Clinical Pharmacology Quiz
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Questions and Answers

What is the body weight of Subject 2?

  • 70 kg (correct)
  • 120 kg
  • 40 kg
  • 60 kg

    • What is the volume of distribution (V) for a typical patient weighing 70 kg?

  • 1.0 L
  • 3.5 L (correct)
  • 2.5 L
  • 4.0 L

    • If Subject 1 weighs 120 kg, what dosing scenario applies based on the provided examples?

  • Normal Dose of 800 mg
  • Fixed Dose of 1000 mg (correct)
  • Weight-Tiered Dose of 10 mg/kg
  • Fixed Dose of 600 mg

    • Which dosing scenario includes a maximum dose for individuals over 70 kg?

    <p>Fixed Dose</p> Signup and view all the answers

    What type of pharmacokinetic model is assumed in this example?

    <p>1CM Model</p> Signup and view all the answers

    What is the clearance (CL) typical for a patient weighing 70 kg?

    <p>0.1 L/day</p> Signup and view all the answers

    Which scenario describes the BW Normalized Dose for a patient weighing 70 kg?

    <p>10 mg/kg</p> Signup and view all the answers

    In the context of dosing, what does the term 'weight-tiered dose' imply?

    <p>Dosing which varies based on body weight categories</p> Signup and view all the answers

    What is the primary goal of clinical pharmacology?

    <p>To optimize the benefit:risk ratio for all patients</p> Signup and view all the answers

    Which of the following roles is NOT typically associated with a career in pharmaceutical sciences?

    <p>Software Engineering</p> Signup and view all the answers

    What does quantitative pharmacology primarily focus on?

    <p>Mathematical modeling of PK and PD</p> Signup and view all the answers

    At what stage of drug development is preclinical PK involved?

    <p>From preclinical stage through translation</p> Signup and view all the answers

    Which factor is NOT considered in clinical pharmacology assessments?

    <p>Cultural impact of diseases</p> Signup and view all the answers

    In the context of pharmaceutical careers, which function is most closely associated with ensuring proper drug formulations?

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

    What is one of the key components that all functions contribute to in pharmaceutical submissions?

    <p>Sections of a submission package</p> Signup and view all the answers

    How does clinical pharmacology affect patient treatment plans?

    <p>By determining the right dose and administration for individual patients</p> Signup and view all the answers

    What type of reviews does the FDA typically conduct for new drug applications (NDAs) and biologics license applications (BLAs)?

    <p>Question-based reviews</p> Signup and view all the answers

    Which acts are related to pediatric drug approvals and studies?

    <p>Pediatric Research Equality Act and Best Pharmaceuticals for Children Act</p> Signup and view all the answers

    Why are FDA guidance documents important for drug development?

    <p>They outline the expectations and regulations related to various drug development topics.</p> Signup and view all the answers

    What is one key recommendation for staying updated on changing FDA regulations?

    <p>Subscribe to the FDA email digest for updates.</p> Signup and view all the answers

    What type of reviews for pediatric approvals can be separately accessed under PREA or BPCA?

    <p>Summary medical and statistical reviews</p> Signup and view all the answers

    What is the normalized dose for a body weight of 10 kg at a dose of 10 mg/kg?

    <p>50 mg</p> Signup and view all the answers

    Which normalization strategy provided the best performance based on the content?

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

    What is the fixed dose for patients over 70 kg according to the weight-tiered dosing?

    <p>1000 mg</p> Signup and view all the answers

    Which dose normalization method is used for calculating FVIII levels?

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

    In which situation is a fixed dose most likely used?

    <p>Wider therapeutic index</p> Signup and view all the answers

    What dosing strategy results in higher exposures for heavier subjects?

    <p>Mg/kg dosing</p> Signup and view all the answers

    What is the dose for Trastuzumab in patients weighing over 70 kg?

    <p>4 mg/kg</p> Signup and view all the answers

    Which option indicates a higher variability dosing approach based on the therapeutic index?

    <p>Weight-tiered dosing</p> Signup and view all the answers

    What is a consideration to be cautious about when generalizing outcomes from body weight-effect models?

    <p>Drug class differences</p> Signup and view all the answers

    What is the primary use for liposomal doxorubicin in oncology?

    <p>Treatment of ovarian cancer</p> Signup and view all the answers

    What does MRSD stand for in the context of starting dose selection?

