Dr. Praveen Balimane, senior staff fellow, Division of Clinical Pharmacology-1 at OCP/OTS/CDER/FDA, spoke during the Society for Laboratory Automation and Screening ADMET Special Interest Group Meeting on “Transporter Evaluation in Drug Development.”
Transporters, like CYPs, are being recognized as proteins that can play a pivotal role in dictating the ADME properties of drugs. A thorough understanding of potential roles of transporters in drug interactions and toxicity is important in drug development. The talk provided a high level overview of various transporter evaluation initiatives at the agency. Some of the topics discussed:
• On-going efforts on decision trees within the DDI guidance
• Novel emerging transporters impacting ADME
• Inter-play of hepatic transporters and liver-toxicity
• Inter-play of renal transporters and renal function
Introduction to drug metabolism case studies for its impacts on drug discover...SAPA-GP
2014/10/02 SAPA-GP Webinar:
Introduction to drug metabolism case studies for its impacts on drug discovery and development
Zhoupeng Zhang
Dept of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
Merck Research Laboratories
Sino-American Pharmaceutical Professionals Association (SAPA)
– A lecture for Medicinal Chemists
(October 2, 2014)
The micronucleus assay is a test used to detect potential genotoxic compounds. It works by identifying micronuclei, which form during cell division from chromosome fragments or whole chromosomes damaged by genotoxins. The assay has regulatory approval and can be conducted in vitro using cell cultures or in vivo using rodents. Cells or animals are exposed to test compounds, cell division is blocked, and cells are analyzed microscopically for the presence of micronuclei to determine if the compound caused genetic damage. The micronucleus assay is a simple, reliable, and reproducible method for toxicological testing.
This document discusses genetic toxicology and genotoxicity testing. It defines genetic toxicology as the study of agents that can damage DNA and chromosomes. It also defines genotoxicity tests as in vitro and in vivo tests to detect compounds that induce genetic damage. The document outlines the importance of genotoxicity testing and describes some standard tests used, including the Ames test, chromosome aberration test, and micronucleus test. It provides details on procedures for these common genotoxicity assays and discusses recommendations for interpreting genotoxicity test results.
Toxicokinetics in preclinical studies by Priyabrata PandaPriyabrata Panda
The document discusses toxicokinetics in preclinical studies. It defines toxicokinetics and describes the aims and objectives of toxicokinetic studies, which include understanding absorption, distribution, metabolism and elimination of chemicals. It also discusses toxicokinetic parameters, models, and evaluation of toxicokinetics in preclinical studies according to ICH S3 guidelines. The guidelines provide guidance on quantifying exposure, determining sampling timepoints, dose levels, routes of administration and more to properly evaluate toxicokinetics in preclinical animal studies.
Formulation and evaluation of modified drug release tablet in tablet dosage w...SriramNagarajan16
Controlled drug dosage forms offer many advantages, such as nearly constant drug level at the site of action,
prevention of peak-valley fluctuation, reduction in dose of drug, reduced dosage frequency, avoidance of side effects
and improved patient compliance. Hence an attempt has been made to develop modified drug release by using tablet in
tablet technique with barrier coating by using natural and synthetic polymers with Salbutamol as model drug. The inner
core tablets were prepared by using direct compression method. The formulation F7 was selected for press coat by using
different polymers like HPMC, Ethyl cellulose, Xanthum gum and Guar gum in different ratios among which 1part of
Xanthum gum and 1part of Guar gum was optimized based on the lag time (20.75% in 4 hours) and percent of drug
release and also further evaluated.
Targeted drug delivery aims to increase the concentration of drugs in specific tissues while reducing systemic toxicity. It can target drugs to the first order (specific organs), second order (specific cell types), or third order (intracellular sites). Approaches include direct application to affected areas, passive accumulation through leaky vasculature, and active targeting using ligands. Parameters that determine efficacy are the size and blood flow of the target, and number of binding sites. Passive targeting uses physiological or physicochemical factors while active targeting uses carriers functionalized with targeting ligands. Main approaches are retrometabolic systems using drug-carrier complexes and prodrugs that are activated after biotransformation. Examples of targeted delivery systems discussed are magnetic nanoparticles, liposomes
This document discusses toxicity testing for drugs. It notes that safety is more important than efficacy. Factors like dosage, route of exposure, species, age and sex can affect toxicity. Tests include acute, sub-acute and chronic/long-term studies. Acute studies in rodents and non-rodents determine lethal dose 50 (LD50), effective dose 50 (ED50), therapeutic index and margin of safety within 14 days. Sub-acute studies last 2-4 weeks, while chronic studies examine effects over months to years, including carcinogenicity, teratogenicity and genetic/dependence liability.
Genotoxicity studies according to oecd guildline.Diana Lou
This document provides information about genotoxicity studies and various genotoxicity testing methods. It discusses that genotoxicity tests identify compounds that cause genetic damage through DNA damage or interference with the cell cycle. The standard battery of genotoxicity tests includes the Ames test (bacterial reverse mutation assay), in vitro mammalian cell micronucleus assay, in vitro mammalian chromosomal aberration assay, and in vivo mammalian erythrocyte micronucleus test, which detect various types of genetic damage. The document outlines the key principles, procedures, and reporting requirements for each of these standard genotoxicity assays.
Introduction to drug metabolism case studies for its impacts on drug discover...SAPA-GP
2014/10/02 SAPA-GP Webinar:
Introduction to drug metabolism case studies for its impacts on drug discovery and development
Zhoupeng Zhang
Dept of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
Merck Research Laboratories
Sino-American Pharmaceutical Professionals Association (SAPA)
– A lecture for Medicinal Chemists
(October 2, 2014)
The micronucleus assay is a test used to detect potential genotoxic compounds. It works by identifying micronuclei, which form during cell division from chromosome fragments or whole chromosomes damaged by genotoxins. The assay has regulatory approval and can be conducted in vitro using cell cultures or in vivo using rodents. Cells or animals are exposed to test compounds, cell division is blocked, and cells are analyzed microscopically for the presence of micronuclei to determine if the compound caused genetic damage. The micronucleus assay is a simple, reliable, and reproducible method for toxicological testing.
This document discusses genetic toxicology and genotoxicity testing. It defines genetic toxicology as the study of agents that can damage DNA and chromosomes. It also defines genotoxicity tests as in vitro and in vivo tests to detect compounds that induce genetic damage. The document outlines the importance of genotoxicity testing and describes some standard tests used, including the Ames test, chromosome aberration test, and micronucleus test. It provides details on procedures for these common genotoxicity assays and discusses recommendations for interpreting genotoxicity test results.
Toxicokinetics in preclinical studies by Priyabrata PandaPriyabrata Panda
The document discusses toxicokinetics in preclinical studies. It defines toxicokinetics and describes the aims and objectives of toxicokinetic studies, which include understanding absorption, distribution, metabolism and elimination of chemicals. It also discusses toxicokinetic parameters, models, and evaluation of toxicokinetics in preclinical studies according to ICH S3 guidelines. The guidelines provide guidance on quantifying exposure, determining sampling timepoints, dose levels, routes of administration and more to properly evaluate toxicokinetics in preclinical animal studies.
