Zannikos P N, Rohatagi S, Jensen B K, DePhillips S L, Rhodes G R
Department of Drug Metabolism and Pharmacokinetics of Aventis Pharma, Collegeville, Pennsylvania, USA.
J Clin Pharmacol. 2000 Oct;40(10):1129-40.
RGD891 is a platelet GPIIb/IIIa receptor antagonist and potent inhibitor of platelet aggregation. This compound is biotransformed in vivo to RGD039, which also exhibits high affinity for the GPIIb/IIIa receptor. Pharmacokinetic/pharmacodynamic modeling was employed to describe the concentration-effect relationship of both compounds following the intravenous administration of RGD891 to healthy volunteers. The overall objectives of this work were to support the dose selection process for future intravenous RGD891 safety and efficacy studies. Various intravenous regimens of RGD891 were administered to healthy volunteers enrolled in three Phase I studies. Frequent plasma samples were collected at regular intervals for later measurement of RGD891 and RGD039 concentrations (validated LC/MS/MS methods). The pharmacokinetics of RGD891 and RGD039 were simultaneously analyzed by nonlinear mixed-effect modeling (NONMEM). Pharmacodynamic activity was assessed in all three studies by the degree to which ADP (20 microM)-induced platelet aggregation was inhibited. Population parameters describing the concentration-effect relationship of RGD891 and RGD039 were then generated using a modified competitive Emax-based model.
Parent compound is by far the predominant active compound circulating in the plasma following intravenous administration of RGD891. The plasma RGD891 concentration-time data were best fit by a two-compartment structural model. The fit of the basic model was improved when total body weight was introduced as a covariate for RGD891 distribution. Between-subject variability in the RGD891 pharmacokinetic parameters--V1, K10, and K21--was less than 17% (coefficient of variation). Formation of the active metabolite (RGD039; Km) and its elimination (Kem) were assumed to be first-order processes (i.e., one-compartment model). The population pharmacokinetic model could only provide a rough estimate of the plasma concentration-time profile for RGD039 after administration of a given intravenous dosage regimen of RGD891 since metabolite concentrations were relatively low and highly variable. The first-order rate constant describing the formation of RGD039 from RGD891 (Km) was also associated with a substantial degree of between-subject variability (44.9%). The potency of RGD891 toward the inhibition of ADP-induced platelet aggregation was described by the population IC50 value (plasma concentration yielding 50% of maximal inhibition), which ranged from 58.0 to 95.4 ng/mL, depending on the pharmacokinetic-pharmacodynamic (PK-PD) model and the data set used. The relatively low concentrations of the active metabolite achieved following intravenous administration of RGD891 did not permit independent estimation of a population IC50 value for RGD039. Therefore, its potency was fixed at 2.2-fold greater than that of the parent compound (based on previous PK-PD analyses). Intersubject variability in the IC50 values was 30%.
Antagonism of the platelet IIb/IIIa receptors by intravenously administered RGD891 was effective in inhibiting ADP-induced platelet aggregation in a reversible and dose-dependent manner. Pharmacodynamic activity was largely attributed to the parent compound and less to the active metabolite based on the relative potencies of both compounds and the plasma concentrations of each achieved following intravenous administration. Intravenous bolus plus maintenance infusion regimens resulted in rapid attainment of steady-state plasma RGD891 concentrations. This combination regimen also provided for a marked and sustained inhibition of platelet aggregation that reached 90% or greater (relative to baseline values) in the higher dose groups. The modified Emax model adequately described inhibition of platelet aggregation following a particular intravenous dosage regimen of RGD891 (within the range of doses administered in the present studies). (ABSTRACT TRUNCATED)
RGD891是一种血小板糖蛋白IIb/IIIa受体拮抗剂，也是血小板聚集的强效抑制剂。该化合物在体内生物转化为RGD039，后者对糖蛋白IIb/IIIa受体也表现出高亲和力。采用药代动力学/药效学建模来描述在健康志愿者静脉注射RGD891后两种化合物的浓度-效应关系。这项工作的总体目标是为未来静脉注射RGD891的安全性和有效性研究的剂量选择过程提供支持。将RGD891的各种静脉给药方案应用于参加三项I期研究的健康志愿者。定期采集频繁的血浆样本，以便随后测量RGD891和RGD039的浓度（经过验证的液相色谱/串联质谱法）。通过非线性混合效应建模（NONMEM）同时分析RGD891和RGD039的药代动力学。在所有三项研究中，通过ADP（20微摩尔）诱导的血小板聚集受到抑制的程度来评估药效学活性。然后使用基于Emax的改良竞争模型生成描述RGD891和RGD039浓度-效应关系的群体参数。
静脉注射RGD891后，母体化合物是血浆中循环的主要活性化合物。血浆RGD891浓度-时间数据最适合用二室结构模型。当将总体重作为RGD891分布的协变量引入时，基本模型的拟合得到改善。RGD891药代动力学参数（V1、K10和K21）的个体间变异性小于17%（变异系数）。活性代谢产物（RGD039；Km）的形成及其消除（Kem）被假定为一级过程（即一室模型）。由于代谢产物浓度相对较低且高度可变，群体药代动力学模型只能对给予RGD891特定静脉给药方案后的RGD039血浆浓度-时间曲线提供粗略估计。描述从RGD891形成RGD039的一级速率常数（Km）也与相当程度的个体间变异性（44.9%）相关。RGD891对ADP诱导的血小板聚集的抑制效力由群体IC50值（产生最大抑制50%的血浆浓度）描述，其范围为58.0至95.4纳克/毫升，具体取决于药代动力学-药效学（PK-PD）模型和所使用的数据集。静脉注射RGD891后达到的活性代谢产物相对较低的浓度不允许独立估计RGD039的群体IC50值。因此，其效力固定为比母体化合物高2.2倍（基于先前的PK-PD分析）。IC50值的个体间变异性为30%。
静脉注射RGD891对血小板IIb/IIIa受体的拮抗作用以可逆和剂量依赖性方式有效抑制ADP诱导的血小板聚集。基于两种化合物的相对效力以及静脉注射后各自达到的血浆浓度，药效学活性主要归因于母体化合物，而较少归因于活性代谢产物。静脉推注加维持输注方案导致血浆RGD891浓度迅速达到稳态。这种联合方案还能显著且持续地抑制血小板聚集，在较高剂量组中达到90%或更高（相对于基线值）。改良的Emax模型充分描述了RGD891特定静脉给药方案后（在本研究给药剂量范围内）的血小板聚集抑制情况。（摘要截选）
