Introduction to Pharmacokinetics and Pharmacodynamics
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Questions and Answers

What is the primary purpose of converting the NOAEL to an HED?

  • To identify the toxicity level of a medication
  • To determine the most effective dose for humans
  • To compare the NOAEL between different drugs
  • To use scaling factors for dose normalization (correct)

    • The MABEL approach is considered less safe than the NOAEL method.

    False (B)

    What does MRSD stand for?

    Maximum recommended starting dose

    The ______ approach uses both NOAEL/HED and MABEL for dose setting.

    <p>Combined</p> Signup and view all the answers

    Match the terms with their corresponding definitions or descriptions:

    <p>NOAEL = No Observed Adverse Effect Level HED = Human Equivalent Dose MABEL = Minimum Anticipated Biological Effect Level MRSD = Maximum Recommended Starting Dose</p> Signup and view all the answers

    What is a common safety factor applied when determining the MRSD?

    <p>10 (C)</p> Signup and view all the answers

    Agonist and antagonist pathways have the same level of concern for starting dose selection.

    <p>False (B)</p> Signup and view all the answers

    What kind of data does the MABEL approach require?

    <p>Exhaustive data</p> Signup and view all the answers

    What is the major elimination pathway for drugs with a molecular weight less than 50 kDa?

    <p>Renal filtration (B)</p> Signup and view all the answers

    IgG-based monoclonal antibodies (mAbs) are typically eliminated quickly due to their high molecular weight.

    <p>False (B)</p> Signup and view all the answers

    What is the effect of increasing FcRn binding at acidic pH?

    <p>Improves recycling efficiency of antibodies.</p> Signup and view all the answers

    The half-life of immunoglobulin E (IgE) is approximately _____ days.

    <p>3-5</p> Signup and view all the answers

    Match the following terms with their definitions:

    <p>FcRn = Receptor that binds IgG at acidic pH PK = Pharmacokinetics TMDD = Target Mediated Drug Disposition FiH = First-in-Human trials</p> Signup and view all the answers

    Which factor influences the slow elimination of IgG-based mAbs?

    <p>Concentration of the target versus the mAb (C)</p> Signup and view all the answers

    What is the primary goal of conducting First-in-Human (FiH) trials?

    <p>To evaluate safety, tolerability, and pharmacokinetics at increasing dose levels.</p> Signup and view all the answers

    Non-IgG proteins, such as IgE, have a long half-life despite being above 50 kDa.

    <p>False (B)</p> Signup and view all the answers

    What is the primary benefit of multi-species scaling in pharmacokinetics?

    <p>It simplifies the prediction of human pharmacokinetics. (A)</p> Signup and view all the answers

    Single species scaling is considered the least predictive approach for human pharmacokinetics.

    <p>False (B)</p> Signup and view all the answers

    What role does plasma protein binding play in species translation?

    <p>It helps in assessing the pharmacokinetic behavior across different species.</p> Signup and view all the answers

    The _____ represents the degree to which a pharmacological substance is distributed in the body relative to the plasma concentration.

    <p>volume of distribution</p> Signup and view all the answers

    Match the following pharmacokinetic terms with their corresponding descriptions:

    <p>Volume of Distribution = A measure of the distribution of a drug in the body Plasma Protein Binding = Interaction of drugs with proteins in plasma Single Species Scaling = Using one species to predict human pharmacokinetics Multi-Species Scaling = Utilizing data from multiple species for predictions</p> Signup and view all the answers

    What does bioavailability (F) refer to in pharmacokinetics?

    <p>The fraction of a given dose that reaches systemic circulation unchanged (C)</p> Signup and view all the answers

    Half-life is defined as the time required for the concentration to fall to 25% of the initial value.

    <p>False (B)</p> Signup and view all the answers

    What is the equation for clearance (CL) in pharmacokinetics?

    <p>CL = dose / AUC</p> Signup and view all the answers

    The rate of drug absorption is denoted as ______.

    <p>ka</p> Signup and view all the answers

    Match the pharmacokinetic terms with their definitions:

    <p>Clearance (CL) = The rate at which the drug is eliminated from the body Half-life (t1/2) = Time required for concentration to drop to 50% Bioavailability (F) = Fraction of drug that reaches systemic circulation Absorption rate (ka) = Rate at which a drug moves from site of administration to measurement site</p> Signup and view all the answers

    What parameter can be predicted for human pharmacokinetics based on allometric scaling?

