变、升高及降低幅度小于30％——增加剂量2μg
降低幅度30％～60％——维持当前剂量
降低幅度超过60％或iPTH低于60pg／ml——减少剂量2μg
•老年人剂量
研究表明，静脉给药后未见65岁以上和65岁以下患者中存在疗效和安全性之间的总体差异。
•透析时剂量
血液透析对本药血浆水平的影响较小，给予本药时可不考虑血液透析的影响。
给药说明
1．磷酸盐制剂或维生素D相关的化合物不能与本药联用。
2．如出现下述情况，应减量或停药：iPTH降低至100pg／ml以下、血钙水平超过11.5mg／d1、Ca×P积(钙磷积)大于75。
3．如发生显著的高钙血症，建议立即减量或停药，并给予低钙饮食，撤除钙补充剂，进行腹膜透析或血液透析(避免使用含游离钙的透析液)，评估电解质和液体参数，检查心电图是否异常(主要是接受洋地黄的患者)。
不良反应
[国外不良反应参考]
1．心血管系统
可见心肌病、心肌梗死、心悸、胸痛、高血压、低血压(包括直立性低血压)、昏厥、水肿(7％)等，其中心悸和水肿与本药的因果关系尚未建立。
2．代谢／内分泌系统
可见酸中毒、脱水、高钙血症、高磷血症、低钾血症。
3．呼吸系统
可见支气管炎、肺炎(2％～5％)、鼻炎、鼻窦炎、鼻出血、咳嗽(罕见干咳)。
4．肌肉骨骼系统
可见关节炎、骨和(或)关节雅司病损害、背痛、小腿痛性痉挛。
5．泌尿生殖系统
可见肾功能异常、泌尿道感染。
6．免疫系统
可见细菌或真菌感染、药物**反应(瘙痒、皮疹、风疹、面部和口部水肿等)。
7．神经系统
可见衰弱、头痛、眩晕、头昏目眩(5％)、抑郁、神经障碍。
8. 胃肠道
可见腹痛、腹泻、直肠病、恶心(6％～1 3％)、呕吐(6％～8％)、口干燥症(3％)。也可出现胃肠道出血(5％)，但与本药的因果关系尚未建立。
9．皮肤偶见皮疹(四肢)
可见皮肤溃疡。
10．眼
可见弱视、视网膜疾患。
11．其他
(1)可见意外损伤、疼痛，5％及以下患者可出现发热、寒战和流感样症状。
(2)长期用药可能增加高钙血症和迁徙性钙化以及高磷血症的风险。
注意事项
1．禁忌症
(1)对本药过敏者(国外资料)。
(2)高钙血症患者(国外资料)。
(3)维生素D中毒者(国外资料)。
2．慎用
(1)孕妇(国外资料)。
(2)哺乳妇女(国外资料)。
3．药物对儿童的影响
儿童用药的安全性和有效性尚未建立。
4．药物对妊娠的影响
动物研究表明，本药对胎仔具有不良效应(致畸、死胎或其他)。尚缺乏孕妇使用本药的安全性数据，用药时应权衡利弊。美国食品药品管理局(FDA)对本药的妊娠安全性分级为C级。
5．药物对哺乳的影响可分泌入哺乳大鼠的乳汁中，尚无人类哺乳期间用药的安全性资料，建议哺乳妇女暂停用药或用药时暂停哺乳。
6．用药前后及用药时应当检查或监测
(1)用药期间监测是否出现高钙血症。
(2)在剂量调整阶段，应密切监测血清全段甲状旁腺素(iPTH)、钙和磷。
药物相互作用
药物-药物相互作用
1．与CYP3A强抑制药(如阿扎那韦、克拉霉素、茚地那韦、伊曲康唑、酮康唑、伏立康唑、奈法唑酮、奈非那韦、利托那韦、沙喹那韦、特利霉素等)联用，可升高本药的血药浓度，导致PTH的过度抑制。可能机制CYP3A强抑制药竞争性抑制CYP3A介导的本药的代谢。因此，合用应谨慎，应监测PTH和血清钙浓度，并可能有必要调整本药的剂量。
2．与洋地黄类化合物合用，可能出现高钙血症引起的洋地黄中毒。
3．与消胆胺合用，可降低本药的浓度。可能机制为消胆胺可减少脂溶性维生素(包括本药)的吸收。
因此，合用时应监测患者是否出现与维生素D缺乏相关的不良反应，如低钙血症和继发性甲状旁腺功能亢进的症状和体征。

