Changes in drug crystallinity in a commercial tacrolimus amorphous formulation result in variable pharmacokinetics.

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL
Lynne S Taylor, Niraj S Trasi, Hitesh S Purohit, Dajun Sun, Minori Kinjo, Zhanglin Ni, Sanjida Mahjabeen, Kairui Kevin Feng, Wei-Jhe Sun, Murali K Matta, Brian Decker, Raymond E Galinsky
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Abstract

Tacrolimus capsules contain the drug as the amorphous form. It is well known that drug crystallinity is a risk factor for the performance of amorphous formulations. This study investigated the impact of varying levels of crystalline drug on the pharmacokinetics of tacrolimus following oral dosing of a 5 mg capsule under fasting conditions. Two treatments with percent crystallinity of 20% and 50% were achieved by exposing a marketed generic tacrolimus product to open dish storage conditions of 35 °C and 75% relative humidity (RH) for up to 20 days. Crystallinity was monitored with X-ray powder diffraction. Prograf®, the reference listed drug (RLD), an amorphous generic drug product, and generic drug products containing 20% and 50% crystalline tacrolimus were evaluated. All four treatments were administered to healthy participants in a randomized, single-dose, four-treatment, four-period, four-way crossover study. Blood sampling occurred over 24 h. The amorphous generic tacrolimus product was determined not to be bioequivalent to the RLD. The capsules containing both 20% and 50% crystalline tacrolimus also failed the bioequivalence recommendations when compared to the amorphous generic or to the RLD. Both levels of crystalline tacrolimus resulted in BE failure for both Cmax and AUC parameters. The impact of tacrolimus crystallization was greater for maximum blood concentration (Cmax) values relative to the area-under-the-curve (AUC) values. This study demonstrates that crystalline tacrolimus formed in a marketed generic product and these changes resulted in variable pharmacokinetics which could be of significant clinical concern.

商用他克莫司无定形制剂中药物结晶度的变化导致不同的药代动力学。
他克莫司胶囊含有无定形形式的药物。众所周知,药物结晶是影响无定形制剂性能的一个风险因素。本研究调查了在空腹条件下口服 5 毫克胶囊后,不同程度的药物结晶对他克莫司药代动力学的影响。将市场上销售的普通他克莫司产品置于 35°C 和 75% 相对湿度 (RH) 的开口盘储存条件下长达 20 天,可获得结晶度分别为 20% 和 50% 的两种处理。结晶度通过 X 射线粉末衍射法进行监测。评估了普罗格拉夫®、参比上市药物(RLD)、无定形仿制药产品以及含有20%和50%结晶他克莫司的仿制药产品。在一项随机、单剂量、四疗程、四阶段、四交叉研究中,健康参与者服用了所有四种治疗药物。采血时间为 24 小时。经测定,无定形非专利他克莫司产品与RLD不具有生物等效性。含有 20% 和 50% 结晶他克莫司的胶囊与无定形仿制药或 RLD 相比,也未通过生物等效性建议。两种含量的结晶他克莫司均导致 Cmax 和 AUC 参数的生物等效性失败。相对于曲线下面积(AUC)值,他克莫司结晶对最大血药浓度(Cmax)值的影响更大。这项研究表明,在市场上销售的非专利产品中形成了结晶的他克莫司,这些变化导致了药代动力学的变化,可能会引起重大的临床问题。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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