Abstract：
Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the OATP1B inhibitory potential because ensitrelvir had increased plasma concentrations of rosuvastatin in this study, raising concerns about breast cancer resistance protein and OATP1B inhibition. Furthermore, CP-I concentrations were compared between active and placebo groups in a first-in-human (FIH) study of ensitrelvir to verify whether the OATP1B inhibitory potential could be estimated at an early drug development stage. In the cocktail DDI study, CP-I did not differ between with/without administration of ensitrelvir, indicating that ensitrelvir has no OATP1B inhibitory effect. Although there were some individual variabilities in CP-I concentrations among the treatment groups in the FIH study, the normalization of CP-I concentrations with pre-dose values minimized these variabilities, suggesting that this normalized method would be helpful for comparing the CP-I from different participants. Finally, we concluded that CP-I concentrations were not affected by ensitrelvir in the FIH study. These results suggested that the CP-I determination in an FIH study and its normalized method can be useful for an early evaluation of the OATP1B-mediated DDI potential in humans.
摘要：
已经研究了卟啉-I（CP-I）作为有机阴离子转运多肽（OATP）1B的内源性生物标志物。这里,我们测定了安替瑞韦鸡尾酒药物相互作用（DDI）研究中的CP-I浓度，以评估OATP1B抑制潜力，因为安替瑞韦在这项研究中增加了瑞舒伐他汀的血浆浓度，引起人们对乳腺癌耐药蛋白和OATP1B抑制的担忧。此外，在ensitrelvir的首次人体（FIH）研究中，比较了活性组和安慰剂组之间的CP-I浓度，以验证是否可以在早期药物开发阶段估计OATP1B抑制潜力。在鸡尾酒DDI研究中，CP-I在服用/不服用ensitrelvir之间没有差异，表明安替瑞韦没有OATP1B抑制作用。尽管在FIH研究中，各治疗组之间的CP-I浓度存在一些个体差异，CP-I浓度与给药前值的归一化使这些变异性最小化，表明这种标准化方法将有助于比较不同参与者的CP-I。最后,我们得出的结论是,在FIH研究中,安替瑞韦对CP-I浓度没有影响.这些结果表明，FIH研究中的CP-I测定及其归一化方法可用于早期评估OATP1B介导的人DDI潜力。