ZEMPLAR - paricalcitol capsule, liquid filled 
Abbott Laboratories
ZEMPLAR®
(paricalcitol) Capsules
DESCRIPTION
Paricalcitol, USP, the active ingredient in Zemplar Capsules, is a synthetically manufactured analog of calcitriol, the metabolically active form of vitamin D indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease. Zemplar is available as soft gelatin capsules for oral administration containing 1 microgram, 2 micrograms or 4 micrograms of paricalcitol. Each capsule also contains medium chain triglycerides, alcohol, and butylated hydroxytoluene. The medium chain triglycerides are fractionated from coconut oil or palm kernel oil. The capsule shell is composed of gelatin, glycerin, titanium dioxide, iron oxide red (2 microgram capsules only), iron oxide yellow (2 microgram and 4 microgram capsules), iron oxide black (1 microgram capsules only), and water.
Paricalcitol is a white, crystalline powder with the empirical formula of C27H44O3, which corresponds to a molecular weight of 416.64. Paricalcitol is chemically designated as 19-nor-1α,3β,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene and has the following structural formula:

CLINICAL PHARMACOLOGY

Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin D hormone. The source of vitamin D in the body is from synthesis in the skin and from dietary intake. Vitamin D requires two sequential hydroxylations in the liver and the kidney to bind to and to activate the vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH)2 D3], is a hormone that binds to VDRs that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis, and to VDRs found in many other tissues, including prostate, endothelium and immune cells. VDR activation is essential for the proper formation and maintenance of normal bone. In the diseased kidney, the activation of vitamin D is diminished, resulting in a rise of PTH, subsequently leading to secondary hyperparathyroidism and disturbances in the calcium and phosphorus homeostasis.1 Decreased levels of 1,25(OH)2D3 have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH)2 D3 and resultant elevated PTH levels, both of which often precede abnormalities in serum calcium and phosphorus, affect bone turnover rate and may result in renal osteodystrophy.

Mechanism of Action

Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the VDR, which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.

Pharmacodynamics

Paricalcitol decreases serum intact parathyroid hormone (iPTH) and increases serum calcium and serum phosphorous in both hemodialysis (HD) and peritoneal dialysis (PD) patients. This observed relationship was quantified using a mathematical model for HD and PD patient populations separately. Computer-based simulations of 100 trials in HD or PD patients (N = 100) using these relationships predict slightly lower efficacy (at least two consecutive ≥ 30% reductions from baseline iPTH) with lower hypercalcemia rates (at least two consecutive serum calcium ≥ 10.5 mg/dL) for lower iPTH-based dosing regimens. Further lowering of hypercalcemia rates was predicted if the treatment with paricalcitol is initiated in patients with lower serum calcium levels at screening.

Based on these simulations, a dosing regimen of iPTH/80 with a screening serum calcium ≤ 9.5 mg/dL, approximately 76.5% (95% CI : 75.6% – 77.3%) of HD patients are predicted to achieve at least two consecutive ≥ 30% reductions from baseline iPTH over a duration of 12 weeks. The predicted incidence of hypercalcemia is 0.8% (95% CI : 0.7% – 1.0%). In PD patients, with this dosing regimen, approximately 83.3% (95% CI : 82.6% – 84.0%) of patients are predicted to achieve at least two consecutive ≥ 30% reductions from baseline iPTH. The predicted incidence of hypercalcemia is 12.4% (95% CI : 11.7% - 13.0%). (see CLINICAL STUDIES; CKD Stage 5 and DOSAGE AND ADMINISTRATION; CKD Stage 5)

Pharmacokinetics

Absorption

Paricalcitol is well absorbed. In healthy subjects, following oral administration of paricalcitol at 0.24 mcg/kg, the mean absolute bioavailability was approximately 72%; the mean maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration time curve (AUC0-∞) were 0.630 ng/mL, 3 hours and 5.25 ng•h/mL, respectively. The mean absolute bioavailability of paricalcitol in CKD Stage 5 patients on hemodialysis (HD) or peritoneal dialysis (PD) was 79% or 86%, respectively. A food effect study in healthy subjects indicated that the Cmax and AUC0-∞ were unchanged when paricalcitol was administered with a high fat meal compared to fasting. Food delays Tmax about 2 hours. The AUC0-∞ of paricalcitol increased proportionally over the dose range of 0.06 to 0.48 mcg/kg in healthy subjects. Following multiple dosing, as once daily in CKD Stage 4 patients, the exposure (AUC) was slightly lower than that obtained after a single dose administration.

Distribution

Paricalcitol is extensively bound to plasma proteins (≥ 99.8%). The mean apparent volume of distribution following a 0.24 mcg/kg dose of paricalcitol in healthy subjects was 34 L. The mean apparent volume of distribution following a 4 mcg dose of paricalcitol in CKD Stage 3 and 3 mcg dose in CKD Stage 4 patients is between 44 and 46 L.

Metabolism

After oral administration of a 0.48 mcg/kg dose of 3H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces, and no parent drug found in the urine. Several metabolites were detected in both the urine and feces. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.

In vitro data suggest that paricalcitol is metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation, 24,26- and 24,28-dihydroxylation and direct glucuronidation.

