PBPK Model of Coproporphyrin I: Evaluation of the Impact of SLCO1B1 Genotype, Ethnicity, and Sex on its Inter‐Individual Variability

Abstract

Coproporphyrin I (CPI) is an endogenous biomarker of OATP1B activity and associated drug-drug interactions. In this study, a minimal physiologically-based pharmacokinetic model was developed to investigate the impact of OATP1B1 genotype (c.521T>C), ethnicity, and sex on CPI pharmacokinetics and interindividual variability in its baseline. The model implemented mechanistic descriptions of CPI hepatic transport between liver blood and liver tissue and renal excretion. Key model parameters (e.g., endogenous CPI synthesis rate, and CPI hepatic uptake clearance) were estimated by fitting the model simultaneously to three independent CPI clinical datasets (plasma and urine data) obtained from white (n = 16, men and women) and Asian-Indian (n = 26, all men) subjects, with c.521 variants (TT, TC, and CC). The optimized CPI model successfully described the observed data using c.521T>C genotype, ethnicity, and sex as covariates. CPI hepatic active was 79% lower in 521CC relative to the wild type and 42% lower in Asian-Indians relative to white subjects, whereas CPI synthesis was 23% higher in male relative to female subjects. Parameter sensitivity analysis showed marginal impact of the assumption of CPI synthesis site (blood or liver), resulting in comparable recovery of plasma and urine CPI data. Lower magnitude of CPI-drug interaction was simulated in 521CC subjects, suggesting the risk of underestimation of CPI-drug interaction without prior OATP1B1 genotyping. The CPI model incorporates key covariates contributing to interindividual variability in its baseline and highlights the utility of the CPI modeling to facilitate the design of prospective clinical studies to maximize the sensitivity of this biomarker. Hepatic uptake via OATP1B1 and 1B3 has been widely recognized as a rate-limiting step in the clearance of anionic drugs, such as statins. 1,2 Considering the high degree of drug-drug interactions (DDIs) associated with OATP1B1 and therapeutic implications, regulatory agencies suggest elucidating factors that can change pharmacokinetics (PKs) of OATP1B1 substrates (https://www.fda.gov/media/ 13458 1/download, https://www.ema.europa.eu/en/docum ents/ scien tific-guide line/guide line-inves tigat ion-drug-inter actio ns-revis ion-1_en.pdf). Genetic polymorphism of SLCO1B1

Organic Anion Transporting Polypeptide 2B1 (OATP2B1) Genetic Variants: In Vitro Functional Characterization and Association With Circulating Concentrations of Endogenous Substrates

“…Males had greater concentrations of CPI and CPIII than females by 31 and 28%, respectively. The sex dependency on circulating CPI was previously reported in a cohort of Japanese subjects ( Mori et al, 2019 ) and is thought to be related to differences in synthesis rate ( Takita et al, 2020 ). In univariate analyses, East Asians had greater concentrations of CPI and CPIII compared to Caucasians ( Figure 4 ).…”

Factors Influencing Plasma Coproporphyrin‐I Concentration as Biomarker of OATP1B Activity in Patients With Rheumatoid Arthritis

“…have reported that healthy Japanese individuals with OATP1B1*15/*15 alleles have higher CP‐I levels compared with those with OATP1B1*1b/*1b or OATP1B1*1b/*15 alleles. Takita et al 27 . have demonstrated that the hepatic activity of CP‐I is 79% lower in c.521CC compared with wild type, and 42% lower in Asian Indian patients compared with White patients.…”

Population pharmacokinetic modeling and simulation to support qualification of pyridoxic acid as endogenous biomarker of OAT1/3 renal transporters

“…However, mechanistic understanding of the disposition of biomarkers and factors contributing to inter-or intra-individual variability in their baseline is still lacking for many. This is of particular relevance for endogenous biomarkers for renal transporters, in contrast to more advanced knowledge and evaluation of endogenous biomarkers for hepatic transporters 3,15,20,24 . In this study a population PK model has been developed for PDA and HVA, two recently identified promising plasma-based biomarkers of renal transporters OAT1/3.…”

“…Modelling and simulation has increasingly been used as a tool to gain mechanistic insight into disposition of transporter biomarkers 3,14,[19][20][21][22][23][24] . These techniques are helpful in understanding the formation, disposition, and elimination process of endogenous biomarkers to facilitate their qualification and inform optimal design of subsequent interaction studies.…”

“…These techniques are helpful in understanding the formation, disposition, and elimination process of endogenous biomarkers to facilitate their qualification and inform optimal design of subsequent interaction studies. Most of the work so far has been reported for endogenous biomarkers of hepatic transporters (organic anion polypeptides OATP1B1 and OATP1B3), specifically coproporphyrin I (CPI) 3,[19][20][21][22]24 . In contrast, very limited number of studies in the literature have investigated endogenous biomarkers of renal transporters, specifically OAT1/3 transporters [25][26][27][28] .…”