    <p>Clearance (B)</p> Signup and view all the answers

    Allometric scaling only applies to small molecules and not to monoclonal antibodies (mAbs).

    <p>False (B)</p> Signup and view all the answers

    What does AUC stand for in pharmacokinetics?

    <p>Area Under the Curve</p> Signup and view all the answers

    What is the primary route of administration that provides 100% bioavailability for biologic therapies?

    <p>Intravenous (I.v.) (B)</p> Signup and view all the answers

    Subcutaneous administration is associated with a higher risk of systemic infection compared to intravenous administration.

    <p>False (B)</p> Signup and view all the answers

    What is the main organ responsible for the metabolism of biologic therapies?

    <p>Liver</p> Signup and view all the answers

    The elimination of biologics is largely achieved through catabolism in the __________ space of cells.

    <p>endosomal</p> Signup and view all the answers

    Match the administration route with its main characteristic:

    <p>I.v. = Invasive with risk of infections s.c. = Patient convenience and lower pain Oral = Difficult due to large molecular size I.m. = Used for intermediate absorption rates</p> Signup and view all the answers

    Which of the following is NOT a disadvantage of intravenous administration?

    <p>Lower risk of systemic infection (C)</p> Signup and view all the answers

    Dosing for biologic therapies administered intravenously is usually less frequent than for those administered subcutaneously.

    <p>False (B)</p> Signup and view all the answers

    What is the disadvantage of subcutaneous administration compared to intravenous administration?

    <p>Greater inter-individual variability</p> Signup and view all the answers

    What is the exponent commonly used in allometric scaling for clearance in pharmacokinetics?

    <p>0.75 (A)</p> Signup and view all the answers

    Allometric scaling suggests that a larger body weight results in a proportional increase in cardiac output.

    <p>False (B)</p> Signup and view all the answers

    What is the purpose of performing bridging in pharmacokinetics and pharmacodynamics?

    <p>To translate data from animal studies to human studies when human data is unavailable.</p> Signup and view all the answers

    The single ascending dose study is abbreviated as _____.

    <p>SAD</p> Signup and view all the answers

    Match the following study phases with their corresponding activities:

    <p>Phase 1 = Testing for safety in a small group of healthy volunteers Phase 2 = Evaluating efficacy and side effects in a larger group Phase 3 = Confirming effectiveness in diverse populations Phase 4 = Post-marketing surveillance and long-term safety</p> Signup and view all the answers

    What does PK/PD stand for in drug development?

    <p>Pharmacodynamics/Pharmacokinetics (B)</p> Signup and view all the answers

    Human PK/PD model building relies exclusively on human data.

    <p>False (B)</p> Signup and view all the answers

    What is the significance of understanding ADME properties in drug development?

    <p>ADME properties help determine the absorption, distribution, metabolism, and excretion of a drug, affecting dosing strategies.</p> Signup and view all the answers

    The term 'bioequivalence' refers to the relationship where two drugs have the same _____.

    <p>bioavailability</p> Signup and view all the answers

    Which of the following is NOT a parameter of the PK model based on the monkey data?

    <p>Renal clearance parameters (A)</p> Signup and view all the answers

    Study Notes

    Introduction to Pharmacokinetics and Pharmacodynamics

    • The field of study focuses on drug action and movement in the body
    • The dose, concentration, and time-driven effect relations are important to understand drug response
    • Paracelsus's quote, "The dose makes the poison," highlights the importance of dosage in drug efficacy and toxicity

    Agenda

    • Definitions and background information on pharmacology and drug action
    • Explanation of pharmacodynamics
    • Explanation of pharmacokinetics
    • Specific PK research focused on biotherapeutics, from research to clinic, discovery, research, non-clinical development, clinical development (NOAEL and MABEL dose setting), and model building
    • Key learning points and takeaways from the presentation

    Definitions and Background

    • Pharmacodynamics: How a drug affects the body, focusing on the relationship between concentration and response, and response duration
    • Pharmacokinetics: The fate of a drug in the body, including absorption, distribution, metabolism, and excretion (ADME)
    • ADME: Absorption (how the drug enters the body), Distribution (where the drug goes), Metabolism (how the drug is broken down), and Excretion (how the drug leaves the body)