Elimination

Paricalcitol is eliminated primarily via hepatobiliary excretion; approximately 70% of the radiolabeled dose is recovered in the feces and 18% is recovered in the urine. In healthy subjects, the mean elimination half-life of paricalcitol is 4 to 6 hours over the studied dose range of 0.06 to 0.48 mcg/kg. The pharmacokinetics of paricalcitol capsule have been studied in patients with chronic kidney disease (CKD) Stage 3 and 4 patients. After administration of 4 mcg paricalcitol capsule in CKD Stage 3 patients, the mean elimination half-life of paricalcitol is 17 hours. The mean half-life of paricalcitol is 20 hours in CKD Stage 4 patients when given 3 mcg of paricalcitol capsule.

Table 1. Paricalcitol Capsule Pharmacokinetic Characteristics in CKD Stage 3 and 4 Patients

Pharmacokinetic Parameters	CKD Stage 3 n = 15*	CKD Stage 4 n = 14*
*   Four mcg paricalcitol capsule was given to CKD Stage 3 patients; three mcg paricalcitol capsule was given to CKD Stage 4 patients.
Cmax (ng/mL)	0.11 ± 0.04	0.06 ± 0.01
AUC0-∞ (ng•h/mL)	2.42 ± 0.61	2.13 ± 0.73
CL/F (L/h)	1.77 ± 0.50	1.52 ± 0.36
V/F (L)	43.7 ± 14.4	46.4 ± 12.4
t1/2	16.8 ± 2.65	19.7 ± 7.2

Special Populations

Geriatric

The pharmacokinetics of paricalcitol have not been investigated in geriatric patients greater than 65 years (see PRECAUTIONS).

Pediatric

The pharmacokinetics of paricalcitol have not been investigated in patients less than 18 years of age.

Gender

The pharmacokinetics of paricalcitol following single doses over 0.06 to 0.48 mcg/kg dose range were gender independent.

Hepatic Impairment

The disposition of paricalcitol (0.24 mcg/kg) was compared in patients with mild (n = 5) and moderate (n = 5) hepatic impairment (as indicated by the Child-Pugh method) and subjects with normal hepatic function (n = 10). The pharmacokinetics of unbound paricalcitol were similar across the range of hepatic function evaluated in this study. No dosing adjustment is required in patients with mild and moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.

Renal Impairment

Following administration of Zemplar Capsules, the pharmacokinetic profile of paricalcitol for CKD Stage 5 on hemodialysis (HD) or peritoneal dialysis (PD) was comparable to that in CKD 3 or 4 patients. Therefore, no special dosing adjustments are required other than those recommended in the Dosage and Administration section (see DOSAGE AND ADMINISTRATION).

Drug Interactions

An in vitro study indicates that paricalcitol is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nM (21 ng/mL) (approximately 20-fold greater than that obtained after highest tested dose). In fresh primary cultured hepatocytes, the induction observed at paricalcitol concentrations up to 50 nM was less than two-fold for CYP2B6, CYP2C9 or CYP3A, where the positive controls rendered a six- to nineteen-fold induction. Hence, paricalcitol is not expected to inhibit or induce the clearance of drugs metabolized by these enzymes.

Omeprazole

The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral) was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol were unaffected when omeprazole was administered approximately 2 hours prior to the paricalcitol dose.

Ketoconazole

The effect of multiple doses of ketoconazole administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-∞ approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone (see PRECAUTIONS).

CLINICAL STUDIES

CKD Stages 3 and 4

The safety and efficacy of Zemplar Capsules were evaluated in three, 24-week, double blind, placebo-controlled, randomized, multicenter, Phase 3 clinical studies in CKD Stage 3 and 4 patients. Two studies used an identical three times a week dosing design, and one study used a daily dosing design. A total of 107 patients received Zemplar Capsules and 113 patients received placebo. The mean age of the patients was 63 years, 68% were male, 71% were Caucasian, and 26% were African-American. The average baseline iPTH was 274 pg/mL (range: 145-856 pg/mL). The average duration of CKD prior to study entry was 5.7 years. At study entry 22% were receiving calcium based phosphate binders and/or calcium supplements. Baseline 25-hydroxyvitamin D levels were not measured.

The initial dose of Zemplar Capsules was based on baseline iPTH. If iPTH was ≤ 500 pg/mL, Zemplar Capsules were administered 1 mcg daily or 2 mcg three times a week, not more than every other day. If iPTH was > 500 pg/mL, Zemplar Capsules were administered 2 mcg daily or 4 mcg three times a week, not more than every other day. The dose was titrated by 1 mcg daily or 2 mcg three times a week every 2 to 4 weeks until iPTH levels were reduced by at least 30% from baseline. The overall average weekly dose of Zemplar Capsules was 9.6 mcg/week in the daily regimen and 9.5 mcg/week in the three times a week regimen.

