他扎罗汀倍他米松乳膏多次局部外用后人体系统吸收和安全性研究

【摘要】 目的 评价他扎罗汀倍他米松乳膏多次局部外用后在健康受试者和银屑病患者中的系统吸收和安全性。方法 2008年9月至2009年4月，在中国医学科学院皮肤病医院入组12例健康受试者，分别进入0.15%/0.15%和0.2%/0.2%他扎罗汀倍他米松乳膏组，每组6例，于两侧前臂屈侧及腰背部共4处，每处每天涂抹0.03 g试验药物，连续用药7 d，于给药前和开始用药后1、3、5、7 d采集静脉血样。2010年10月至2011年3月在中国医学科学院皮肤病医院收集60例非头部银屑病患者，按照3∶1∶1比例随机分配进入0.05%/0.05%他扎罗汀倍他米松乳膏组（36例）、0.05%二丙酸倍他米松乳膏组（12例）和0.05%他扎罗汀凝胶组（12例），他扎罗汀倍他米松乳膏组和他扎罗汀凝胶组早上用空白基质乳膏、晚上用试验药物；二丙酸倍他米松乳膏组早晚各使用1次试验药物；各组均在患病部位连续用药6周，分别于用药前和开始用药后2、4、6周采集静脉血样。液相色谱串联质谱法测定血浆中他扎罗汀酸和倍他米松的浓度。记录受试者不良事件，用药前后检查受试者血尿常规和肝肾功能。结果 12例健康受试者在开始给药1、3、5和7 d后体内他扎罗汀酸和倍他米松的浓度均低于定量下限浓度（0.04 μg/L）。银屑病患者连续用药2、4和6周后，他扎罗汀倍他米松乳膏组2例（5.56%）检出他扎罗汀酸，最高浓度为0.112 μg/L，4例（11.11%）检出倍他米松，最高浓度为0.201 μg/L；二丙酸倍他米松乳膏组12例中2例检出倍他米松，最高浓度为0.112 μg/L。在所有健康受试者及患者中均未观察到与试验药物相关的系统不良反应或实验室指标异常。结论 他扎罗汀倍他米松乳膏多次局部外用系统吸收少，无蓄积，具有良好的系统安全性。

Systemic absorption and safety of multiple doses of topical tazarotene/betamethasone dipropionate cream in healthy subjects and patients with psoriasis

【Abstract】 Objective To evaluate the systemic absorption and safety of multiple doses of topical tazarotene/betamethasone dipropionate cream in healthy subjects and patients with psoriasis. Methods From September 2008 to April 2009, 12 healthy subjects collected from Hospital for Skin Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College were randomly and equally divided into tazarotene 0.15%/betamethasone dipropionate 0.15% cream group and tazarotene 0.2%/betamethasone dipropionate 0.2% cream group; these subjects were instructed to apply 0.03 g of the test drug per day on each of the 4 body sites, including the flexor aspects of bilateral forearms, waist and back, for 7 consecutive days, and venous blood samples were obtained before, and 1, 3, 5 and 7 days after the start of drug application. From October 2010 to August 2011, 60 patients with non-cephalic psoriasis collected from the Hospital for Skin Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College were randomly divided into 3 groups at a ratio of 3∶1∶1, i.e., tazarotene 0.05%/betamethasone dipropionate 0.05% cream group （n = 36） and tazarotene 0.05% gel group （n = 12） topically treated with a cream vehicle in the morning and the test drug at night, and betamethasone dipropionate 0.05% cream group （n = 12） topically treated with the test drug twice a day （once in the morning and again in the evening）; the treatment lasted 6 consecutive weeks, and venous blood samples were collected before, and 2, 4 and 6 weeks after drug application. Liquid chromatography-tandem mass spectrometry was performed to determine the concentrations of tazarotenic acid and betamethasone in plasma. During the trial, adverse events in the subjects were recorded, routine blood and urine examinations were carried out, and liver and kidney function were evaluated before and after treatment. Results The plasma concentrations of tazarotenic acid and betamethasone in the 12 healthy subjects were below the lower limit of quantitation （0.04 μg/L） after 1-, 3-, 5- and 7-day treatment. After the consecutive treatment, After consecutive treatment, tazarotenic acid and betamethasone were detected in 2 （5.56%） and 4 （11.11%） patients respectively at week 2, 4 or 6 in the tazarotene 0.05%/betamethasone dipropionate 0.05% cream group, and the highest plasma concentrations of tazarotenic acid and betamethasone were 0.112 and 0.201 μg/L respectively; in the betamethasone dipropionate 0.05% cream group, betamethasone was detected in 2 of 12 patients, and the highest plasma concentration of betamethasone was 0.112 μg/L. No test drug-related systemic adverse reactions or laboratory abnormalities were observed in any of the healthy subjects or patients. Conclusion Multiple doses of topical tazarotene/betamethasone dipropionate cream has advantages of little systemic absorption, no long-term accumulation and good systemic safety.