    PK vs PD

    • Pharmacodynamics (PD): Determines the drug's effect on the body and the effect's change over time for a given drug dose
    • Pharmacokinetics (PK): Determines the drug's fate in the body and the concentration change over time for a given drug dose

    PK/PD

    • Concentration (PK) is always underlying the effect (PD)
    • Rarely a 1:1 association between the drug concentration and the effect.
    • Double concentration does not always equal a double effect.
    • Time delays between the concentration and the effect may occur.
    • Dose-concentration-time-effect relation can be described using mathematical PK/PD models

    Questions to be answered by PK/PD Assessments

    • Which initial dose should be given?
    • What is the optimal maintenance dose?
    • What is the appropriate dosing frequency?
    • How high a drug dose can be tolerated?
    • Which administration route is best?

    Pharmacodynamics Details

    • Explores how a drug impacts the body, analyzing the relationship between concentration and response duration
    • Studies encompass single and repeated doses, with multiple dose levels (large dose interval) preferred
    • In vitro, ex vivo, and in vivo studies are relevant

    PK: Absorption, Distribution, Metabolism, Excretion (ADME)

    • Understanding the journey of a drug within the body is crucial, encompassing absorption, distribution, metabolism, and excretion (ADME)
    • The concepts of absorption, distribution, metabolism, and excretion—ADME—describe the fate of a drug in the body.

    PK Parameters Summarizing Drug Exposure

    • Key PK parameters commonly used are Cmax, Tmax, AUC, half-life, clearance, and volume of distribution, used in clinical trials and exposure-response analysis
    • These parameters summarize the pharmacological properties and total exposure of a drug

    Comparison of ADME Properties

    • Small molecules (less than 1 kDa) and therapeutic proteins (greater than 1 kDa) show different ADME properties
    • Small molecules are typically absorbed orally and metabolized in the liver
    • Therapeutic proteins usually require intravenous or subcutaneous administration and can have slower elimination.

    PK with Focus on Biotherapeutics

    • Delivery of biologics is challenging due to large molecular size, poor permeability, and degradation in the gastrointestinal tract
    • Biologics commonly administered intravenously or subcutaneously
    • Subcutaneous administration is more convenient for patients and reduces risk of systemic infection

    Altering PK of Biologics

    • Strategies to alter PK properties of biologics include subcutaneous administration, coupling to carriers like polyethylene glycol and albumin, and fusion to Fc-regions, among others
    • Improving FcRn binding allows for targeted drug delivery and prolonged circulation
    • Modulating non-specific endocytosis and altering isoelectric point to improve drug efficacy and reduced clearance

    Elimination of Biologics

    • Renal filtration is the major elimination pathway for low-molecular-weight drugs
    • Large molecules, like antibodies (IgGs), have negligible renal clearance.
    • Elimination largely mediated by catabolism to peptides and amino acids
    • Target-mediated drug disposition (TMDD) can influence the elimination kinetics of biologics

    Research-Clinic

    • Preclinical and clinical aspects are linked
    • The primary goal is patient treatment
    • Evaluations of safety, tolerability, and PK/PD are done at increasing doses in humans
    • Data from PK and PD are used for Phase II trials
    • Clinical development, from discovery to later phases, involves lead candidate selection and drug-drug interaction analysis.

    Discovery/Research Investigations

    • Important aspects such as mode of action, pharmacokinetic properties, and plasma protein binding in the discovery/research phase are necessary.
    • Concentration-response data in humans and tox species are essential for dose determination.
    • Comparing results from animal to human research is crucial.