    <p>Maximum Recommended Starting Dose</p> Signup and view all the answers

    What is the primary basis for setting doses relative to NOAEL in relevant toxic species?

    <p>Allometrically scaled exposure</p> Signup and view all the answers

    What does MABEL aim to achieve in therapeutic drug dosing?

    <p>To start dosing at the level expected to achieve a sub-maximal effect</p> Signup and view all the answers

    In the context of FIH dose selection approaches, what is usually the starting dose for therapeutic proteins?

    <p>1/6th of HNSTD observed in primates</p> Signup and view all the answers

    What does HED refer to when discussing drug dosing?

    <p>Human equivalent dose</p> Signup and view all the answers

    What is the significance of selecting a dose based on the Pharmacologically Active Dose (PAD)?

    <p>It is set relative to preclinical pharmacokinetics/pharmacodynamics efficacy models.</p> Signup and view all the answers

    In which scenario might a higher starting dose be justified despite an uncertain safety profile?

    <p>In relapsed/refractory diseases with high mortality and unmet medical needs</p> Signup and view all the answers

    Which of the following is a component to consider during in vitro cytotoxicity assays for targeted drugs?

    <p>Concentration of the tumor-associated antigen (TAA)</p> Signup and view all the answers

    What is the potential risk of using a lower starting dose in FIH dose selection?

    <p>Less potential benefits for patients</p> Signup and view all the answers

    What is a primary advantage of a higher starting dose in FIH studies?

    <p>Earlier potential benefits for FIH studies in patients</p> Signup and view all the answers

    What does the 3+3 dose escalation design primarily evaluate?

    <p>Initial safety with 3 patients per dose, then 3 more if safe</p> Signup and view all the answers

    What is an important characteristic of MABEL-based starting dose for Teclistamab?

    <p>0.3 µg/kg IV Q2W</p> Signup and view all the answers

    Which source provides the most sensitive cell line for T cell activation studies?

    <p>Peripheral blood mononuclear cells (PBMCs)</p> Signup and view all the answers

    What can drive the maximum dose in traditional FIH studies?

    <p>Injection volume considerations</p> Signup and view all the answers

    Which method may utilize a Bayesian Optimal Interval (BOIN) for dose escalation decisions?

    <p>3+3 dose escalation design</p> Signup and view all the answers

    What is a disadvantage of longer studies with smaller doses in FIH dose selection?

    <p>Less potential benefits for patients</p> Signup and view all the answers

    Which factor may be incorporated into ongoing review of pharmacokinetic data?

    <p>Safety concerns or unexpected observations</p> Signup and view all the answers

    What is the relationship between dose levels in traditional FIH studies?

    <p>Differentiation of exposure is recommended between levels</p> Signup and view all the answers

    What does the term 'effector:target cell ratios' refer to?

    <p>The number of T cells relative to tumor cells</p> Signup and view all the answers

    What is the typical maximum dose escalation in a 3+3 dose design?

    <p>A half log or 3-fold increase</p> Signup and view all the answers

    In the context of drug development, what is the term 'step-up regimen' mostly associated with?

    <p>Gradual increase in dosing based on efficacy results</p> Signup and view all the answers

    Study Notes

    Clinical Pharmacology and PK/PD of Therapeutic Proteins: An Industry Perspective

    • The presentation is about the clinical pharmacology and pharmacokinetics/pharmacodynamics (PK/PD) of therapeutic proteins from an industry perspective.
    • The outline covers different stages of drug development, including pre-investigational new drug (IND) applications, phase 2/3 trials, and biological license applications (BLAs).
    • A section on clinical pharmacology studies and concerns is included, along with considerations for PK and target assay, pediatric considerations and immunogenicity.

    Introduction

    • The presentation discusses the pre-investigational new drug (IND) application through first-in-human (FIH) studies and proceeding to phase 2/3 trials and biological license application (BLA).

    Outline

    • Part 1 covers the initial stages from introduction to IND application and FIH studies, phase 2/3 trials to BLA.
    • Part 2 addresses other clinical pharmacology considerations including PK and target assay considerations, pediatric considerations, and immunogenicity.

    Personal Background/Disclosure

    • The presenter is a senior director of clinical pharmacology at Regeneron, with experience at AbbVie.
    • They have a PhD in Pharmaceutical Sciences, a BS in Pharmaceutical Sciences, and a BA in Mathematics.
    • Their research interests include clinical pharmacology, therapeutic proteins, pediatric drug development, monoclonal antibodies, and drug-drug interactions.