In the clinical studies, doses were titrated for any of the following reasons: if iPTH fell to < 60 pg/mL, or decreased > 60% from baseline, the dose was reduced or temporarily withheld; if iPTH decreased < 30% from baseline and serum calcium was ≤ 10.3 mg/dL and serum phosphorus was ≤ 5.5 mg/dL, the dose was increased; and if iPTH decreased between 30 to 60% from baseline and serum calcium and phosphorus were ≤ 10.3 mg/dL and ≤ 5.5 mg/dL, respectively, the dose was maintained. Additionally, if serum calcium was between 10.4 to 11.0 mg/dL, the dose was reduced irrespective of iPTH, and the dose was withheld if serum calcium was > 11.0 mg/dL. If serum phosphorus was > 5.5 mg/dL, dietary counseling was provided, and phosphate binders could have been initiated or increased. If the elevation persisted, the Zemplar Capsules dose was decreased. Seventy-seven percent (77%) of the Zemplar Capsules treated patients and 82% of the placebo treated patients completed the 24-week treatment. The primary efficacy endpoint of at least two consecutive ≥ 30% reductions from baseline iPTH was achieved by 91% of Zemplar Capsules treated patients and 13% of the placebo treated patients (p < 0.001). The proportion of Zemplar Capsules treated patients achieving two consecutive ≥ 30% reductions was similar between the daily and the three times a week regimens (daily: 30/33, 91%; three times a week: 62/68, 91%).

The incidence of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL), hyperphosphatemia and elevated Ca x P product in Zemplar Capsules treated patients was similar to placebo. There were no treatment related adverse events associated with hypercalcemia or hyperphosphatemia in the Zemplar Capsules group. No increases in urinary calcium or phosphorous were detected in Zemplar Capsules treated patients compared to placebo.

The pattern of change in the mean values for serum iPTH during the studies are shown in Figure 1.

Figure 1. Mean Values for Serum iPTH Over Time in the Three Double-Blind, Placebo-Controlled, Phase 3, CKD Stage 3 and 4 Studies Combined

The mean changes from baseline to final treatment visit in serum iPTH, calcium, phosphorus, calcium-phosphorus product (Ca x P), and bone-specific alkaline phosphatase are shown in Table 2.

Table 2. Mean Changes from Baseline to Final Treatment Visit in Serum iPTH, Bone Specific Alkaline Phosphatase, Calcium, Phosphorus, and Calcium x Phosphorus Product in Three Double-Blind, Placebo-Controlled, Phase 3, CKD Stage 3 and 4 Studies Combined

	Zemplar Capsules	Placebo
iPTH (pg/mL)	n = 104	n = 110
Mean Baseline Value	266	279
Mean Final Treatment Value	162	315
Mean Change from Baseline (SE)	-104 (9.2)	+35 (9.0)
Bone Specific Alkaline Phosphatase (mcg/L)	n = 101	n = 107
Mean Baseline	17.1	18.8
Mean Final Treatment Value	9.2	17.4
Mean Change from Baseline (SE)	-7.9 (0.76)	-1.4 (0.74)
Calcium (mg/dL)	n = 104	n = 110
Mean Baseline	9.3	9.4
Mean Final Treatment Value	9.5	9.3
Mean Change from Baseline (SE)	+0.2 (0.04)	-0.1 (0.04)
Phosphorus (mg/dL)	n = 104	n = 110
Mean Baseline	4.0	4.0
Mean Final Treatment Value	4.3	4.3
Mean Change from Baseline (SE)	+0.3 (0.08)	+0.3 (0.08)
Calcium x Phosphorus Product (mg2/dL2)	n = 104	n = 110
Mean Baseline	36.7	36.9
Mean Final Treatment Value	40.7	39.7
Mean Change from Baseline (SE)	+4.0 (0.74)	+2.9 (0.72)

CKD Stage 5

The safety and efficacy of Zemplar Capsules were evaluated in a Phase 3, 12-week, double blind, placebo-controlled, randomized, multicenter study in patients with CKD Stage 5 on HD or PD. The study used a three times a week dosing design. A total of 61 patients received Zemplar Capsules and 27 patients received placebo. The mean age of the patients was 57 years, 67% were male, 50% were Caucasian, 45% were African-American, and 53% were diabetic. The average baseline iPTH was 701 pg/mL (range: 216-1933 pg/mL). The average time since first dialysis across all subjects was 3.3 years.

The initial dose of Zemplar Capsules was based on baseline iPTH/60. Subsequent dose adjustments were based on iPTH/60 as well as primary chemistry results that were measured once a week. Starting at Treatment Week 2, study drug was maintained, increased or decreased weekly based on the results of the previous week’s calculation of iPTH/60. Zemplar Capsules were administered three times a week, not more than every other day.

The proportion of patients achieving at least two consecutive ≥ 30% reductions from baseline iPTH was achieved by 88% of Zemplar Capsules treated patients and 13% of the placebo treated patients. The proportion of patients achieving at least two consecutive ≥ 30% reductions from baseline iPTH was similar for HD and PD patients.

