Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd., 4123 Allschwil, Switzerland.
Biomolecules. 2023 Sep 8;13(9):1365. doi: 10.3390/biom13091365.
The P2Y receptor antagonist selatogrel is being developed for subcutaneous self-administration with a ready-to-use autoinjector at the onset of acute myocardial infarction (AMI) symptoms. The unique pharmacological profile of selatogrel (fast, potent, and short-acting) can bridge the time gap between the onset of AMI and first medical care. A clinical Phase 1 study showed a time-dependent pharmacodynamic interaction between selatogrel and loading doses of clopidogrel and prasugrel. As treatment switching is a common clinical practice, the assessment of subsequent switching from a clopidogrel loading dose to the first maintenance dose of oral P2Y receptor antagonists is highly relevant. Model-based predictions of inhibition of platelet aggregation (IPA) for the drugs triggering pharmacodynamic interactions were to be derived to support clinical guidance on the transition from selatogrel to oral P2Y receptor antagonists. Scenarios with selatogrel 16 mg administration or placebo followed by a clopidogrel loading dose and, in turn, prasugrel or ticagrelor maintenance doses at different times of administration were studied. Population pharmacokinetic/pharmacodynamic modeling and simulations of different treatment scenarios were used to derive quantitative estimates for IPA over time. Following selatogrel/placebo and a clopidogrel loading dose, maintenance treatment with ticagrelor or a prasugrel loading dose followed by maintenance treatment quickly achieved sustained IPA levels above 80%. Prior to maintenance treatment, a short time span from 18 to 24 h was identified where IPA levels were predicted to be lower with selatogrel than with placebo if clopidogrel was administered 12 h after selatogrel or placebo. Predicted IPA levels reached with placebo alone and a clopidogrel loading dose at 4 h were consistently lower than with selatogrel administration, followed by a clopidogrel loading dose at 12 h. If a clopidogrel loading dose is administered at 12 h, selatogrel maintains higher IPA levels up to 16 h. IPA levels are subsequently lower than on the placebo until the administration of the first maintenance dose. Model-based predictions informed the transition from selatogrel subcutaneous administration to oral P2Y therapy. The application of modeling techniques illustrates the value of employing pharmacokinetic and pharmacodynamic modeling for the simulation of various clinical scenarios of switching therapies.
P2Y 受体拮抗剂替卡格雷洛正在开发中，用于在急性心肌梗死 (AMI) 症状发作时通过即用型自动注射器进行皮下自我给药。替卡格雷洛独特的药理学特性（起效快、作用强且作用时间短）可以缩短 AMI 发作与首次医疗救治之间的时间间隔。一项临床 I 期研究表明，替卡格雷洛与氯吡格雷和普拉格雷负荷剂量之间存在时间依赖性药效学相互作用。由于治疗转换是一种常见的临床实践，因此评估从氯吡格雷负荷剂量转换为口服 P2Y 受体拮抗剂的首剂维持剂量具有重要意义。 为了支持关于从替卡格雷洛转换为口服 P2Y 受体拮抗剂的临床指导，需要对触发药效学相互作用的药物的血小板聚集抑制 (IPA) 进行基于模型的预测。 研究了替卡格雷洛 16 mg 给药或安慰剂后给予氯吡格雷负荷剂量，然后在不同时间给予普拉格雷或替格瑞洛维持剂量的方案。使用群体药代动力学/药效学模型和不同治疗方案的模拟来推导出随时间变化的 IPA 的定量估计。 在替卡格雷洛/安慰剂和氯吡格雷负荷剂量之后，替格瑞洛或普拉格雷负荷剂量后维持治疗迅速达到超过 80%的持续 IPA 水平。在维持治疗之前，发现从替卡格雷洛或安慰剂给药后 18 至 24 小时的短时间内，预测如果在替卡格雷洛或安慰剂给药后 12 小时给予氯吡格雷，替卡格雷洛的 IPA 水平将低于安慰剂。单独给予安慰剂和氯吡格雷负荷剂量 4 小时时预测的 IPA 水平始终低于替卡格雷洛给药，然后在 12 小时时给予氯吡格雷负荷剂量。如果在 12 小时时给予氯吡格雷负荷剂量，替卡格雷洛可将 IPA 水平维持在较高水平直至 16 小时。随后，IPA 水平低于安慰剂，直到给予首剂维持剂量。 基于模型的预测为从替卡格雷洛皮下给药转换为口服 P2Y 治疗提供了信息。建模技术的应用说明了应用药代动力学和药效学模型模拟各种治疗转换临床场景的价值。