Formulation and evaluation of modified drug release tablet in tablet dosage w...SriramNagarajan16
Controlled drug dosage forms offer many advantages, such as nearly constant drug level at the site of action,
prevention of peak-valley fluctuation, reduction in dose of drug, reduced dosage frequency, avoidance of side effects
and improved patient compliance. Hence an attempt has been made to develop modified drug release by using tablet in
tablet technique with barrier coating by using natural and synthetic polymers with Salbutamol as model drug. The inner
core tablets were prepared by using direct compression method. The formulation F7 was selected for press coat by using
different polymers like HPMC, Ethyl cellulose, Xanthum gum and Guar gum in different ratios among which 1part of
Xanthum gum and 1part of Guar gum was optimized based on the lag time (20.75% in 4 hours) and percent of drug
release and also further evaluated.
Targeted drug delivery aims to increase the concentration of drugs in specific tissues while reducing systemic toxicity. It can target drugs to the first order (specific organs), second order (specific cell types), or third order (intracellular sites). Approaches include direct application to affected areas, passive accumulation through leaky vasculature, and active targeting using ligands. Parameters that determine efficacy are the size and blood flow of the target, and number of binding sites. Passive targeting uses physiological or physicochemical factors while active targeting uses carriers functionalized with targeting ligands. Main approaches are retrometabolic systems using drug-carrier complexes and prodrugs that are activated after biotransformation. Examples of targeted delivery systems discussed are magnetic nanoparticles, liposomes
This document discusses toxicity testing for drugs. It notes that safety is more important than efficacy. Factors like dosage, route of exposure, species, age and sex can affect toxicity. Tests include acute, sub-acute and chronic/long-term studies. Acute studies in rodents and non-rodents determine lethal dose 50 (LD50), effective dose 50 (ED50), therapeutic index and margin of safety within 14 days. Sub-acute studies last 2-4 weeks, while chronic studies examine effects over months to years, including carcinogenicity, teratogenicity and genetic/dependence liability.
Genotoxicity studies according to oecd guildline.Diana Lou
This document provides information about genotoxicity studies and various genotoxicity testing methods. It discusses that genotoxicity tests identify compounds that cause genetic damage through DNA damage or interference with the cell cycle. The standard battery of genotoxicity tests includes the Ames test (bacterial reverse mutation assay), in vitro mammalian cell micronucleus assay, in vitro mammalian chromosomal aberration assay, and in vivo mammalian erythrocyte micronucleus test, which detect various types of genetic damage. The document outlines the key principles, procedures, and reporting requirements for each of these standard genotoxicity assays.
Phase 1 clinical trials are the first studies done in humans of a new drug or treatment. They aim to determine the drug's safety and side effects, identify the maximum tolerated dose, and understand how the body processes the drug through pharmacokinetic evaluation. Phase 1 trials typically involve small groups of healthy volunteers or patients and start with low doses that are gradually increased. The results of phase 1 trials provide information needed to design subsequent clinical trial phases that further evaluate efficacy.
The document discusses novel drug delivery systems. It describes various targeted, controlled, and modulated drug delivery systems. It discusses different routes of administration including oral, pulmonary, injectable, infusion, ocular, nasal, topical, implantable, transmucosal, transdermal, and others. It also describes carrier types such as nanoparticles, liposomes, microspheres, and monoclonal antibodies. Finally, it provides details on some specific delivery methods and technologies.
This document discusses methods for assessing drug effects on renal and gastrointestinal systems in safety pharmacology studies. For renal function, in vivo mammalian models using rats and dogs are commonly used to assess glomerular function through clearance tests, tubular function through urine analysis, and hemodynamic function through blood flow measurements. In vitro and in silico models are also discussed. For gastrointestinal function, methods described include assessing gastric emptying and intestinal motility using in vitro tissue/organ baths and in vivo animal models, measuring gastric secretion in cell preparations and ligated rats, modeling nausea and emesis in ferrets and dogs, and measuring absorption in Caco-2 cell cultures and perfused intestinal segments of rats.
Toxicokinetic evaluation in preclinical studies by Shivam Diwaker Shivam Diwaker
Toxicokinetics evaluation in preclinical studies was presented. The presentation covered absorption, distribution, biotransformation and excretion of chemicals. Key points included how toxicokinetics quantifies exposure through measures like volume of distribution and clearance. The importance of evaluating metabolites and the factors influencing distribution and metabolism were discussed. Toxicokinetic studies are conducted at various stages of preclinical and clinical development to interpret toxicity results and support human trials. Alternative approaches to decrease animal usage in toxicokinetics were also presented.
The growing field of Personalized therapy and newer approaches for dosage forms related to Personalization for the safe and effective treatment of patients. The field of personalized medicine aims at converting the term of "one drug fits all " approach to Personalized therapy. Thus, shifting emphasis in medicine from reaction to prevention.
This document outlines the syllabus for the subject Biopharmaceutics and Pharmacokinetics at Dr. Babasaheb Ambedkar Marathwada University. The syllabus covers 14 sections that include topics such as absorption, distribution, metabolism, elimination of drugs, pharmacokinetic models, bioavailability and bioequivalence. Some key areas covered are factors affecting drug absorption, distribution and elimination processes in the body, pharmacokinetic parameters and concepts such as volume of distribution, clearance and half-life. Mathematical treatments of compartment models and methods to determine pharmacokinetic parameters are also included.
Drug transport and drug targeting - rumana hameedRumana Hameed
This document discusses genetic polymorphisms in drug transporters and drug targets. It covers various methods of targeted drug delivery including first, second, and third order targeting based on the specific cells or tissues targeted. Passive and active targeting approaches are described along with examples like magnetic drug targeting using nanoparticles, liposomes, transdermal patches, and brain-targeted delivery systems. The conclusion emphasizes that targeted drug delivery can reduce dose and side effects by assisting drugs to reach the desired site.
Toxicokinetics is the study of how the body affects a toxic substance over time through absorption, distribution, metabolism, and excretion. Toxicokinetic studies help explain toxicity results by quantifying exposure levels in animals and relating them to dose levels and time. Such studies are important for interpreting toxicity findings, designing further studies, and assessing the relevance of results to human safety. Key objectives include describing systemic exposure levels in toxicity studies and relating them to toxic effects.
This document discusses toxicokinetics and alternative methods to animal toxicity testing.
It begins by defining toxicokinetics as the study of how chemicals are absorbed, distributed, metabolized and excreted by the body. It then describes some importance of toxicokinetics in drug development.
It also discusses various alternative methods to animal testing including using tissue and cell cultures, human-based methods, computer simulations, and organ-on-a-chip technologies as ways to reduce and replace animal use in toxicity testing.
in vitro Drug Metabolism Assays to Support IND Submissions | MicroConstantsMicroConstants
This document discusses drug development and preclinical testing. It describes the ideal characteristics of a drug candidate from a DMPK perspective, such as good solubility, bioavailability, and balanced clearance. It also lists some common ADME issues like poor permeability, metabolism, and distribution, as well as in vitro studies that can help address these issues. Finally, it notes that an IND application must contain information on pharmacology/toxicology studies, manufacturing, and clinical protocols and investigators in order to assess safety and quality for initial human testing.
Radiotracers are radiolabeled compounds that can be used to study drug metabolism and disposition. Three key applications are discussed:
1) Absorption studies using radiolabeled drugs allow accurate quantification of the amount of drug and metabolites absorbed without needing authentic standards. A case study shows how radiolabeling helped study saquinavir absorption.
