A Mechanistic Pharmacokinetic Model for Liver Transporter Substrates Under Liver Cirrhosis Conditions

Li, Rui; Barton, Hugh A.; Maurer, TS

doi:10.1002/psp4.39

Cited by 29 publications

(26 citation statements)

References 39 publications

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“…Predictions of the role of drug transporters in specific populations are further hindered by the lack of knowledge pertaining to disease‐ or population‐specific factors. Recently, data on hepatic transporters in patients with hepatic impairment have been populated . Continued research is expected to enhance the overall predictability of the PBPK model for drug transporters.…”

Section: Discussionmentioning

confidence: 99%

The Application of Physiologically Based Pharmacokinetic Modeling to Predict the Role of Drug Transporters: Scientific and Regulatory Perspectives

Pan

Hsu

Grimstein

et al. 2016

The Journal of Clinical Pharma

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Transporters play an important role in drug absorption, disposition, and drug action. The evaluation of drug transporters requires a comprehensive understanding of transporter biology and pharmacology. Physiologically based pharmacokinetic (PBPK) models may offer an integrative platform to quantitatively evaluate the role of drug transporters and its interplay with other drug disposition processes such as passive drug diffusion and elimination by metabolizing enzymes. To date, PBPK modeling and simulations integrating drug transporters lag behind that for drug-metabolizing enzymes. In addition, predictive performance of PBPK has not been well established for predicting the role of drug transporters in the pharmacokinetics of a drug. To enhance overall predictive performance of transporter-based PBPK models, it is necessary to have a detailed understanding of transporter biology for proper representation in the models and to have a quantitative understanding of the contribution of transporters in the absorption and metabolism of a drug. This article summarizes PBPK-based submissions evaluating the role of drug transporters to the Office of Clinical Pharmacology of the US Food and Drug Administration. Keywordstransporter, drug-drug interaction, physiologically based pharmacokinetic models, predictive performance Drug transporters play a critical role in drug absorption, disposition, and action.1,2 However, recognition of the importance of drug transporters and the implementation of a routine assessment in drug development lag behind the metabolizing enzymes. In addition, interpretation of the clinical significance of transporter data is more difficult than that for metabolizing enzymes for several reasons. First, the biology and pharmacology of certain transporters, especially the emerging transporters, are not fully understood. Second, major drug transporters are ubiquitously distributed in the body. For example, if a drug is tested as a substrate of P-glycoprotein (P-gp) in vitro, one needs to consider the role of P-gp in oral absorption through the intestine, distribution into the central nervous system, and elimination via active section in the liver and kidneys. Third, drug transporters are differentially localized in a variety of polarized cells, including enterocytes, hepatocytes, and proximal tubule cells. Within these cells, some transporters are located on the apical side, others on the basolateral side. These transporters often have distinctive functions (eg, efflux versus uptake) and regulate drug concentrations inside and outside the cells. Fourth, regulation of drug concentrations inside and outside the cells may be mediated simultaneously by transporters and passive diffusion processes. If a Pgp substrate has high passive permeability, it may still be effectively absorbed from intestinal lumen. Finally, transporter activities may affect a drug's contact with drug-metabolizing enzymes, a phenomenon known as enzyme-transporter interplay. Physiologically based pharmacokinetic (PBPK) models comb...

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Section: Discussionmentioning

confidence: 99%

The Application of Physiologically Based Pharmacokinetic Modeling to Predict the Role of Drug Transporters: Scientific and Regulatory Perspectives

Pan

Hsu

Grimstein

et al. 2016

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…When applied appropriately, the PBPK models are expected to provide more accurate predictions for transporter‐mediated disposition and DDIs as compared with static models. Examples of the use of PBPK modeling for the prediction of transporter‐mediated pharmacokinetics and DDIs are limited but increasing rapidly . An elegant in vitro–in vivo extrapolation (IVIVE)‐linked mechanistic PBPK framework has been developed to predict transporter‐mediated DDI between rosuvastatin and cyclosporine, with good accuracy.…”

