Search

Daprodustat is the first oral hypoxia‐inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B‐mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically‐based PK (PBPK) modeling of its drug–drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by OATP1B1/1B3 in the transfected cell systems and primary human and monkey hepatocytes. A single‐dose oral rifampin (OATP1B inhibitor) reduced daprodustat intravenous clearance by a notable 9.9 ± 1.2‐fold (P < 0.05) in cynomolgus monkeys. Correspondingly, volume of distribution at steady‐state was also reduced by 5.0 ± 1.1‐fold, whereas the half‐life change was minimal (1.5‐fold), corroborating daprodustat hepatic uptake inhibition by rifampin. A PBPK model accounting for OATP1B‐CYP2C8 interplay was developed, which well described daprodustat PK and DDIs with gemfibrozil (CYP2C8 and OATP1B inhibitor) and trimethoprim (weak CYP2C8 inhibitor) within 25% error of the observed data in healthy subjects. About 18‐fold increase in daprodustat area under the curve (AUC) following gemfibrozil treatment was found to be associated with strong CYP2C8 inhibition and moderate OATP1B inhibition. Moreover, PK modulation in hepatic dysfunction and subjects with CKD, in comparison to healthy control, was well‐captured by the model. CYP2C8 and/or OATP1B inhibitor drugs (e.g., gemfibrozil, clopidogrel, rifampin, and cyclosporine) were predicted to perpetrate moderate‐to‐strong DDIs in healthy subjects, as well as, in target CKD population. Daprodustat can be used as a sensitive CYP2C8 index substrate in the absence of OATP1B modulation. [ABSTRACT FROM AUTHOR]

During its fourth transporter workshop in 2021, the International Transporter Consortium (ITC) provided updates on emerging clinically relevant transporters for drug development. Previously highlighted and new transporters were considered based on up‐to‐date clinical evidence of their importance in drug–drug interactions and potential for altered drug efficacy and safety, including drug–nutrient interactions leading to nutrient deficiencies. For the first time, folate transport pathways (PCFT, RFC, and FRα) were examined in‐depth as a potential mechanism of drug‐induced folate deficiency and related toxicities (e.g., neural tube defects and megaloblastic anemia). However, routine toxicology studies conducted in support of drug development appear sufficient to flag such folate deficiency toxicities, whereas prospective prediction from in vitro folate metabolism and transport inhibition is not well enough established to inform drug development. Previous suggestion of a retrospective study of intestinal OATP2B1 inhibition to explain unexpected decreases in drug exposure were updated. Furthermore, when the absorption of a new molecular entity is more rapid and extensive than can be explained by passive permeability, evaluation of the OATP2B1 transport may be considered. Emerging research on hepatic and renal OAT2 is summarized, but current understanding of the importance of OAT2 was deemed insufficient to justify specific consideration for drug development. Hepatic, renal, and intestinal MRPs (MRP2, MRP3, and MRP4) were revisited. MRPs may be considered when they are suspected to be the major determinant of drug disposition (e.g., direct glucuronide conjugates); MRP2 inhibition as a mechanistic explanation for drug‐induced hyperbilirubinemia remains justified. There were no major changes in recommendations from previous ITC whitepapers. [ABSTRACT FROM AUTHOR]

Quantitative prediction of drug‐drug interactions (DDIs) involving organic anion transporting polypeptide (OATP)1B1/1B3 inhibition is limited by uncertainty in the translatability of experimentally determined in vitro inhibition potency (half‐maximal inhibitory concentration (IC50)). This study used an OATP1B endogenous biomarker‐informed physiologically‐based pharmacokinetic (PBPK) modeling approach to predict the effect of inhibitor drugs on the pharmacokinetics (PKs) of OATP1B substrates. Initial static analysis with about 42 inhibitor drugs, using in vitro IC50 values and unbound liver inlet concentrations (Iin,max,u), suggested in vivo OATP1B inhibition risk for drugs with R‐value (1+ Iin,max,u/IC50) above 1.5. A full‐PBPK model accounting for transporter‐mediated hepatic disposition was developed for coproporphyrin I (CP‐I), an endogenous OATP1B biomarker. For several inhibitors (cyclosporine, diltiazem, fenebrutinib, GDC‐0810, itraconazole, probenecid, and rifampicin at 3 different doses), PBPK models were developed and verified against available CP‐I plasma exposure data to obtain in vivo OATP1B inhibition potency—which tend to be lower than the experimentally measured in vitro IC50 by about 2‐fold (probenecid and rifampicin) to 37‐fold (GDC‐0810). Models verified with CP‐I data are subsequently used to predict DDIs with OATP1B probe drugs, rosuvastatin and pitavastatin. The predicted and observed area under the plasma concentration‐time curve ratios are within 20% error in 55% cases, and within 30% error in 89% cases. Collectively, this comprehensive study illustrates the adequacy and utility of endogenous biomarker‐informed PBPK modeling in mechanistic understanding and quantitative predictions of OATP1B‐mediated DDIs in drug development. [ABSTRACT FROM AUTHOR]

Drug-Drug Interactions Involving Renal OCT2/MATE Transporters: Clinical Risk Assessment May Require Endogenous Biomarker-Informed Approach Moreover, I in vitro i substrate studies using transporter-transfected HEK293 cells confirm that both NMN and metformin have similar phenotype; that is, both are substrates to OCT2 and MATEs, but not substrates of organic anion transporters (OAT1, 2, and 3; B Figure b S1). Organic cation transporter (OCT)2 and multidrug and toxin extrusion pump (MATE)1/2K facilitate renal secretion of many cationic drugs; and are of significance pertaining to drug-drug interaction (DDI) risk. Moreover, the rich dose-dependent biomarker data could be used to calibrate I in vivo i IC SB 50 sb via static or PBPK models, such that these models can be used to project DDI with substrate drugs, like metformin at the relevant clinical doses of the investigational drug. [Extracted from the article]

Drug Metabolism Reviews has an impressive track record of providing scientific reviews in the area of xenobiotic biotransformation over 47 years. It has consistently proved to be resourceful to many scientists from pharmaceutical industry, academia, regulatory agencies working in diverse areas including enzymology, pharmacology, pharmacokinetics, and toxicology. Over the last 5 years Drug metabolism Reviews has annually published an industry commentary aimed to highlight novel insights and approaches that have made significant impacts on the field of biotransformation (led by Cyrus Khojasteh). We hope to continue this tradition by providing an overview of advances made in the field of drug transporters during 2020. The field of drug transporters is rapidly evolving as they play an essential role in drug absorption, distribution, clearance, and elimination. In this review, we have selected outstanding drug transporter articles that have significantly contributed to moving forward the field of transporter science with respect to translation and improved understanding of diverse aspects including uptake clearance, clinical biomarkers, induction, proteomics, emerging transporters, and tissue targeting. The theme of this review consists of a synopsis that summarizes each article followed by our commentary. The objective of this work is not to provide a comprehensive review but rather to exemplify novel insights and state-of-the-art highlights of recent research that have advanced our understanding of drug transporters in drug disposition. We are hopeful that this effort will prove useful to the scientific community and as such request feedback, and further extend an invitation to anyone interested in contributing to future reviews. [ABSTRACT FROM AUTHOR]