2) Tissue distribution studies involve measuring radioactivity levels in tissues to determine exposure. A case study found liver, ileum and large intestine had greatest exposure to a radiolabeled drug.
3) Whole body radiography provides a visual survey of drug distribution across major organs over time and can identify sites of accumulation missed by other methods. P
Toxicology testing, also known as safety assessment, or toxicity testing, is conducted to determine the degree to which a substance can damage a living or non-living organism. It is often conducted by researchers using standard test procedures to comply with governing regulations, for example for medicines and pesticides. Much toxicology is considered to be part of the field of preclinical development. Stages of in vitro and in vivo research are conducted to determine safe doses of exposure in humans before a first-in-man study. Toxicology testing may be conducted by the pharmaceutical industry, biotechnology companies or contract research organizations.
Drug development is a high-risk enterprise. The typical new drug takes 10-12 years to get to market and costs up to $500 million. Pharmaceutical companies face continually increasing challenges in drug development— shorter product life cycles, global competition, as well as daunting technical and regulatory hurdles. Meanwhile, as a result of the Human Genome Project and high throughput drug development methods, there are many more drug candidates to test. Thus, there is growing pressure on pharmaceutical and biopharmaceutical companies.
This document discusses the process of new drug discovery, including target identification, validation strategies like transgenic animals and antisense technology, hit discovery through physiological and high-throughput screening, lead optimization of absorption, distribution, metabolism, and excretion, prediction of drug safety using in vitro, in vivo, and ex vivo methods, estimation of starting doses for clinical trials, and the phases of clinical trials. The conclusion emphasizes that the ultimate test is how the drug performs and that developing a drug requires strategic decisions across many disciplines.
Drug discovery begins with identifying a biological target associated with a disease. Targets are validated through techniques like gene silencing to confirm their role in the disease process. Potential drug candidates, or leads, are identified through screening libraries of compounds or rational drug design. Leads undergo optimization to improve their safety, efficacy, and other properties. The entire drug discovery and development process takes an average of 15 years and over $800 million, with high failure rates contributing to the rising costs of drug development.
The document discusses drug targeting and targeted drug delivery systems. It defines drug targeting as delivering a drug only to its site of action and not to non-target organs, tissues, or cells. It discusses various types, approaches, and levels of drug targeting. It also discusses factors that affect drug targeting and various targeted drug delivery systems including prodrugs, liposomes, niosomes, nanoparticles, and microparticles.
Molecular basis of targated drug delivery system chatapPravin Chinchole
The document discusses targeted drug delivery systems and their molecular basis. It describes various types of targeted delivery such as ligand-driven receptor mediated delivery and active targeting using carriers with ligands. The key components of targeted delivery systems are described, including carriers to protect and deliver drugs to targets. Methods of targeting include passive targeting of tissues as well as active targeting of cells and intracellular sites using ligands that bind to receptors to direct delivery.
This document provides an overview of the drug discovery and development process. It discusses target identification, where researchers identify biomolecules associated with disease. Target validation then confirms the target's role in the disease. Lead identification involves finding compounds that interact with the target. Leads undergo optimization to improve properties. The methods discussed include high-throughput screening of compound libraries and structure-based drug design. The document also notes the high costs of drug development and increasing innovation deficit in the pharmaceutical industry.
This document discusses saturation kinetics and nonlinear pharmacokinetics. It explains that drug clearance follows first-order kinetics at low concentrations but can become saturated and shift to zero-order kinetics at high concentrations due to limited enzyme capacity. This nonlinear behavior is described by Michaelis-Menten kinetics. A few drugs like phenytoin exhibit saturation kinetics in the therapeutic range, making their dosing more complex due to changing half-lives with concentration. Understanding saturation and nonlinear pharmacokinetics is important for safely dosing drugs that exhibit these behaviors.
The document provides guidelines for testing chemicals for reproductive toxicity as outlined by the OECD. It discusses testing chemicals on both male and female rats to assess effects on fertility. For males, rats are dosed for a minimum of 4 weeks and examined for effects on testes and epididymides weight and histopathology as well as sperm motility and morphology. For females, rats are dosed throughout mating, pregnancy and lactation periods and assessed for effects on fertility, gestation, and offspring parameters. Clinical observations and pathology exams are also conducted.
APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING.docxfestockton
APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING 175CJON.ONS.ORG
C
Nephrotoxicity
Evidence in patients receiving cisplatin therapy
Elizabeth A. Duffy, DNP, RN, CPNP, Wendy Fitzgerald, RN, MSN, PPCNP-BC, CPON®, Kelley Boyle, MSN, RN, PCNS-BC, and Radha Rohatgi, PharmD, BCOP
CISPLATIN IS A PLATINUM COMPOUND THAT HAS BEEN USED as a chemotherapeutic
agent for many different cancers, including ovarian, testicular, lung, cervical,
and bladder cancers (Ruggiero, Rizzo, Trombatore, Maurizi, & Riccardi, 2016;
Santoso, Lucci, Coleman, Shafer, & Hannigan, 2003). The primary dose-
limiting toxicity of cisplatin is nephrotoxicity, a well-known side effect
(Jones, Spunt, Green, & Springate, 2008; Miller, Tadagavadi, Ramesh, &
Reeves, 2010). Nephrotoxicity involves glomerular or tubular dysfunction
of the kidneys after exposure to medications, other treatments, or toxins
(Skinner, 2011). Nephrotoxicity associated with cisplatin is related to accu-
mulation of metabolites in the renal proximal tubule cells of the kidneys,
where about 90% of cisplatin undergoes urinary excretion (Ruggiero et al.,
2016). Accumulation of these metabolites causes direct inflammation; the
production of reactive oxygen species, which leads to oxidative cell damage;
and cell death (Miller et al., 2010; Ruggiero et al., 2016). Many methods are
available to measure kidney function and define nephrotoxicity or acute
kidney injury (see Table 1).
Most patients receiving cisplatin experience acute impairment of glo-
merular and tubular function in varying degrees. Toxicity is dependent on
individual cisplatin pharmacokinetics and is usually more severe with high
total cisplatin doses and when other potential nephrotoxic medications are
given concurrently (Skinner, 2011; Womer, Pritchard, & Barratt, 1985). In one
study, children aged 10 years or older at treatment had a lower glomerular
filtration rate 10 years after therapy compared to children aged younger than
10 years at treatment (Skinner et al., 2009).
Nephrotoxicity can be reversible, but for some individuals, it can result
in permanent kidney injury, chronic progressive renal failure, or renal tubule
function impairment (Skinner et al., 2009). Chronic and severe reductions
of renal function have several sequelae. The immediate impact may be dose
reduction or cessation of potentially lifesaving nephrotoxic chemotherapy,
thereby increasing the risk of relapse or progression of the cancer. In the
event of a disease relapse or progression, changes to renal function may limit
enrollment in phase 1 or 2 clinical trials because of inclusion parameters
related to baseline renal function.
Hydration and diuretics have been used in conjunction with cisplatin
administration for decades to improve the excretion of cisplatin and reduce
the incidence of nephrotoxicity. One method of promoting this excretion is
through osmotic diuresis with mannitol (Morgan et al., 2014). However, the
amount ...