Section: Progress In Methods For Predicting Hepatic Drug Transporter‐mentioning

confidence: 99%

“…Examples of the use of PBPK modeling for the prediction of transportermediated pharmacokinetics and DDIs are limited but increasing rapidly. [73][74][75][76][79][80][81][82][83][84][85][86] An elegant in vitro-in vivo extrapolation (IVIVE)-linked mechanistic PBPK framework has been developed to predict transportermediated DDI between rosuvastatin and cyclosporine, with good accuracy. This involves OATP1B1, OAT1B3, OATP2B1, NTCP, and BCRP, expressed at different physiological locations.…”

Section: Pbpk Modelmentioning

confidence: 99%

Role of Hepatic Drug Transporters in Drug Development

Liu

Sahi

2016

The Journal of Clinical Pharma

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Hepatic drug transporters can play an important role in pharmacokinetics and the disposition of therapeutic drugs and endogenous substances. Altered function of hepatic drug transporters due to drug-drug interactions (DDIs), genetic polymorphisms, and disease states can often result in a change in systemic and/or tissue exposure and subsequent pharmacological/toxicological effects of their substrates. Regulatory agencies including the US Food and Drug Administration, European Medicines Agency, and Japan Pharmaceuticals and Medical Devices Agency have issued guidance for industry on drug interaction studies, which contain comprehensive recommendations on in vitro and in vivo study tools and cutoff values to evaluate the DDI potential of new molecular entities mediated by hepatic drug transporters. In this report we summarize the latest regulatory and scientific progress of hepatic drug transporters in clinical DDIs, pharmacogenetics, drug-induced liver injury (DILI), as well as methods for predicting transporter-mediated pharmacokinetics and DDIs. Keywords hepatic drug transporters, drug-drug interactions, pharmacokinetics, drug developmentLiver plays a critical role in drug metabolism and excretion of substances from the body. Hepatic elimination comprises multiple intrinsic processes: basolateral uptake of compounds from the blood side (extracellular space) into hepatocytes (phase 0), basolateral efflux from hepatocytes into the blood, phase I/phase II metabolism, and biliary excretion (phase III). 1 The influence of all of these processes in overall hepatic intrinsic clearance (CL int,all,h ) is described quantitatively by the extended clearance concept 2 :CL int, all, h = PS inf × CL int, met + CL int, bile PS eff + CL int, met + CL int, bile where PS inf , PS eff , CL int,met , and CL int,bile represent basolateral uptake intrinsic clearance, sinusoidal efflux intrinsic clearance, metabolic intrinsic clearance, and biliary efflux intrinsic clearance, respectively.Membrane transporters play a key role in the uptake clearance of many drugs from hepatic sinusoidal blood (PS inf ) and in the excretion of parent compounds and/or metabolites from hepatocytes into bile (CL int,bile ) or the systemic circulation (PS eff ). 3

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“…In addition to investigating PK in healthy volunteers, there should be close attention to understanding the compound’s PK characteristics in hepatically impaired populations. Several pathophysiological changes, which regularly occur in individuals with cirrhosis and PH, can significantly impact drug disposition in this population (Table ) . The 2003 U.S. Food and Drug Administration (FDA) Guidance for Industry recommends a formal PK study in hepatically impaired individuals if (1) hepatic metabolism and/or excretion accounts for >20% of the absorbed drug’s or its active metabolite’s disposition, or (2) the test compound is either known or suspected to have a narrow therapeutic window, or (3) there is insufficient information about the compound’s metabolism and excretion and its predicted therapeutic window.…”

Section: Pharmacokinetic and Pharmacodynamic Evaluation In Ph Clinicamentioning

confidence: 99%

Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension

et al. 2019

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Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta‐blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners.

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A Mechanistic Pharmacokinetic Model for Liver Transporter Substrates Under Liver Cirrhosis Conditions

Cited by 29 publications

References 39 publications

The Application of Physiologically Based Pharmacokinetic Modeling to Predict the Role of Drug Transporters: Scientific and Regulatory Perspectives

The Application of Physiologically Based Pharmacokinetic Modeling to Predict the Role of Drug Transporters: Scientific and Regulatory Perspectives

Role of Hepatic Drug Transporters in Drug Development

Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension

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