Feng Sheng, Bo Qingyan, Coleman Hugh A, Charoin Jean Eric, Zhu Mingfen, Xiao Jim, Jin Yuyan
Pharmaceutical Sciences, Roche Innovation Center Shanghai, Shanghai, China.
I2O DTA, Roche Innovation Center Shanghai, Shanghai, China.
J Clin Pharmacol. 2021 Aug;61(8):1027-1034. doi: 10.1002/jcph.1817. Epub 2021 Apr 21.
Coproporphyrins (CP-I and CP-III) in plasma are considered potential markers for assessing liver organic anion-transporting polypeptide transporter OATP1B activity and monitoring OATP1B-mediated drug-drug interactions (DDIs) in clinical settings. However, the effect of altered renal clearance (CL ) on CP-I and CP-III plasma exposure has rarely been examined. Therefore, the purpose of this study is to further evaluate CP-I and CP-III as clinical endogenous markers for OATP1B activity and to investigate the impact of CL on DDI assessments for the first time. In this study, 18 healthy participants were recruited to receive RO7049389 (a potential inhibitor of OATP1B) 800 mg twice daily for 6 days and a single dose of pitavastatin (a probe drug of OATP1B) before and after RO7049389 treatment. Plasma concentrations of pitavastatin, CP I, CP III, and the amounts of CP-I and CP-III excreted in urine were measured. Seventeen healthy participants completed the study. After multiple doses of RO7049389, the area under the plasma concentration-time curve from time 0 to 12 hours of pitavastatin increased 1.95-fold (90% confidence interval [CI], 1.58-2.41), while for CP-I and CP-III it increased 3.00-fold (90%CI, 2.35-3.82) and 2.84-fold (90%CI, 2.22-3.65), respectively. Concurrently, the CL of CP-I decreased by 31% (90%CI, 23%-39%), and that of CP-III decreased by 70% (90%CI, 61%-77%). In conclusion, CP-I and CP-III in plasma display the potential to be applied as endogenous markers for the evaluation of OATP1B inhibition in clinical trials. While renal transporters contribute significantly to the CL of CP-III, it would be better to investigate the impact of the CL on plasma exposure of CP-III during clinical DDI assessments.
血浆中的粪卟啉（CP-I和CP-III）被认为是评估肝脏有机阴离子转运多肽转运体OATP1B活性以及在临床环境中监测OATP1B介导的药物-药物相互作用（DDIs）的潜在标志物。然而，肾清除率（CL）改变对CP-I和CP-III血浆暴露的影响很少被研究。因此，本研究的目的是进一步评估CP-I和CP-III作为OATP1B活性的临床内源性标志物，并首次研究CL对DDI评估的影响。在本研究中，招募了18名健康参与者，每天两次服用800 mg RO7049389（一种潜在的OATP1B抑制剂），持续6天，并在RO7049389治疗前后服用单剂量匹伐他汀（一种OATP1B的探针药物）。测量了匹伐他汀、CP I、CP III的血浆浓度以及尿中排出的CP-I和CP-III的量。17名健康参与者完成了研究。多次服用RO7049389后，匹伐他汀从0至12小时的血浆浓度-时间曲线下面积增加了1.95倍（90%置信区间[CI]，1.58 - 2.41），而CP-I和CP-III分别增加了3.00倍（90%CI，2.35 - 3.82）和2.84倍（90%CI，2.22 - 3.65）。同时，CP-I的CL下降了31%（90%CI，23% - 39%），CP-III的CL下降了70%（90%CI，61% - 77%）。总之，血浆中的CP-I和CP-III有潜力作为临床试验中评估OATP1B抑制作用的内源性标志物。虽然肾转运体对CP-III的CL有显著贡献，但在临床DDI评估期间，最好研究CL对CP-III血浆暴露的影响。