Phase 1 clinical trials are the first studies done in humans of a new drug or treatment. They aim to determine the drug's safety and side effects, identify the maximum tolerated dose, and understand how the body processes the drug through pharmacokinetic evaluation. Phase 1 trials typically involve small groups of healthy volunteers or patients and start with low doses that are gradually increased. The results of phase 1 trials provide information needed to design subsequent clinical trial phases that further evaluate efficacy.
The document discusses novel drug delivery systems. It describes various targeted, controlled, and modulated drug delivery systems. It discusses different routes of administration including oral, pulmonary, injectable, infusion, ocular, nasal, topical, implantable, transmucosal, transdermal, and others. It also describes carrier types such as nanoparticles, liposomes, microspheres, and monoclonal antibodies. Finally, it provides details on some specific delivery methods and technologies.
This document discusses methods for assessing drug effects on renal and gastrointestinal systems in safety pharmacology studies. For renal function, in vivo mammalian models using rats and dogs are commonly used to assess glomerular function through clearance tests, tubular function through urine analysis, and hemodynamic function through blood flow measurements. In vitro and in silico models are also discussed. For gastrointestinal function, methods described include assessing gastric emptying and intestinal motility using in vitro tissue/organ baths and in vivo animal models, measuring gastric secretion in cell preparations and ligated rats, modeling nausea and emesis in ferrets and dogs, and measuring absorption in Caco-2 cell cultures and perfused intestinal segments of rats.
Toxicokinetic evaluation in preclinical studies by Shivam Diwaker Shivam Diwaker
Toxicokinetics evaluation in preclinical studies was presented. The presentation covered absorption, distribution, biotransformation and excretion of chemicals. Key points included how toxicokinetics quantifies exposure through measures like volume of distribution and clearance. The importance of evaluating metabolites and the factors influencing distribution and metabolism were discussed. Toxicokinetic studies are conducted at various stages of preclinical and clinical development to interpret toxicity results and support human trials. Alternative approaches to decrease animal usage in toxicokinetics were also presented.
The growing field of Personalized therapy and newer approaches for dosage forms related to Personalization for the safe and effective treatment of patients. The field of personalized medicine aims at converting the term of "one drug fits all " approach to Personalized therapy. Thus, shifting emphasis in medicine from reaction to prevention.
This document outlines the syllabus for the subject Biopharmaceutics and Pharmacokinetics at Dr. Babasaheb Ambedkar Marathwada University. The syllabus covers 14 sections that include topics such as absorption, distribution, metabolism, elimination of drugs, pharmacokinetic models, bioavailability and bioequivalence. Some key areas covered are factors affecting drug absorption, distribution and elimination processes in the body, pharmacokinetic parameters and concepts such as volume of distribution, clearance and half-life. Mathematical treatments of compartment models and methods to determine pharmacokinetic parameters are also included.
Drug transport and drug targeting - rumana hameedRumana Hameed
This document discusses genetic polymorphisms in drug transporters and drug targets. It covers various methods of targeted drug delivery including first, second, and third order targeting based on the specific cells or tissues targeted. Passive and active targeting approaches are described along with examples like magnetic drug targeting using nanoparticles, liposomes, transdermal patches, and brain-targeted delivery systems. The conclusion emphasizes that targeted drug delivery can reduce dose and side effects by assisting drugs to reach the desired site.
Toxicokinetics is the study of how the body affects a toxic substance over time through absorption, distribution, metabolism, and excretion. Toxicokinetic studies help explain toxicity results by quantifying exposure levels in animals and relating them to dose levels and time. Such studies are important for interpreting toxicity findings, designing further studies, and assessing the relevance of results to human safety. Key objectives include describing systemic exposure levels in toxicity studies and relating them to toxic effects.
This document discusses toxicokinetics and alternative methods to animal toxicity testing.
It begins by defining toxicokinetics as the study of how chemicals are absorbed, distributed, metabolized and excreted by the body. It then describes some importance of toxicokinetics in drug development.
It also discusses various alternative methods to animal testing including using tissue and cell cultures, human-based methods, computer simulations, and organ-on-a-chip technologies as ways to reduce and replace animal use in toxicity testing.
in vitro Drug Metabolism Assays to Support IND Submissions | MicroConstantsMicroConstants
This document discusses drug development and preclinical testing. It describes the ideal characteristics of a drug candidate from a DMPK perspective, such as good solubility, bioavailability, and balanced clearance. It also lists some common ADME issues like poor permeability, metabolism, and distribution, as well as in vitro studies that can help address these issues. Finally, it notes that an IND application must contain information on pharmacology/toxicology studies, manufacturing, and clinical protocols and investigators in order to assess safety and quality for initial human testing.
Radiotracers are radiolabeled compounds that can be used to study drug metabolism and disposition. Three key applications are discussed:
1) Absorption studies using radiolabeled drugs allow accurate quantification of the amount of drug and metabolites absorbed without needing authentic standards. A case study shows how radiolabeling helped study saquinavir absorption.
2) Tissue distribution studies involve measuring radioactivity levels in tissues to determine exposure. A case study found liver, ileum and large intestine had greatest exposure to a radiolabeled drug.
3) Whole body radiography provides a visual survey of drug distribution across major organs over time and can identify sites of accumulation missed by other methods. P
Toxicology testing, also known as safety assessment, or toxicity testing, is conducted to determine the degree to which a substance can damage a living or non-living organism. It is often conducted by researchers using standard test procedures to comply with governing regulations, for example for medicines and pesticides. Much toxicology is considered to be part of the field of preclinical development. Stages of in vitro and in vivo research are conducted to determine safe doses of exposure in humans before a first-in-man study. Toxicology testing may be conducted by the pharmaceutical industry, biotechnology companies or contract research organizations.
Drug development is a high-risk enterprise. The typical new drug takes 10-12 years to get to market and costs up to $500 million. Pharmaceutical companies face continually increasing challenges in drug development— shorter product life cycles, global competition, as well as daunting technical and regulatory hurdles. Meanwhile, as a result of the Human Genome Project and high throughput drug development methods, there are many more drug candidates to test. Thus, there is growing pressure on pharmaceutical and biopharmaceutical companies.
This document discusses the process of new drug discovery, including target identification, validation strategies like transgenic animals and antisense technology, hit discovery through physiological and high-throughput screening, lead optimization of absorption, distribution, metabolism, and excretion, prediction of drug safety using in vitro, in vivo, and ex vivo methods, estimation of starting doses for clinical trials, and the phases of clinical trials. The conclusion emphasizes that the ultimate test is how the drug performs and that developing a drug requires strategic decisions across many disciplines.
Drug discovery begins with identifying a biological target associated with a disease. Targets are validated through techniques like gene silencing to confirm their role in the disease process. Potential drug candidates, or leads, are identified through screening libraries of compounds or rational drug design. Leads undergo optimization to improve their safety, efficacy, and other properties. The entire drug discovery and development process takes an average of 15 years and over $800 million, with high failure rates contributing to the rising costs of drug development.
The document discusses drug targeting and targeted drug delivery systems. It defines drug targeting as delivering a drug only to its site of action and not to non-target organs, tissues, or cells. It discusses various types, approaches, and levels of drug targeting. It also discusses factors that affect drug targeting and various targeted drug delivery systems including prodrugs, liposomes, niosomes, nanoparticles, and microparticles.
