Coproporphyrin I as an endogenous biomarker to detect reduced OATP1B activity and shift in elimination route in chronic kidney disease

Hiroyuki Takita, Daniel Scotcher, Xiaoyan Chu, Ka Lai Yee, Kayode Ogungbenro, Aleksandra Galetin

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Coproporphyrin I (CPI) is an endogenous biomarker of organic anion transporting polypeptides 1B transporter (OATP1B). CPI plasma baseline was reported to increase with severity of chronic kidney disease (CKD). Further, ratio of CPI area under the plasma concentration-time curve in the presence/absence of OATP1B inhibitor rifampicin (AUCR) was higher in CKD patients compared to healthy subjects, in contrast to pitavastatin (a clinical OATP1B probe). This study investigated mechanism(s) contributing to altered CPI baseline in CKD patients by extending previously developed physiologically-based pharmacokinetic model to this patient population. CKD-related covariates were evaluated in a step-wise manner on CPI fraction unbound in plasma (fu,p), OATP1B-mediated hepatic uptake clearance (CLactive), renal clearance (CLR), and endogenous synthesis (ksyn). CPI model successfully recovered increased baseline and rifampicin-mediated AUCR in CKD patients by accounting for the following disease-related changes: 13% increase in fu,p, 29% and 39% decrease in CLactive in mild and moderate-to-severe CKD, respectively, decrease in CLR proportional to decline in GFR, and 27% decrease in ksyn in severe CKD. Almost complete decline in CPI renal elimination in severe CKD increased its fraction transported by OATP1B, rationalizing differences in the CPI-rifampicin interaction observed between healthy and CKD patients. In conclusion, mechanistic modelling performed here supports CKD-related decrease in OATP1B function to inform prospective PBPK modelling of OATP1B-mediated DDIs in these patients. Monitoring of CPI allows detection of CKD-drug interaction risk for OATP1B drugs with combined hepatic and renal elimination which may be under-estimated by extrapolating the interaction risk based on pitavastatin data in healthy subjects.
Original languageEnglish
JournalClinical Pharmacology & Therapeutics
Early online date2 Jun 2022
Publication statusPublished - 2 Jun 2022


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