The incidences of hypercalcemia (defined as two consecutive serum calcium values > 10.5 mg/dL) in patients treated with Zemplar Capsules was 6.6% as compared to 0% for patients given placebo. In PD patients the incidences of hypercalcemia in patients treated with Zemplar Capsules was 21% as compared to 0% for patients given placebo. The pattern of change in the mean values for serum iPTH during the studies are shown in Figure 2. The rate of hypercalcemia with Zemplar Capsules may be reduced with a lower dosing regimen based on the iPTH/80 formula as shown by computer simulations. The hypercalcemia rate can be further predicted to decrease, if the treatment is initiated in only those with baseline serum calcium ≤ 9.5 mg/dL. (see CLINICAL PHARMACOLOGY; Pharmacodynamics and DOSAGE AND ADMINISTRATION; CKD Stage 5)

Figure 2. Mean Values for Serum iPTH Over Time in a Phase 3, Double-Blind, Placebo-Controlled CKD Stage 5 Study

INDICATIONS AND USAGE

Zemplar Capsules are indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 3 and 4, and CKD Stage 5 patients on hemodialysis (HD) or peritoneal dialysis (PD).

CONTRAINDICATIONS

Zemplar Capsules should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or hypersensitivity to any ingredient in this product (see WARNINGS).

WARNINGS

Excessive administration of vitamin D compounds, including Zemplar Capsules, can cause over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease. Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to similar abnormalities and patient monitoring and individualized dose titration is required.

Pharmacologic doses of vitamin D and its derivatives should be withheld during Zemplar treatment to avoid hypercalcemia.

PRECAUTIONS

General

Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar Capsules.

Information for Patients

The patient or guardian should be informed about compliance with dosage instructions, adherence to instructions about diet and phosphorus restriction, and avoidance of the use of unapproved nonprescription drugs. Phosphate-binding agents may be needed to control serum phosphorus levels in patients, but excessive use of aluminum containing compounds should be avoided. Patients also should be informed about the symptoms of elevated calcium (see ADVERSE REACTIONS).

Laboratory Tests

During the initial dosing or following any dose adjustment of medication, serum calcium, serum phosphorus, and serum or plasma iPTH should be monitored at least every two weeks for 3 months after initiation of Zemplar therapy or following dose-adjustments in Zemplar therapy, then monthly for 3 months, and every 3 months thereafter.

Drug Interactions

Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A.

A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0-∞ (see CLINICAL PHARMACOLOGY). Since paricalcitol is partially metabolized by CYP3A and ketoconazole is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole.

Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in CD-1 mice, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1, 3, 10 mcg/kg given three times weekly (2 to 15 times the AUC at a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The incidence rate of uterine leiomyoma was significantly different than the control group at the highest dose of 10 mcg/kg. In a 104-week carcinogenicity study in rats, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15, 0.5, 1.5 mcg/kg (< 1 to 7 times the exposure following a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol. Paricalcitol did not exhibit genetic toxicity in vitro with or without metabolic activation in the microbial mutagenesis assay (Ames Assay), mouse lymphoma mutagenesis assay (L5178Y), or a human lymphocyte cell chromosomal aberration assay. There was also no evidence of genetic toxicity in an in vivo mouse micronucleus assay. Paricalcitol had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose (equivalent to 13 times a human dose of 14 mcg based on surface area, mcg/m2).

Pregnancy

Pregnancy Category C

Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times a human dose of 14 mcg or 0.24 mcg/kg (based on body surface area, mcg/m2), and when administered to rats at a dose two times the 0.24 mcg/kg human dose (based on body surface area, mcg/m2). At the highest dose tested, 20 mcg/kg administered three times per week in rats (13 times the 14 mcg human dose based on surface area, mcg/m2), there was a significant increase in the mortality of newborn rats at doses that were maternally toxic and are known to produce hypercalcemia in rats. No other effects on offspring development were observed. Paricalcitol was not teratogenic at the doses tested.

Paricalcitol (20 mcg/kg) has been shown to cross the placental barrier in rats. There are no adequate and well-controlled clinical studies in pregnant women. Zemplar Capsules should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers

Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. In the nursing patient, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Geriatric Use

Of the total number (n = 220) of CKD Stages 3 and 4 patients in clinical studies of Zemplar Capsules, 49% were age 65 and over, while 17% were age 75 and over. Of the total number (n = 88) of CKD Stage 5 patients in the pivotal study of Zemplar Capsules, 28% were age 65 and over, while 6% were age 75 and over. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pediatric Use

Safety and efficacy of Zemplar Capsules in pediatric patients have not been established.