Molecular basis of targated drug delivery system chatapPravin Chinchole
The document discusses targeted drug delivery systems and their molecular basis. It describes various types of targeted delivery such as ligand-driven receptor mediated delivery and active targeting using carriers with ligands. The key components of targeted delivery systems are described, including carriers to protect and deliver drugs to targets. Methods of targeting include passive targeting of tissues as well as active targeting of cells and intracellular sites using ligands that bind to receptors to direct delivery.
This document provides an overview of the drug discovery and development process. It discusses target identification, where researchers identify biomolecules associated with disease. Target validation then confirms the target's role in the disease. Lead identification involves finding compounds that interact with the target. Leads undergo optimization to improve properties. The methods discussed include high-throughput screening of compound libraries and structure-based drug design. The document also notes the high costs of drug development and increasing innovation deficit in the pharmaceutical industry.
This document discusses saturation kinetics and nonlinear pharmacokinetics. It explains that drug clearance follows first-order kinetics at low concentrations but can become saturated and shift to zero-order kinetics at high concentrations due to limited enzyme capacity. This nonlinear behavior is described by Michaelis-Menten kinetics. A few drugs like phenytoin exhibit saturation kinetics in the therapeutic range, making their dosing more complex due to changing half-lives with concentration. Understanding saturation and nonlinear pharmacokinetics is important for safely dosing drugs that exhibit these behaviors.
The document provides guidelines for testing chemicals for reproductive toxicity as outlined by the OECD. It discusses testing chemicals on both male and female rats to assess effects on fertility. For males, rats are dosed for a minimum of 4 weeks and examined for effects on testes and epididymides weight and histopathology as well as sperm motility and morphology. For females, rats are dosed throughout mating, pregnancy and lactation periods and assessed for effects on fertility, gestation, and offspring parameters. Clinical observations and pathology exams are also conducted.
APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING.docxfestockton
APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING 175CJON.ONS.ORG
C
Nephrotoxicity
Evidence in patients receiving cisplatin therapy
Elizabeth A. Duffy, DNP, RN, CPNP, Wendy Fitzgerald, RN, MSN, PPCNP-BC, CPON®, Kelley Boyle, MSN, RN, PCNS-BC, and Radha Rohatgi, PharmD, BCOP
CISPLATIN IS A PLATINUM COMPOUND THAT HAS BEEN USED as a chemotherapeutic
agent for many different cancers, including ovarian, testicular, lung, cervical,
and bladder cancers (Ruggiero, Rizzo, Trombatore, Maurizi, & Riccardi, 2016;
Santoso, Lucci, Coleman, Shafer, & Hannigan, 2003). The primary dose-
limiting toxicity of cisplatin is nephrotoxicity, a well-known side effect
(Jones, Spunt, Green, & Springate, 2008; Miller, Tadagavadi, Ramesh, &
Reeves, 2010). Nephrotoxicity involves glomerular or tubular dysfunction
of the kidneys after exposure to medications, other treatments, or toxins
(Skinner, 2011). Nephrotoxicity associated with cisplatin is related to accu-
mulation of metabolites in the renal proximal tubule cells of the kidneys,
where about 90% of cisplatin undergoes urinary excretion (Ruggiero et al.,
2016). Accumulation of these metabolites causes direct inflammation; the
production of reactive oxygen species, which leads to oxidative cell damage;
and cell death (Miller et al., 2010; Ruggiero et al., 2016). Many methods are
available to measure kidney function and define nephrotoxicity or acute
kidney injury (see Table 1).
Most patients receiving cisplatin experience acute impairment of glo-
merular and tubular function in varying degrees. Toxicity is dependent on
individual cisplatin pharmacokinetics and is usually more severe with high
total cisplatin doses and when other potential nephrotoxic medications are
given concurrently (Skinner, 2011; Womer, Pritchard, & Barratt, 1985). In one
study, children aged 10 years or older at treatment had a lower glomerular
filtration rate 10 years after therapy compared to children aged younger than
10 years at treatment (Skinner et al., 2009).
Nephrotoxicity can be reversible, but for some individuals, it can result
in permanent kidney injury, chronic progressive renal failure, or renal tubule
function impairment (Skinner et al., 2009). Chronic and severe reductions
of renal function have several sequelae. The immediate impact may be dose
reduction or cessation of potentially lifesaving nephrotoxic chemotherapy,
thereby increasing the risk of relapse or progression of the cancer. In the
event of a disease relapse or progression, changes to renal function may limit
enrollment in phase 1 or 2 clinical trials because of inclusion parameters
related to baseline renal function.
Hydration and diuretics have been used in conjunction with cisplatin
administration for decades to improve the excretion of cisplatin and reduce
the incidence of nephrotoxicity. One method of promoting this excretion is
through osmotic diuresis with mannitol (Morgan et al., 2014). However, the
amount ...
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INTRODUCTION
What is pharmacogenomics
History
Principle
So what’s new about pharmacogenomics?
single nucleotide polymorphism (SNP)?
Genes commonly involved in pharmacogenomic drug metabolism and response
The anticipated benefits of pharmacogenomics
Pharmacogenetics Research/Database Program
Some of the barriers to using pharmacogenomics
Conclusion
References
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Praveen Balimane Addresses SLAS ADMET Special Interest Group at SLAS2015
1. 1
Dr. Praveen Balimane
Senior staff fellow
Division of Clinical Pharmacology-1 at
OCP/OTS/CDER/FDA
2015 SLAS ADMET SPECIAL INTEREST GROUP MEETING
Washington DC
Moderator:
David M. Stresser, Ph.D.
Corning® GentestSM Contract Research Services
“Transporter Evaluation in Drug Development.”
2. 2
ADMET Special Interest group - Mission
•Advance drug discovery and development by promoting
the discussion and dissemination of topics and ideas for
the integration of higher throughput technologies with
methods for determining toxicity, pharmacokinetics and
metabolism.
•Accelerate the drug discovery pipeline and shorten the
time of the development of new drugs that cure illnesses
and improve quality of life.
3. 3
Past Speakers and topics
Year Speaker Topic
2012 Michael Fisher, Alnylam Metabolic Stability assays
2013 Adrian Fretland, Lilly Impact of regulatory guidance on in vitro
DDI testing
2014 David Stresser, Corning Time-dependent inhibition of P450
2015 Praveen Balimane, FDA Transporter Evaluation in Drug
Development
All slide decks from past talks are
available on our Linked-In page:
4. Transporter Evaluation in
Drug Development
ADMET Special Interest Group
SLAS Meeting
Washington D.C (Feb 11th, 2015) 4
Praveen Balimane, Ph.D.
Office of Clinical Pharmacology
Office of Translational Sciences
CDER, FDA
5. Disclaimer
The contents of this presentation are my own
personal opinions and do not necessarily
reflect the official views and/or policy of the
FDA or any government agency.
5
6. Topics
• Overview- ADMET, Transporters DDI
– Decision trees (Pgp and OATP)
– Novel transporters- MATE, BSEP’s
– Hepatic transporters: safety interplay
– Renal transporters: creatinine
• Open forum
6
7. 7
TUFT’s REPORT: Total cost of developing
a drug is 2.6 Billion $$
Joseph Dimasi et. al., TUFTS center for study of Drug Development, Nov- 2014
Higher than the GDP
of Bhutan, Somalia,
Aruba……..many more
BUMPER approval
Rate in 2014
41 novel meds !!!
