Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar
Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar
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DOI：
10.1007/s13346-016-0346-3
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发表时间：
2017-01-01
影响因子：
5.4
通讯作者：
Steeghs, Neeltje
中科院分区：
文献类型：
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作者：
Sawicki, Emilia;Verheijen, Remy B.;Steeghs, Neeltje
埃拉西达是一种通透性糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）的抑制剂，是一种有前途的药物吸收促进剂，这些药物是这些药物外排转运蛋白的底物。然而，埃拉西达几乎不溶于水，导致生物利用度低，目前限制了其临床应用。研究了一种新型非晶固体分散体（ASD）片的体外溶出度和临床药代动力学。在USP II型溶出仪中比较了ASD片剂和结晶粉末混合物的溶出度。在一项探索性临床研究中，对12名健康志愿者口服剂量为25,250或1000mg的ASD片剂的药代动力学进行了评估。目标Cmax根据既往临床数据设定为= 200 ng/mL。ASD片剂的体外溶出度是结晶粉末混合物的16.9 +/- 3.7倍。在探测范围内，C-max和AUC0-8随剂量线性增加。在1000 mg剂量水平下，Cmax达到200 ng/mL。在此剂量下，Cmax和AUC0-8分别为326 +/- 67 ng/mL和13.4 +/- 8.6 +/- 10(3)ng.h/mL。综上所述，ASD片剂耐受性良好，导致相关的药代动力学暴露，可用于概念验证临床研究。
Elacridar is an inhibitor of the permeability glycoprotein (P-gp) and the breast cancer resistance protein (BCRP) and is a promising absorption enhancer of drugs that are substrates of these drug-efflux transporters. However, elacridar is practically insoluble in water, resulting in low bioavailability which currently limits its clinical application. We evaluated the in vitro dissolution and clinical pharmacokinetics of a novel amorphous solid dispersion (ASD) tablet containing elacridar. The dissolution from ASD tablets was compared to that from a crystalline powder mixture in a USP type II dissolution apparatus. The pharmacokinetics of the ASD tablet were evaluated in an exploratory clinical study at oral doses of 25, 250, or 1000 mg in 12 healthy volunteers. A target Cmax was set at = 200 ng/mL based on previous clinical data. The in vitro dissolution from the ASD tablet was 16.9 +/- 3.7 times higher compared to that from a crystalline powder mixture. C-max and AUC0-8 increased linearly with dose over the explored range. The target Cmax of = 200 ng/mL was achieved at the 1000-mg dose level. At this dose, the Cmax and AUC0-8 were 326 +/- 67 ng/mL and 13.4 +/- 8.6 +/- 10(3) ng.h/mL, respectively. In summary, the ASD tablet was well tolerated, resulted in relevant pharmacokinetic exposure, and can be used for proof-of-concept clinical studies.