首页> 外文期刊>Arzneimittel-Forschung: =Drug Research >Usefulness of the parent compound determination in bioequivalence evaluation of clopidogrel generic products.
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Usefulness of the parent compound determination in bioequivalence evaluation of clopidogrel generic products.

机译:母体化合物测定在氯吡格雷非专利产品生物等效性评估中的有用性。

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OBJECTIVE: The aim of the presented comparative study was to evaluate the bioavailability of clopidogrel (CAS 113665-84-2) formulations containing clopidogrel bisulfate (CAS 135046-48-9, CBS) 75 mg based on the parent compound (CBS) and its metabolite SR 26334 - clopidogrel carboxylic acid (CAS 144457-28-3, CCA) determination. METHODS: This paper presents the results of a comparative, randomized, two-way cross-over study on 48 healthy male volunteers assessing the bioequivalence of two products of clopidogrel 75 mg in form of film-coated tablets. In each of the two periods, separated by a 7-day washout period, a single dose of 150 mg (2 x 75 mg) of test and reference preparations was administered under fasting condition. Nineteen blood samples for determination of CBS and CCA were collected up to 48 h post dose. The CBS and CCA concentrations were quantified by a selective ultra performance liquid chromatographic-tandem mass spectrometric (UPLC-MS/MS) method. Pharmacokinetic parameters such as AUCinf, AUCt, Cmax, tmax, t1/2 were estimated using a non-compartmental model. Bioequivalence evaluation and calculation of CI were performed for clopidogrel and its metabolite by two one-sided t-test procedures by Schuirmann. RESULTS: In case of CCA the values of pharmacokinetic parameters were similar for the two products (test vs reference): AUCinf: 15773 vs. 15691 ng x h/mL, AUCt: 15,462 vs. 15,315 ng x h/mL, Cmax: 4919 vs. 4699 ng/mL, tmax: 0.84 vs. 0.93 h, t1/2: 7.92 vs. 8.41 h. Points of estimation of the ratios test/reference were near to 100% and CI in ranges 80-125% were fulfilled for all tested parameters. Pharmacokinetic parameters values of CBS were: AUCinf: 1.96 vs. 1.84 ng x h/mL (test vs reference), AUCt: 1.91 vs. 1.81 ng x h/mL, Cmax, 1.44 vs. 1.52 ng/mL, tmax: 0.90 vs. 0.99 h, t1/2: 0.74 vs. 0.57 h. The parametric 90%-confidence interval (CI) was in the range of 80-125% for AUCt ratio and AUCinf ratio. The CI range of Cmax fulfilled the widened range of 75-133% (according to the study protocol). Unfortunately, the very high variability of pharmacokinetic parameters (over 50%) contributed to low power of the test. CONCLUSIONS: Measurement of CBS concentrations should not be a reliable one for the bioequivalence assessment, due to very low concentrations, very small and variable values of AUC and high intra-subject variability. Thus, bioequivalence evaluation should be based on CCA determination. In the presented study evaluation based on CCA unequivocally and with the proper power confirmed the bioequivalence between the investigated clopidogrel products.
机译:目的:本比较研究的目的是评估基于母体化合物(CBS)含有75 mg硫酸氢氯吡格雷(CAS 135046-48-9,CBS)的氯吡格雷(CAS 113665-84-2)制剂的生物利用度,代谢物SR 26334-氯吡格雷羧酸(CAS 144457-28-3,CCA)的测定。方法:本文介绍了一项针对48位健康男性志愿者的比较,随机,双向比较研究的结果,该研究评估了75 mg氯吡格雷薄膜衣片形式的两种产品的生物等效性。在两个阶段的每个阶段中,以7天的清除期间隔开来,在禁食条件下给予150 mg(2 x 75 mg)的单剂测试和参考制剂。给药后48小时,收集了19份用于测定CBS和CCA的血样。通过选择性超高效液相色谱-串联质谱(UPLC-MS / MS)方法对CBS和CCA浓度进行定量。使用非房室模型估算药代动力学参数,如AUCinf,AUCt,Cmax,tmax,t1 / 2。氯吡格雷及其代谢物的生物等效性评估和CI的计算通过Schuirmann进行的两个单侧t检验程序进行。结果:在CCA的情况下,两种产品的药代动力学参数值相似(测试与参考):AUCinf:15773对15691 ng xh / mL,AUCt:15462对15315 ng xh / mL,Cmax:4919对。 4699 ng / mL,tmax:0.84对0.93小时,t1 / 2:7.92对8.41小时。测试/参考比率的估计点接近100%,并且所有测试参数均满足80-125%的CI。 CBS的药代动力学参数值为:AUCinf:1.96 vs. 1.84 ng xh / mL(测试相对于参考),AUCt:1.91 vs. 1.81 ng xh / mL,Cmax,1.44 vs. 1.52 ng / mL,tmax:0.90 vs.0.99 h,t1 / 2:0.74对0.57h。 AUCt比率和AUCinf比率的参数90%置信区间(CI)在80-125%的范围内。 Cmax的CI范围满足75-133%的扩展范围(根据研究方案)。不幸的是,药代动力学参数的非常高的可变性(超过50%)导致测试的功效低下。结论:CBS浓度的测量不宜用于生物等效性评估,因为其浓度非常低,AUC值非常小且易变,且受试者内部变异性很高。因此,生物等效性评估应基于CCA确定。在提出的研究评估中,明确基于CCA并以适当的能力证实了所研究的氯吡格雷产品之间的生物等效性。

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