- 17 first-in-class
- 17 orphan/rare
10. 10
Impact of Transporters
• Global effect on ADMET
• Targeted drug accumulation in organs – efficacy & safety
• DDI’s: anticipate and manage
• Polymorphism & clinical variability
12. Regulatory Guidance/Guideline on Drug Interactions
• U.S. Food and Drug Administration (FDA)’s Draft Guidance for
Industry: Drug Interaction Studies—Study Design, Data
Analysis, Implications for Dosing, and Labeling
Recommendations (2012)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292
362.pdf)
–In addition to P-gp, transporter-related drug interaction evaluations and
decision trees are included for additional transporters (BCRP, OATP1B1/3,
OAT1/3 and OCT2)
• European Medicines Agency (EMA) Guideline on the
Investigation of Drug Interactions (2012)
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606
.pdf)
• Pharmaceuticals Medical Devices Agency (PMDA) Draft
Guideline on Drug Interactions (2013)
(http://search.e-gov.go.jp/servlet/Public?CLASSNAME=PCMMSTDETAIL&id=495130206)
12
13. Since 2007, 40-60% of NME drug
labels contain transporter information
(N=183).
0
10
20
30
40
50
60
70
2003 2004 2005 2006 2007 2008 2009 2010 2011
Year of approval
%ofNMEPIswithtransporter.
information
Transporter information has been increasingly included in
the FDA Approved New Molecular Entities (NMEs) Labeling
(2003-2011)
Agarwal S, et al. Pharm Res. 2013, 30:899-910; Lee S-C, et al, book chapter, 2014; Yu J, et al., DMD, 2014
86%
15% 18%
15%
8%
1.4%
9.5%
1.4%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
%ofNME
P-gp
BCRP
OATP
OCT
OAT
MATE
MRP
BSEP
Transporters
P-gp is the mostly studied transporter
(N=74)
13
In 2012, 79% of NME labels contain transporter information (N=33) and 96% were P-
gp; BCRP: 36%; OATP: 48%; OCT: 33%; OAT: 27%; MATE (N=1, 3%); MRP (N=5, 15%);
BSEP (N=2, 6%).
2012-2013
70-80%
14. 1414
The Challenges to Study Transporter DDI
• The issues presented by transporters are significantly more
complex than for metabolizing enzymes
– Involved in absorption, distribution and excretion: multiple processes of
concern
– Broad tissue distribution: different effects at different sites
– Functional redundancy: different transporters and different subfamilies
– Uptake and efflux transporters: need to consider both to assess the overall
effect
– Applicability of kinetic parameters and their interpretation
– Measuring drug exposure in plasma may not reflect impact on a drug’s
disposition (e.g., toxicity)
Tweedie D, et al, Clin Pharm Ther, July 2013
15. 15
NME as a Substrate
Does the drug level depend on a given transporter?
• Route of elimination
– Hepatic major
– Renal major
– Rate limiting step
• Physicochemical properties of the drug
– e.g., BCS or BDDCS
• Structure
– e.g., OATs for anions and OCTs for cation
– Caveat: some cations transported by OATs (cimetidine, sitagliptin)
– similarity to known substrates
16. Evaluation of NME as a Substrate for Transporters
Determine whether
NME is a P-gp
and/or BCRP
substrate in vitro
All NMEs
Hepatic or biliary
secretion major?
e.g., ≥ 25%
total clearance?
Renal active
secretion major?
e.g., ≥ 25%
total clearance?
Refer to P-gp and
BCRP decision tree
for the need to
conduct in vivo studies
Determine whether
NME is an OATP1B1
or OATP1B3
Substrate in vitro
Determine whether
NME is an OAT1, OAT3
or OCT2 substrate in vitro
Refer to OATP1B1/1B3
decision tree for the
need to conduct in
vivo studies
Refer to OAT1/3 and
OCT2/MATE decision tree
for the need to conduct
in vivo studies
Yes or unknown Yes or unknown
(modified from page 31 of 75- FDA 2012 draft guidance) ;
Other
trasnporters,
e. g. , MRP, may
need to be
evaluated.
16
Also consider MATEs
Tweedie D, et al. Clin Pharm Ther, July 2013
17. NME as an Inhibitor
Does the drug affect a given transporter?
• Inhibitors can be substrates or non-substrates for a given transporter.
• The need to study depends on whether drugs are likely co-
administered with known substrates of major human transporters.
• Their concentration (free, total, Cmax etc.) in target site dictates their
effect
• All drug-related moieties (parent, metabolites, active/inactive) can
act as inhibitors
17
18. 18
Transporter Inhibitor Decision Trees
P-gp/BCRP OATP1B1/OATP1B3
OAT1/OAT3/OCT2/MATEs
Goal: Determine whether in vivo
studies are needed based on in
vitro assessment.
It is not intended to use in vitro
data to determine the magnitude
of an in vivo interaction.
FDA 2012 Draft DDI Guidance
19. 19
Examples of Transporter-Related PMR/PMC
2011-2012
Year Drug Name
(Brand Name)
Transporter-Related PMR or PMC
2011 VILAZODONE
HYDROCHLORIDE
(VIIBRYD)
DDI with digoxin (P-gp)
2011 BOCEPREVIR
(VICTRELIS)
DDI with digoxin (P-gp)
2011 RILPIVIRINE
(EDURANT)
DDI with digoxin (P-gp)
2011 EZOGABINE
(POTIGA)
Substrate of renal transporters
DDI with digoxin (P-gp)
2011 RIVAROXABAN
(XARELTO)
Renal impairment plus P-gp/moderate CYP3A inhibitor
2012 IVACAFTOR
(KALYDECO)
DDI with digoxin (P-gp)
2012 EVG/COBI/FTC/TFV
(STRIBILD)
In vitro as substrate and/or inhibitor of major transporters as stated in
the guidance (plus MRP2, MRP4, BSEP, MATE1 and OCT1).
2012 TERIFLUNOMIDE
(AUBAGIO)
DDI with rosuvastastin (BCRP and OATP1B1)
PMR/PMC: Postmarketing requirement/Postmarketing commitment
Tweedie D, et al. CPT, July 2013
21. 21
P-gp Inhibition Decision Tree
-Initially proposed in Zhang L et. al., Xenobiotica, 38(7–8): 709–724, 2008
-2012 FDA draft Drug Interaction Guidance
[I]1 is
total Cmax
Bi-directional transport assay with a probe P-gp
substrate (e.g. in Caco-2 or MDR1-overexpressing
polarized epithelial cell lines)
Net flux ratio of a probe substrate decreases
with increasing concentrations of the
investigational drug
Net flux ratio of the probe substrate is not
affected with increasing concentrations of the
investigational drug.
Poor or non-inhibitorProbably a P-gp inhibitor
Determine Ki or IC50 of the
inhibitor
An in vivo drug interaction
study with a P-gp
substrate
is not needed.
An in vivo drug interaction
study with a P-gp substrate
such as digoxin is
recommended.
[I]1/IC50 (or Ki) ≥ 0.1
or
[I]2/IC50 (or Ki) ≥ 10
[I]1/IC50 (or Ki) < 0.1
and
[I]2/IC50 (or Ki) < 10
[I]2 (gut concentration)/IC50≥ 10
is New (Not in 2006 draft DDI
Guidance).