ADVERSE REACTIONS

CKD Stages 3 and 4

The safety of Zemplar Capsules has been evaluated in three 24-week (approximately six-month), double-blind, placebo-controlled, multicenter clinical studies involving 220 CKD Stage 3 and 4 patients. Six percent (6%) of Zemplar Capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. All reported adverse events occurring in at least 2% in either treatment group are presented in Table 3.

Table 3. Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Zemplar-Treated Group of Three, Double-Blind, Placebo-Controlled, Phase 3, CKD Stage 3 and 4 Studies; All Treated Patients

	Number (%) of Subjects
Body Systema COSTART V Term	Zemplar Capsules (n = 107)		Placebo (n = 113)
a.   Includes all patients with events in that body system.
Overall	88	(82%)	86	(76%)
Body as a Whole	49	(46%)	40	(35%)
Accidental Injury	10	(9%)	8	(7%)
Pain	8	(7%)	7	(6%)
Viral Infection	8	(7%)	8	(7%)
Allergic Reaction	6	(6%)	2	(2%)
Headache	5	(5%)	5	(4%)
Abdominal Pain	4	(4%)	2	(2%)
Back Pain	4	(4%)	1	(1%)
Infection	4	(4%)	4	(4%)
Asthena	3	(3%)	2	(2%)
Chest Pain	3	(3%)	1	(1%)
Fever	3	(3%)	1	(1%)
Infection Fungal	3	(3%)	0	(0%)
Cyst	2	(2%)	0	(0%)
Flu Syndrome	2	(2%)	1	(1%)
Infection Bacterial	2	(2%)	1	(1%)
Cardiovascular	27	(25%)	19	(17%)
Hypertension	7	(7%)	4	(4%)
Hypotension	5	(5%)	3	(3%)
Syncope	3	(3%)	1	(1%)
Cardiomyopathy	2	(2%)	0	(0%)
Congestive Heart Failure	2	(2%)	5	(4%)
Myocardial Infarct	2	(2%)	0	(0%)
Postural Hypotension	2	(2%)	0	(0%)
Digestive	29	(27%)	31	(27%)
Diarrhea	7	(7%)	5	(4%)
Nausea	6	(6%)	4	(4%)
Vomiting	6	(6%)	5	(4%)
Constipation	4	(4%)	4	(4%)
Gastroenteritis	3	(3%)	3	(3%)
Dyspepsia	2	(2%)	2	(2%)
Gastritis	2	(2%)	4	(4%)
Rectal Disorder	2	(2%)	0	(0%)
Hemic and Lymphatic System	4	(4%)	10	(9%)
Hypervolemia	2	(2%)	4	(4%)
Ecchymosis	2	(2%)	4	(4%)
Metabolic and Nutritional Disorders	24	(22%)	34	(30%)
Edema	7	(7%)	5	(4%)
Uremia	7	(7%)	9	(8%)
Gout	4	(4%)	6	(5%)
Dehydration	3	(3%)	1	(1%)
Acidosis	2	(2%)	1	(1%)
Hyperkalemia	2	(2%)	3	(3%)
Hyperphosphatemia	2	(2%)	4	(4%)
Hypoglycemia	2	(2%)	4	(4%)
Hypokalemia	2	(2%)	1	(1%)
Musculoskeletal	12	(11%)	9	(8%)
Arthritis	5	(5%)	1	(1%)
Leg Cramps	3	(3%)	0	(0%)
Myalgia	2	(2%)	5	(4%)
Nervous	18	(17%)	12	(11%)
Dizziness	5	(5%)	5	(4%)
Vertigo	5	(5%)	0	(0%)
Depression	3	(3%)	0	(0%)
Insomnia	2	(2%)	2	(2%)
Neuropathy	2	(2%)	1	(1%)
Respiratory	26	(24%)	25	(22%)
Pharyngitis	11	(10%)	12	(11%)
Rhinitis	5	(5%)	4	(4%)
Bronchitis	3	(3%)	1	(1%)
Cough Increased	3	(3%)	2	(2%)
Sinusitis	3	(3%)	1	(1%)
Epistaxis	2	(2%)	1	(1%)
Pneumonia	2	(2%)	0	(0%)
Skin and Appendages	17	(16%)	10	(9%)
Rash	6	(6%)	3	(3%)
Pruritus	3	(3%)	3	(3%)
Skin Ulcer	3	(3%)	0	(0%)
Skin Hypertrophy	2	(2%)	0	(0%)
Vesiculobullous Rash	2	(2%)	1	(1%)
Special Senses	9	(8%)	11	(10%)
Amblyopia	2	(2%)	0	(0%)
Retinal Disorder	2	(2%)	0	(0%)
Urogenital System	10	(9%)	10	(9%)
Urinary Tract Infection	3	(3%)	1	(1%)
Kidney Function Abnormal	2	(2%)	1	(1%)

CKD Stage 5

The safety of Zemplar Capsules has been evaluated in one 12-week, double-blind, placebo-controlled, multicenter clinical study involving 88 CKD Stage 5 patients. Sixty-one patients received Zemplar Capsules and 27 patients received placebo.