    Non-Clinical Development

    • Non-clinical development aims to characterize the toxic effects, dose dependence, and potential reversibility of a drug.
    • Estimating a safe starting dose and determining the appropriate maximal exposure are critical parts of this stage.
    • Defining parameters for clinical monitoring of possible adverse effects

    Exposure Response for First-in-Human Dose (FHD)

    • Evaluating the safety and efficacy of drug candidates by plotting and characterizing the exposure-response relationship, a key measure in clinical safety and efficacy determination.
    • Key metrics such as NOAELs (no observed adverse effect level), and MABELs (minimum anticipated biological effect level) are used

    Dose Setting: NOAEL Approach and MABEL Approach

    • NOAEL approach determines the no observed adverse effect level.
    • MABEL approach analyzes and determines the minimum anticipated biological effect level
    • A combined approach using both NOAEL/HED and MABEL is recommended

    Risk Factors for Selecting Starting Dose

    • Factors like stimulation, inhibition, dose response curve characteristics (steep or mild), and potential toxicologic or adverse reactions.
    • Factors to assess in clinical trials are severity of adverse effects, reversibility, monitorability, and nature of targets (novelty, extent of experience, known or unknown pathways/targets)

    Strategy for Human PK/PD Model Building

    • Predicting human PK based on data from closely related compounds, understanding the mechanisms, predicting uncertainty, and determining appropriate mechanistic and quantitative structure-property relationship (QSPR) or quantitative structure-activity relationship (QSAR) modelling data.
    • Allometric scaling is a major component.

    The (PK/PD) Pathway to First-in-Human Trial

    • In vitro and in vivo studies are used to predict drug concentration and effect in humans
    • Allometric scaling is used to translate data from animal studies to estimate human PK parameters
    • Predicted human doses are crucial starting points for clinical trials

    Strategy for Human PK/PD Model Building (Pharmacodynamics)

    • The essential elements of selecting models mimicking human biology and disease models
    • Importance of species-specific PD data if available
    • Demonstrating the relationship between animal and human data in appropriate approaches.

    Translation of PK/PD from Animals to Humans (Allometric Scaling)

    • Physiological processes and proportionality factors linking animals to humans
    • Relationships between body weight, cardiac output, renal clearance, heat production, and related parameters
    • This method helps translate animal models to human parameters

    Human PK/PD Model Building

    • Describes how in vitro and in vivo PK/PD data are utilized to create models reflecting physiological characteristics in humans, including model evaluation and development.

    Clinical Development

    • An overview of clinical development phases, including discovery, non-clinical activities, clinical trial design, dose setting, and regulatory considerations.

    Learnings

    • PK and PD are necessary for establishing a safe and effective dose regimen for patients
    • Understanding differences in ADME between small molecules and biologics
    • Evaluating dosing strategies (dose, frequency, administration routes) is crucial
    • Combining in vitro, ex vivo, and animal studies are needed for accurate dose predictions in humans.

    Mode of Action (MoA)

    • Definition: MoA is the biochemical interaction a drug undergoes creating a pharmacological effect
    • Importance of MoA: Determining differences in species receptor/enzyme expression, and homologous/different effects in various tissues.

    Elimination of Antibodies

    • Conventional antibody clearance occurs via membrane-bound antigen transfer to lysosomes for degradation
    • Antibodies utilize FcRn recycling for recycling to plasma and binding to other antigens.

    Non-Clinical Development (Required Data)

    • Non-clinical studies focus on single (or repeated) dose toxicity, genotoxicity, carcinogenicity, reproductive toxicity, local tolerance, and tissue cross-reactivity, including the needed duration of clinical trial studies, immunological assessments, etc.
    • Species differences in target expression need consideration.

    Species Differences in Target Expression

    • Quantitative and qualitative differences in target expression between animal species and humans significantly impact dose prediction and response evaluation.
    • Species comparative analysis of target expression is crucial for accurate prediction of human responses.

    Important PK Parameters (Needed for Dose Setting)

    • Key PK parameters such as Volume of distribution (V), clearance (CL), half-life (t₁/₂), bioavailability (F), and absorption rate (ka) for understanding drug kinetics in the human body.
    • These are crucial for accurate dose determination.

    Scaling of PK from Animals to Humans

    • Allometric scaling is a method for translating animal PK data to humans using body weight and other physiological parameters
    • Subsequent allometric scaling enables human PK profile simulation.

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    Pharmacokinetics/Pharmacodynamics PDF

    Description

    This quiz explores the essential principles of pharmacokinetics and pharmacodynamics, crucial for understanding drug action and movement in the body. Learn about the definitions, key concepts, and the significance of dosage according to Paracelsus's famous quote. Examine specific research related to biotherapeutics and take notes on the critical details presented.

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