[I]2 is
Dose/250 mL
Different from ITC
Whitepaper (unbound
Cmax)
22. 22
In Vitro and In Vivo Digoxin Data
Recent NDA approvals (2003-2010)
Drug name [I]1/IC50
(unbound Cmax)
[I]1/IC50
(total Cmax)
[I]2/IC50 Digoxin
Cmax
(% Change)
Digoxin
AUC
(% Change)
Lapatinib <0.1 1 1355 NA 180
Dronedarone <0.1 0.09 1349 NA 150
Ranolazine <0.1 0.04 2987 46 60
Darunavir <0.1 0.33 146 15 58
Tolvaptan <0.1 0.23 109 30 20
Etravirine <0.1 0.04 76 19 18
Tetrabenazine <0.1 0.01 6 13 2
Maraviroc <0.1 0.01 13 4 0.5
Deferasirix <0.1 0.003 4.3 -8.7 -8
Lacosamide <0.1 0.01 1 4.8 2.4
Sitagliptin <0.1 0.02 2 18 11
-Agarwal S, Zhang L, Huang, S-M, Clin Pharmacol Ther 89(1): February 2011 (poster presentation at
the annual ASCPT meeting, Dallas, TX, March 2-5, 2011);
-Agarwal, Arya and Zhang, JCP, 2012.
False Positive
False Negative
~82% predictive !!
23. 23
Igut (Ient) Algorithm Exploration
• Because [I]2 assumes that the entire dose is
dissolved in the gut, the use of [I]2/IC50 criteria
may lead to false positives, especially for drugs
with low solubility.
• A new algorithm, [I]gut/IC50, was explored to
determine whether this algorithm could
potentially reduce the false positive rate by
considering the actual absorption of the drugs
into the enterocytes
– [I]gut ([I]ent) is defined as Fa×ka×Dose/Qen
Agarwal, Arya and Zhang, JCP, 2012;
Agarwal S, et al, Clin Pharmacol Ther : February 2012 (poster presentation at the annual ASCPT meeting, National
Harbor, MD, March 14-17, 2012) (Poster Session III-3, 7-8 am, March 17, 2012)
24. 24
Igut (Ient) Algorithm Exploration
Dataset of 24 drugs that have both in vitro and in
vivo P-gp inhibition data (digoxin as the
substrate)
12 drugs showed positive interaction with digoxin in
vivo
12 drugs showed negative interaction with digoxin in
vivo
5 False positives and 1 false negative
[I]gut values were determined from inhibitors’ in
vivo PK data.
Data Sources:
Zhang et al; Xenobiotica. 2008 Jul;38(7-8):709-24.
Agarwal et al; J Clin Pharmacol. 2012 Feb 7. [Epub ahead of print].
Fenner at al; Clin Pharmacol Ther. 2009 Feb;85(2):173-81.
25. 25
Igut (Ient) Algorithm Exploration
1
(8%)
11
(92%)
10
(83%)
2
(17%)
FN TP
TN FP
1
(8%)
11
(92%)
7
(58%)
5
(42%)
[I]gut,/IC50 ≥2 [I]2/IC50≥ 10
Predicted
Observed
• A distinct [I]gut/IC50 cut off value that could eliminate all 5 false positives in our dataset
of 24 drugs was not identified.
• [I]gut/IC50 cutoff of ≥2 (as “predicted positive”) appears to classify 3 out of 5 FPs
(based on [I]2/IC50 ≥ 10) as “true negatives”, reducing false positive rate from 42% to 17%
without changing FN rate.
• Talinolol remains as a false negative by either algorithm.
• False positives and false negatives may be caused by mechanisms that cannot be
captured in the in vitro P-gp inhibition assay.
• [I]gut/IC50 algorithm needs further validation to confirm its utility as an additional algorithm.
Agarwal S, et al, Clin Pharmacol Ther : February 2012 (poster presentation at the annual ASCPT
meeting, National Harbor, MD, March 14-17, 2012) (Poster Session III-3, 7-8 am, March 17, 2012)
27. 27
2nd International Transporter Consortium
Transporter Workshop (March 2012)
Zamek-Gliszczynski et al. Clin Pharmacol Ther, November 2012
Red: Critical
transporter
proteins to
evaluate
prospectively
Green:
additional one
to evaluate
prospectively
Yellow:
retrospective
evaluation
27
28. 28
Emerging Transporters
-Impact on a Broad Range of Drugs
• Multidrug And Toxin Extrusion Transporters: MATEs
• Drugs and Conjugate Efflux Pumps of the ABCC
Family (MRP2, other MRPs)
• Bile Salt Export Pump (ABCB11)
2nd ITC Transporter Workshop (March 2012)
29. 29
MATE (SLC47A) Transporters
• Efflux transporters
– Proton-antiproters
• MATE1
– Liver and kindey
• MATE2 and MATE2K
– Kidney
Hillgren K, et al, CPT, 94, 52-63, 2013
30. 30
Clinical Importance
• Polymorphism of MATE1/2 has been linked to clinical
effects in metformin-treated subjects
• Reduced metformin response
• MATEs mediates clinical drug-drug interactions (DDIs)
previously attributed to OCT2
– Overlapping substrate between MATEs and OCT2
• MATEs also transport anionic compounds and zwitterions
– Some differential specificity of inhibitors
• Inhibition of MATEs may increase tissue concentration
of substrate drugs
– Renal toxicity consideration if the substrate drug is renal
toxic
Hillgren K, et al, CPT, 94, 52-63, 2013
31. 31
Putative MATE-Mediated Clinical DDIs
Hillgren K, et al, CPT, 94, 52-63, 2013 and references therein
MATE Mediates Clinical Drug Drug Interactions
Previously Attributed to OCT2
Perpetrators inhibit BOTH the MATE’s and OCT
32. 32
Recommendation from ITC
• MATEs need to be considered for prospective
investigation along with OCT2 and OATs.
NME as a substrate NME as an inhibitor
Hillgren K, et al, CPT, 94, 52-63, 2013
(Change in creatinine clearance may indicate renal
transporter DDI)
33. 33
BSEP (ABCB11)
• An efflux transporter expressed on the
canilicular membrane of the hepatocytes
• Secrete bile acids to bile
– Bile acids are taken up by multiple transporters
including NTCP and OATPs.
Hillgren K, et al, CPT, 94, 52-63, 2013
34. 34
Clinical Importance
• Mutations in the ABCB11 gene lead to accumulation of bile
salts in the liver and progressive intrahepatic cholestasis.
– The clinical spectrum of ABCB11 mutations covering benign
recurrent intrahepatic cholestasis type 2 to progressive familial
intrahepatic cholestasis type 2 (PFIC2), also known as BSEP
deficiency syndrome
– Other common polymorphism in ABCB11 is c.1331T>C (p.V444A)
leads to lower BSEP levels.
• Inhibition of BSEP can lead to increased bile salts in the liver
that may lead to cholestasis.