The proportion of patients who terminated prematurely from the study due to adverse events was 7% for Zemplar Capsules treated patients and 7% for placebo patients.

Adverse events occurring in the Zemplar Capsules group at a frequency of 2% or greater and more frequently than in the placebo group are as follows:

Table 4. Treatment-Emergent Adverse Events by Body System Occurring in ≥ 2% of Subjects in the Zemplar-Treated Group , Double-Blind, Placebo-Controlled, Phase 3, CKD Stage 5 Study; All Treated Patients

	Number (%) of Subjects
Body Systema COSTART V Term	Zemplar Capsules (n=61)		Placebo (n = 27)
a.   Includes all patients with events in that body system.
Overall	43	(70%)	19	(70%)
Body as a Whole	27	(44%)	8	(30%)
Infection	9	(15%)	3	(11%)
Asthenia	3	(5%)	0	(0%)
Peritonitis	3	(5%)	0	(0%)
Accidental Injury	2	(3%)	0	(0%)
Headache	2	(3%)	0	(0%)
Digestive	18	(30%)	4	(15%)
Diarrhea	7	(11%)	3	(11%)
Constipation	3	(5%)	0	(0%)
Nausea and Vomiting	3	(5%)	0	(0%)
Dyspepsia	2	(3%)	0	(0%)
Hemic and Lymphatic System	6	(10%)	0	(0%)
Hypervolemia	3	(5%)	0	(0%)
Ecchymosis	2	(3%)	0	(0%)
Metabolic and Nutritional Disorders	7	(11%)	0	(0%)
Hypoglycemia	2	(3%)	0	(0%)
Peripheral Edema	2	(3%)	0	(0%)
Uremia	2	(3%)	0	(0%)
Nervous	12	(20%)	2	(7%)
Dizziness	4	(7%)	0	(0%)
Insomnia	3	(5%)	0	(0%)
Anxiety	2	(3%)	0	(0%)
Respiratory	8	(13%)	4	(15%)
Sinusitis	2	(3%)	0	(0%)
Urogenital System	6	(10%)	4	(15%)
Urinary Tract Infection	2	(3%)	0	(0%)

OVERDOSAGE

Excessive administration of Zemplar Capsules can cause hypercalcemia, hypercalciuria, and hyperphosphatemia, and over suppression of PTH (see WARNINGS).

Treatment of Overdosage

The treatment of acute overdosage of Zemplar Capsules should consist of general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and institution of a low-calcium diet are also indicated in accidental overdosage. Due to the relatively short duration of the pharmacological action of paricalcitol, further measures are probably unnecessary. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered depending on the patient's underlying condition. These include the use of drugs such as phosphates and corticosteroids, as well as measures to induce an appropriate forced diuresis.

DOSAGE AND ADMINISTRATION

CKD Stages 3 and 4

Zemplar Capsules may be administered daily or three times a week. When dosing three times weekly, the dose should be administered no more frequently than every other day. The average weekly doses for both daily and three times a week dosage regimens are similar (see CLINICAL STUDIES).

Zemplar Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.

Initial Dose

The initial dose of Zemplar Capsules for CKD Stage 3 and 4 patients is based on baseline intact parathyroid hormone (iPTH) levels.

Baseline iPTH Level	Daily Dose	Three Times a Week Dose*
To be administered not more often than every other day
≤ 500 pg/mL	1 mcg	2 mcg
> 500 pg/mL	2 mcg	4 mcg

Dose Titration

Dosing must be individualized and based on serum or plasma iPTH levels, with monitoring of serum calcium and serum phosphorus. The following is a suggested approach in titration.

		Dose Adjustment at 2 to 4 Week Intervals
iPTH Level Relative to Baseline	Zemplar Capsule Dose	Daily Dosage	Three Times a Week Dosage*
To be administered not more often than every other day
The same or increased Decreased by < 30%	Increase	1 mcg	2 mcg
Decreased by ≥ 30%, ≤ 60%	Maintain
Decreased > 60% iPTH < 60 pg/mL	Decrease	1 mcg	2 mcg

If a patient is taking the lowest dose on the daily regimen and a dose reduction is needed, the dose can be decreased to 1 mcg three times a week. If a further dose reduction is required, the drug should be withheld as needed and can be restarted at a lower dose. If a patient is on a calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If hypercalcemia or an elevated Ca x P is observed, the dose of Zemplar should be reduced or interrupted until these parameters are normalized.

Serum calcium and phosphorus levels should be closely monitored after initiation of Zemplar Capsules and during dose titration periods and coadministration with strong P450 3A inhibitors (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

CKD Stage 5

Zemplar Capsules are to be administered three times a week, no more frequently than every other day.

Zemplar Capsules may be taken without regard to food. No dosing adjustment is required in patients with mild and moderate hepatic impairment.