    Experience in Clinical Development of Small Molecule and Biologics

    • DUPIXENT (dupilumab), an anti-IL-4Ra mAb, is FDA-approved for atopic dermatitis, asthma, chronic rhinosinusitis, and other conditions.
    • Itepekimab (anti-IL-33 mAb) is in Phase 3 for COPD and Phase 2 for NCFB.
    • Vonsetamig (BCMAXCD3 bispecific Ab) is in Phase 1 for desensitization of patients needing a kidney transplant.
    • Glecaprevir/pibrentasvir (Mavyret) is approved for chronic Hepatitis C Virus (HCV) infections.
    • Lutikizumab is in Phase 2 for osteoarthritis, with ongoing development in other conditions.
    • Rovalpituzumab-tesirine is for small cell lung cancer. (Trial terminated in Phase 2)

    Finding information on Clinical Studies

    • Most Phase 2/3 studies leading to drug approvals are published in peer-reviewed manuscripts.
    • Many top journals include clinical study protocols as supplementary materials.
    • Clinicaltrials.gov and clinicaltrialsregister.eu require registration of all Phase 2/3 studies

    FDA Summary Reviews

    • The BLA number 761055 is for Dupixent (dupilumab)
    • Summary reviews include key documents like the approval letter, printed labeling, risk factor assessment, etc and summary of clinical pharmacology /biopharmaceutics relevant reviews.

    Finding information on Pediatric Drug Approvals

    • Reviews of pediatric studies under BPCA(Best Pharmaceuticals for Children Act) and PREA (Pediatric Research Equity Act) from 2012-present are usually available.

    FDA Guidances and Email Updates

    • FDA guidance documents outline expectations for topics in drug development, organized by functional area.
    • Subscribe to email digests for updates on changing regulations, to FDA guidance documents and Clinical Pharmacology Corner.

    What is Clinical Pharmacology?

    • Clinical pharmacology is about getting the right drug at the right dose to the right patient at the right time.
    • It addresses if the target mechanism is relevant for the patient population and right dose and frequency
    • Considerations include special patient characteristics, immunogenicity, drug-drug interactions and food effect that impact the exposure of the drug.

    Dose Selection

    • FIH dose selection follows a process that encompasses preclinical and clinical development stages.
    • The process involves multiple dosing stages and considerations for clinical use.
    • The specific strategies can vary depending on the therapy.
    • Various methodologies to reach a dose (e.g., 3+3, etc)

    Relevant Data Package for IND/FIH Planning

    • For monoclonal antibodies, essential data includes in vitro characterization (e.g., binding affinity, concentration producing 50% of maximal effect), in vivo animal studies (e.g. demonstrating mechanism of action), toxicology studies establishing safety, and allometrically scaled PK to predict human exposure.

    Initial toxicology studies

    • The types of toxicology studies used for small molecules as compared to therapeutic proteins.
    • Non-human primates (NHPs) are a key species for some toxicology studies given their closer genetic relationship to humans.

    Design concepts for general toxicology studies

    • The design considerations for toxicology studies, including considerations like doses, recovery periods, and routes of administration.
    • No observed adverse effect level is also included.

    Selecting the First-in-Human (FIH) Population

    • Factors considered when selecting an FIH population including criteria for patient screening, disease status and risk levels.

    FIH Dose Selection Approaches

    • Different methods (e.g., MRSD, NOAEL, HNSTD, PAD, and MABEL) for selecting initial doses during FIH trials for therapeutic proteins.

    Traditional FIH Single Ascending Dose Study

    • An overview of the study designs implemented to assess immunogenicity, safety and efficacy of monoclonal antibodies, and small molecules in healthy human subjects.

    3+3 Dose Escalation Design

    • A description of the 3+3 design used in clinical trials, particularly in oncology and similar conditions
    • The methodology and steps in choosing the next dosing level in terms of the dosing scheme

    MABEL Case Study: Teclistamab (BCMAxCD3)

    • Overview of a specific MAB case showing usage and process of choosing a starting dose.
    • Data are presented that show both functional drug and total target molecules being measured.

    Phase 2/3 to BLA

    • The transition from Phase 2/3 trials to subsequent biosimilar license applications (BLAs)

    Is your program ready for Phase 2?

    • Considerations about costs, patient selection and how these trials can vary for oncology studies compared to other conditions

    The Phase 2 study landscape

    • An overview of several scenarios of phase 2 studies, from Proof of Concept to Dose-Ranging (DR).

