Introduction to Pharmacokinetics and Pharmacodynamics

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.