Pharma Medica Research Inc., 6100 Belgrave Road, Mississauga, ON, L5R 0B7, Canada.
Clin Drug Investig. 2019 Mar;39(3):309-317. doi: 10.1007/s40261-019-00752-1.
Following oral administration of abiraterone acetate, the parent compound abiraterone acetate is rapidly metabolized to abiraterone. To our knowledge, bioanalytical methods to date have not been able to detect the parent compound in human plasma, and bioassay was only performed on the metabolite. A highly sensitive bioanalytical method was developed and validated to measure plasma concentrations of the parent compound. In this study, both analytes were assayed and used to evaluate the full pharmacokinetic profile of abiraterone acetate tablets.
This was an open-label, single-dose, one-period, one-treatment, pharmacokinetic study performed in 18 healthy subjects. Each subject was administered four tablets (corresponding to a total dose of 1000 mg) of abiraterone acetate. Blood samples for pharmacokinetic analysis were collected up to 60 h post-dose. Subjects' plasma concentrations for abiraterone acetate were assayed using highly sensitive validated bioanalytical methods with a lower limit of quantitation (LLOQ) of 0.5 pg/ml for abiraterone acetate and 0.1 ng/ml for abiraterone. Safety assessments were performed throughout the study.
The pharmacokinetic results for abiraterone acetate showed a mean for the maximum plasma concentration (C) of 54.67 ± 68.30 pg/ml, and a median time to maximum concentrations (t) of 5.53 h (range 2.67-35.00 h). The means for area under the concentration-time curve (AUC) from time 0 h to infinity (AUC) and AUC from time zero h to the time of the last measurable abiraterone acetate concentrations (AUC) were 386.13 ± 266.80 pg·h/ml and 460.07 ± 378.78 pg·h/ml, respectively. The apparent elimination half-life (t) showed a mean of 8.98 ± 3.92 h. None of the adverse events that affected three subjects (16.7%) were related to the study drug.
The ability to detect the low plasma abiraterone acetate concentrations, in addition to abiraterone, resulted in a complete characterization of the pharmacokinetics of abiraterone acetate that was not possible with other analytical methods that only measured the metabolite. The development of new bioanalytical methods such as these will allow for a more thorough understanding of the pharmacokinetics of abiraterone acetate, and this, in turn, can have an impact on both future examinations into abiraterone acetate pharmacokinetic behaviour and the evaluation of its generic formulations.
醋酸阿比特龙口服给药后，母体化合物醋酸阿比特龙迅速代谢为阿比特龙。据我们所知，迄今为止的生物分析方法尚未能够在人血浆中检测到母体化合物，并且仅对代谢物进行了生物测定。开发并验证了一种高灵敏度的生物分析方法来测量母体化合物的血浆浓度。在这项研究中，同时测定了这两种分析物，并用于评估醋酸阿比特龙片剂的完整药代动力学特征。
这是一项开放标签、单剂量、单周期、单治疗、药代动力学研究，在 18 名健康受试者中进行。每个受试者服用四片（相当于 1000mg 总剂量）醋酸阿比特龙。在给药后 60 小时内采集用于药代动力学分析的血样。使用高度敏感的验证生物分析方法测定醋酸阿比特龙的血浆浓度，醋酸阿比特龙的定量下限（LLOQ）为 0.5pg/ml，阿比特龙的 LLOQ 为 0.1ng/ml。整个研究过程中进行了安全性评估。
醋酸阿比特龙的药代动力学结果显示，最大血浆浓度（C）的平均值为 54.67±68.30pg/ml，最大浓度时间（t）的中位数为 5.53 小时（范围 2.67-35.00 小时）。从 0 小时到无穷大的浓度时间曲线下面积（AUC）和从 0 小时到最后可测量的醋酸阿比特龙浓度的 AUC（AUC）的平均值分别为 386.13±266.80pg·h/ml 和 460.07±378.78pg·h/ml。表观消除半衰期（t）的平均值为 8.98±3.92 小时。影响 3 名受试者（16.7%）的 3 种不良事件均与研究药物无关。
除了能够检测到低浓度的血浆醋酸阿比特龙外，还能检测到阿比特龙，这使得醋酸阿比特龙的药代动力学特征得以全面描述，而其他仅测量代谢物的分析方法则无法做到这一点。此类新生物分析方法的开发将有助于更深入地了解醋酸阿比特龙的药代动力学特性，进而对醋酸阿比特龙药代动力学行为的未来研究和对其仿制药制剂的评估产生影响。
