1. PBPK Model of Coproporphyrin I: Evaluation of the Impact of SLCO1B1 Genotype, Ethnicity, and Sex on its Inter‐Individual Variability
- Author
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Hong Shen, Karelle Ménochet, Yueping Zhang, Hiroyuki Takita, Kayode Ogungbenro, Shelby Barnett, and Aleksandra Galetin
- Subjects
Male ,Coproporphyrins ,Physiologically based pharmacokinetic modelling ,Genotype ,Physiology ,Urine ,Kidney ,Models, Biological ,Sensitivity and Specificity ,Article ,Drug Development ,Pharmacokinetics ,Liver tissue ,Ethnicity ,Humans ,Medicine ,Drug Interactions ,Pharmacology (medical) ,Coproporphyrin I ,Observer Variation ,Sex Characteristics ,biology ,Liver-Specific Organic Anion Transporter 1 ,business.industry ,Research ,lcsh:RM1-950 ,Biological Transport ,Articles ,Healthy Volunteers ,lcsh:Therapeutics. Pharmacology ,Liver ,Modeling and Simulation ,biology.protein ,Biomarker (medicine) ,Female ,SLCO1B1 ,business ,Biomarkers - Abstract
Coproporphyrin I (CPI) is an endogenous biomarker of organic anion transporting polypeptides 1B (OATP1B) activity and associated drug-drug interactions. In this study, a minimal physiologicallybased pharmacokinetic model was developed to investigate the impact of OATP1B1 genotype (c.521T>C), ethnicity, and sex on CPI pharmacokinetics and inter-individual 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, CPI hepatic uptake clearance) were estimated by fitting the model simultaneously to three independent CPI clinical datasets (plasma and urine data) obtained from Caucasian (n=16, male and female) and Asian-Indian (n=26, all male) subjects, with c.521 variants (TT, TC, and CC). The optimized CPI model successfully described the observed data using three covariates (c.521T>C genotype, ethnicity, and sex). Hepatic active uptake of CPI decreased by 75% in 521CC relative to the wild type and by 37% in Asian-Indians relative to Caucasians. CPI synthesis was 24% lower in female relative to male. 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 under-estimation of CPI-drug interaction without prior OATP1B1 genotyping. The CPI model incorporates key covariates contributing to inter-individual variability in its baseline and highlights the utility of the CPI modelling to facilitate the design of prospective clinical studies to maximise the sensitivity of this biomarker.
- Published
- 2021