– Targeted inactivation of BSEP in mice is known to cause persistent
cholestasis
CPT, 94, 52-63, 2013
37. 37
Role of BSEP Transporters in DILI
Tox. Sciences, 118, 2, 485-500, 2010
200 marketed drugs used to assess the relationship
between BSEP inhibition and liver injury
IC50 < 25 uM
Cyclosporin
Nefazodone
Rosiglitazone
Rifampin
Ritanovir
Troglitazone
Bosentan
IC50 > 100 uM
Asprin
Antipyrine
Caffeine
Cimetidine
Desipramine
Famotidine
Metformin
Nadolol
Sulfasalazine
Timolol
Verapamil
38. 38
• >600 compounds
• When factoring for exposure, 95% of the
annotated compounds with a Css/BSEP IC50 ratio
≥ 0.1 were associated with some form of liver
injury.
• Drugs with a Css/BSEP IC50 ratio ≥ 0.1 and a
Css/MRP IC50 ratio ≥ 0.1 had almost a 100%
correlation with some evidence of liver injury in
humans.
• integration of BSEP and MRP2 data is a useful
tool for informing the potential for liver injury
due to altered bile acid transport.
ToxSci Advance Access published November 5, 2013
Morgan et al., TOXICOLOGICAL SCIENCES, 2013
40. 40
Recommendation from ITC
• Restrospective testing
– At this stage, it is impossible to define a value for a BSEP
inhibition constant that will realistically predict significant
BSEP-mediated DILI.
– In vitro characterization of BSEP–drug interactions is
certainly warranted after the appearance of cholestatic
issues in clinical trials or safety studies
Systematic studies required with ALL relevant
transporters (BSEP, NTCP, MRP2, OATP,?) to assess
the “causal link”
42. Creatinine-Drug Interactions
• Creatinine = biomarker probe to predict the kidney function (GFR)
• Creatinine is found to be a substrate of multiple renal transporters including
OCT2, MATE1, MATE2K, and OAT2.
• Increase in serum creatinine can be due to :
– renal toxicity or
– inhibition of creatinine transport pathways by new molecular entities.
42
Lepist E-I, et al., Kidney Int. 2014, 86(2):350-7.
Huang Y, AAPS Webinar, May 2014
43. Increase in serum creatinine
(without alteration in renal function)?
• Common features by a group of drugs in the literature and
in NDA submissions:
– ~10-30% increase in sCr in clinical trials accompanied by
decrease in CLcr
– No effect on actual GFR (aGFR) as assessed by inulin, sinistrin,
iohexol, iothalamate, or Cr-EDTA
– No impact on various renal function biomarkers (e.g., albumin,
blood urea nitrogen (BUN), Cystatin C, β-microglobulin, N-
acetyl-β-glucosaminidase (NAG), para-aminohippurate (PAH),
etc.)
– The increase in sCr generally has rapid-onset upon drug
administration and is reversible, returning to baseline after
discontinuation of the drugs.
43
V Arya, X Yang, et. al., ASCPT 2014, Atlanta, GA.
44. Inhibition of renal transporters may account for
the increase in serum creatinine
44
Can increase in creatinine concentration be used as an “indicator” of in vivo
renal transporter inhibition by the new molecular entity?
V Arya, X Yang, et. al., ASCPT 2014, Atlanta, GA.
Can in vitro inhibition of renal transporters (MATE’s, OCT) be an early predictor
of potential increase in creatinine concentration in clinic
and
45. 45
Summary
• Transporters should be considered in the overall drug
development strategy
– May be a critical factors contributing to DDI, toxicity and efficacy
• Novel transporters:
– MATEs to be prospectively studied for new drugs as their substrates or
inhibitors along with other renal transporters (OCT2 and OATs).
– MRP2 and BSEP may play a role in liver toxicity and should be studied if
there is preclinical or clinical signs of liver toxicity to understand the
mechanisms.
– Other transporters may be important for drug delivery and drug target
and should be studied on a case-by-case basis.
• Emerging science and novel models (KO- cell lines, humanized
animal models etc.) will continue to shape the transporter field
and Regulatory Guidance's
46. 46
Acknowledgements
• Lei Zhang
• Shiew-Mei Huang
• Sheetal Agarwal
• Jaya Vaidyanathan
• Ping Zhao
• Kellie Reynolds
• Vikram Arya
• Xinning Yang
• Leslie Chinn
• Other FDA Transporter Scientific Interest Group Members
• ITC members
• IQC members
• Sabbatical scientists at the FDA
47. Transporters, like CYPs, are being recognized as proteins that
can play a pivotal role in dictating the ADME properties of
drugs. A thorough understanding of potential roles of
transporters in drug interactions and toxicity is important in
drug development. The talk will provide a high level overview
of various transporter evaluation initiatives at the agency.
Some of the topics which will be discussed: On-going efforts
on decision trees within the DDI guidance, novel emerging
transporters impacting ADME, inter-play of hepatic
transporters and liver-toxicity, and inter-play of renal
transporters and renal function etc.
47
Transporter Evaluation in Drug Development
48. 48
Drug Transporter Assessment Strategy
Central tenet is the clinical plan, which considers the therapeutic
area, co-medicines and the patient population.
CLINICAL STRATEGY
•Therapeutic area
– Comedicines
•Product Profile
•Development Plan
•Physicochemical
properties
UNDERSTANDING TRANSLATION
Discovery to
First Time In
Human (FTIH)
FTIH to Proof of
Concept (POC)
POC to New
Drug Application
(NDA)/Marketing
•Drug labeling
•Non-clinical
mechanistic and/or
investigative studies
•Clinical Studies
•Non-clinical studies
(in vitro and in vivo)
•Clinical Studies
•Pharmacokinetics
•Safety
Polli J, Clin Pharm Advisory Committee Meeting, 2010; Tweedie D, et al, Clin Pharm Ther, July 2013
49. 49
P-gp is the Most Studied Transporter
2003-2006 2007-2011
Total # of approved NMEs 87 95
# (%) of NME labeling that have information on a
specific transporter
16
(18%)
41
(43 %)
# of NME labeling that have information
on P-gp
12 39
# of NME labeling that have transporter
information other than P-gp such as BCRP,
OATP, etc
4 12
Transporter-related PMR* or PMC*
P-gp
20
16
Agarwal, Fan and Zhang (manuscripts in preparation)
*PMR: Post-marketing requirement; PMC: Post-marketing commitment
50. 50
Transporters and Liver Toxicity
• Drug-induced liver injury could be multi-
factorial.
– BSEP inhibition shows correlation but not all leads to
drug-induced liver injury (DILI). DILI can be caused by
other mechanisms.
– Other transporter involvement?
• Uptake transporters?
• Efflux transporters?
– Factors affecting BSEP expression?
– Metabolites?
• A comprehensive panel may need to be
evaluated to predict the risk.
51. 51
In Vitro and In Vivo Digoxin Data
Recent NDA approvals (2003-2010)
In vivo outcome of 9 /11 NMEs (82%) were
accurately predicted.
Two false positives: etravirine and maraviroc
The 2 false positives partially may be attributed
to potential P-gp induction effects that may off-
set their inhibition effects
Etravirine is a CYP3A inducer
Maraviroc did not interact with midazolam in vivo
It is a weak P-gp inhibitor (IC50 ~183 uM, I2/IC50 ~12)
-Agarwal S, Zhang L, Huang, S-M, Clin Pharmacol Ther 89(1): February 2011 (poster presentation at
the annual ASCPT meeting, Dallas, TX, March 2-5, 2011);
-Agarwal, Arya and Zhang, JCP, 2012.