    Therapeutic index (TI) and protein therapeutics

    • Explaining the therapeutic index and its significance in relation to the safety and efficacy of protein therapeutics.

    Dose selection and injection volume limits

    • Factors to consider for dose and volume limits for subcutaneous therapeutic proteins.

    Normalizing doses and exposure across patients

    • Considerations about methods for standardizing dosages and exposures across different patient populations, and the pros/cons of different approaches

    Characterizing the impact of body size on PK

    • Discussing the methods for normalizing drug dosages according to body weight and other relevant characteristics.

    Simulating different body-size normalization algorithms

    • Different approaches are presented that can provide suitable exposure for both larger and smaller subjects for the same compound.

    Commercial examples of body size normalization

    • Showing examples of how different companies have adapted dosing schemes based on body size and other factors.

    The rush to pivotal studies

    • Issues of time pressures and economic considerations.

    FDA's "Project Optimus"

    • The goals of this project are to improve how dose-finding is conducted for oncology treatments.

    Phase 3, BLAs, and clinical pharmacology

    • Overview of the role of clinical pharmacology in providing supportive analyses after Phase 3 trials.
    • It relates the drug's exposure and efficacy/safety relationships

    Exposure-response

    • Analyzing how drug exposure relates to the clinical outcome, or surrogate endpoints, using plots.

    Exposure-Response Case Study

    • Case study example showing exposure-response analyses for a drug in children.

    Hysteresis plots

    • Explanation on how these plots are used to relate declining drug concentration with target saturation.

    Pediatric Considerations

    • How pediatric development studies should leverage information gained in adult studies.
    • The consideration of the development/ontogeny aspects when extrapolating PK from adult studies to children
    • Pediatric approval considerations for drugs.

    Immunogenicity

    • Overview of the challenges of immunogenicity in therapeutic proteins, and approaches taken to address them.
    • A case study on the immunogenicity profile of certain compounds.

    PK and Target Assay Considerations

    • Overview of assays used to measure PK (and considerations around which form of the drug is measured).
    • Discussion around what is being measured in drug PK assays that are used in human subjects.

    Measuring PK of mAbs to Cellular Targets

    • Many cellular targets also have soluble versions, which must be considered.

    Bispecific antibodies

    • Discussion on how bispecific antibodies require additional considerations relative to standard monoclonal antibodies.

    Soluble target can act as a drug sink

    • The potential role of soluble targets in affecting the exposure of therapeutic proteins or monoclonal antibodies

    Measuring total target for antibodies against soluble antigens

    • Analyzing the concentrations of total target and how they are associated with the exposure of a compound in a clinical context.

    Modeling maturation of clearance

    • How the clearance of monoclonal antibodies in children differs from adults and the different models that have been used to understand the time-dependent clearance

    Pediatric Development

    • How to leverage existing information from adult studies when evaluating the pharmacokinetics of the same drug in children..

    Pediatric PK/Safety Studies of Dupilumab in Patients

    • Presenting different experimental plans, as well as examples of PK/safety studies conducted.
    • Detailing of particular cases that involved children

    Dupilumab Pediatric AD Phase 3 Dose Selection

    • Discussion on how dose selection for pediatric clinical trials was informed by the available dosage forms, convenient dosing intervals and body weights.

    Dupilumab 200/300 mg (<60/≥60 kg) Q2W

    • Discussing how 200/300 mg Q2W dupilumab regimens were statistically better or superior to 300 mg Q4W in adolescents.

    Ontogeny and Pediatric PK Considerations

    • Discussing how antibody pharmacokinetics can differ in young children due to factors such as developmental status.

    Conclusions

    • The goal of clinical pharmacology is to identify the right dose of the right drug.
    • Encourage collection of dose-ranging PK and PD data at an early stage.
    • Clinical pharmacology for therapeutic proteins involves new technologies continually evolving from new technologies.
    • Certain aspects of clinical pharmacology for protein therapeutics are simpler than traditional small molecule drugs, like immunogenicity, but there are different challenges

    Questions?

    • QnA session about the presentation content and related topics.

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    Description

    Test your knowledge on clinical pharmacology concepts including dosing scenarios, volume of distribution, and pharmacokinetic models. This quiz covers various aspects of drug development and pharmaceutical sciences, designed for students and professionals interested in the field.

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