【Background】Coproporphyrin I (CPI) is a sensitive endogenous biomarker of organic anion transporting polypeptides (OATP) 1B transporters. This study developed a reduced PBPK model to investigate the impact of OATP1B1 c.521T＞C genotype, ethnicity and sex on baseline plasma concentration and AUCR of CPI.
【Methods】The model implemented mechanistic descriptions of CPI hepatic transport between liver blood and liver tissue and renal excretion. Key model parameters (endogenous synthesis rate (k_syn), hepatic uptake clearance (CL_act)) were estimated using clinical data from 42 subjects. Covariate data (OATP1B1 genotype, ethnicity and sex) were available for all subjects. CPI AUCR with hypothetical OATP1B inhibitors were simulated using the developed CPI model and over the range of CL_act and k_syn relative to values in male Caucasians with 521TT genotype.
【Results】The optimized CPI model successfully described the observed data using three covariates. CPI CL_act decreased by 75% in subjects with 521CC genotype relative to the wild type and by 37% in Asian-Indians relative to Caucasians. CPI k_syn was 24% lower in female relative to male. Baseline CPI increased with decreasing CL_act (the effect of OATP1B1 genotype or ethnicity), whereas opposite trend was seen with decrease in k_syn (the effect of sex). Theoretical simulations illustrated high sensitivity of CPI AUCR to changes in CL_act and more pronounced impact of the genetic effect on the CPI AUCR, whereas differences in k_syn did not affect the interaction magnitude.
【Conclusion】CPI AUCR is highly sensitive to changes in CL_act, but not to k_syn; the latter highlights no risk of underestimation of the interaction magnitude if female subjects are included in the clinical study. The CPI model can facilitate the design of prospective clinical studies in subjects with multiple covariates to maximise the sensitivity of the biomarker [1].
【Reference】1. Takita et al. (2021) CPT Pharmacometrics Syst. Pharmacol. 10, 137－147.