Initial Dose

The initial dose of Zemplar Capsules in micrograms is based on a baseline iPTH level (pg/mL)/80. To minimize the risk of hypercalcemia patients should be treated only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower (see CLINICAL PHARMACOLOGY; Pharmacodynamics and CLINICAL STUDIES; CKD Stage 5).

Dose Titration

Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels. A suggested dose titration of paricalcitol capsules is based on the following formula:

Titration dose (micrograms) = most recent iPTH level (pg/ml)/80

Serum calcium and phosphorus levels should be closely monitored after initiation, during dose titration periods, and with co-administration of strong P450 3A inhibitors. If an elevated serum calcium or elevated Ca x P is observed and the patient is on a calcium-based phosphate binder, the binder dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. If serum calcium or Ca x P are elevated, the dose should be decreased by 2 to 4 micrograms lower than that calculated by the most recent iPTH/80. If further adjustment is required, the dose of paricalcitol capsules should be reduced or interrupted until these parameters are normalized.

As iPTH approaches the target range, small, individualized dose adjustments may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH, Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio may be warranted.
FDA批准雅培帕立骨化醇胶囊用于肾病并发症早期治疗
雅培公司（Abbott）5月27日宣布，FDA批准其活性维生素D治疗药物帕立骨化醇（paricalcitol，Zemplar）1、2和4 mcg胶囊剂用于预防和治疗继发性甲状旁腺功能亢进症（SHPT）。本品对接受透析和移植手术前的Ⅲ及Ⅳ期慢性肾脏疾病（CKD）患者的SHPT显示预防及治疗疗效。
本品为口服制剂，其活性成份帕立骨化醇的注射制剂于1998年上市，并已成为透析患者最广泛使用的SHPT预防及治疗药物。本品通过更为便利的口服途径给药降低甲状旁腺激素（PTH）水平，同时对血钙及血磷水平具有最小影响。PTH降低是SHPT治疗疗效的一个关键性指标。
3项Ⅲ期临床研究结果表明，本品能安全、有效地降低并发SHPT 的Ⅲ及Ⅳ期CKD患者PTH水平。在24周的治疗后，本品组91%的患者PTH水平明显且持续降低，而安慰剂组这一比例仅为13%。PTH水平明显且持续降低是指PTH至少连续2次降低30%以上（包括30%），并且在治疗第9周患者PTH平均降低30%以上。
本品常见的不良反应发生情况与安慰剂类似。另外，偶见治疗不当引发的维生素D中毒、血钙过多以及对本品成份过敏。
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注：以下产品不同规格和不同价格，购买以咨询为准！
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产地国家: 德国
原产地英文商品名:
ZEMPLAR 1MCG/CAP 28CAPS/BOTTLE
原产地英文药品名:
PARICALCITOL
中文参考商品译名:
ZEMPLAR 1微克/胶囊 28胶囊/瓶
中文参考药品译名:
帕立骨化醇
生产厂家中文参考译名:
雅培
生产厂家英文名:
ABBOTT
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产地国家: 德国
原产地英文商品名:
ZEMPLAR 2MCG/CAP 28CAPS/BOTTLE
原产地英文药品名:
PARICALCITOL
中文参考商品译名:
ZEMPLAR 2微克/胶囊 28胶囊/瓶
中文参考药品译名:
帕立骨化醇
生产厂家中文参考译名:
雅培
生产厂家英文名:
ABBOTT
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产地国家: 美国
原产地英文商品名:
ZEMPLAR 4MCG/CAP 30CAPS/BOTTLE
原产地英文药品名:
PARICALCITOL
中文参考商品译名:
ZEMPLAR 4微克/胶囊 30胶囊/瓶
中文参考药品译名:
帕立骨化醇
生产厂家中文参考译名:
雅培
生产厂家英文名:
ABBOTT
-----------------------------------------------------------
产地国家: 美国
原产地英文商品名:
ZEMPLAR 2MCG/CAP 30CAPS/BOTTLE
原产地英文药品名:
PARICALCITOL
中文参考商品译名:
ZEMPLAR 2微克/胶囊 30胶囊/瓶
中文参考药品译名:
帕立骨化醇
生产厂家中文参考译名:
雅培
生产厂家英文名:
ABBOTT
----------------------------------------------------------
产地国家: 美国
原产地英文商品名:
ZEMPLAR 1MCG/CAP 30CAPS/BOTTLE
原产地英文药品名:
PARICALCITOL
中文参考商品译名:
ZEMPLAR 1微克/胶囊 30胶囊/瓶
中文参考药品译名:
帕立骨化醇
生产厂家中文参考译名:
雅培
生产厂家英文名:
ABBOTT
该药品相关信息网址1:
http://www.zemplar.com/
该药品相关信息网址2:
http://www.drugs.com/zemplar.html
该药品相关信息网址3:
http://www.rxlist.com/zemplar-drug.htm