Lecture Notes: Model Informed Drug Development - PK Modeling

Presenter

• Stacy Tannin Bal, Lead of Pharmacometrics, Estell Pharma Global Development
• Email provided for feedback

Introduction

• Focus on model-informed drug development (MID)
• Importance of modeling and simulation in pharmacometrics

Key Questions in Drug Development

• Appropriate individual dose for a patient
• Dose adjustments for non-responders or adverse events
• Impact of missed doses or overdosing
• Effect onset and duration

Importance of Pharmacokinetics (PK) and Pharmacodynamics (PD)

• PK: Relates dose to drug concentration profile (dose, regimen, formulation)
• PD: Links drug concentration to downstream response (direct or complex)

Objectives of Pharmacometrics

• Ensure right dose, drug, patient, and timing
• Balance efficacy and safety

Modeling Types and Application

• PK Modeling: How dose becomes concentration
• PKPD Modeling: Concentration leads to response
• Disease Progression Modeling: Disease changes over time without drug
• Quantitative Systems Pharmacology: Link PK to complex disease models

Pharmacokinetics (PK) Basics

• Physical/chemical process: Absorption, Distribution, Metabolism, Excretion (ADME)
• Parameters: Clearance, Volume of distribution, Half-life, Exposure, Cmax, Tmax

Data Collection Stages

• Pre-Clinical: Wide range dosing, scaling to humans
• First-In-Human: Single/multiple ascending doses, steady-state PK
• Clinical Pharmacology Studies: Food effect, renal/hepatic impairment, drug interactions
• Later Phase Studies: PK in target populations, variability assessment

PK Analysis Methods

• Non-Compartmental Analysis (NCA): Direct data use, fewer assumptions
• Compartmental Analysis: Model-based, interpolation/extrapolation
• Population PK (PopPK): Nonlinear mixed effects modeling, covariate analysis

Nonlinearity and Saturation

• Linear PK vs Nonlinear (dose-dependent processes)
• Saturation: Active transport, protein binding, metabolism

Absorption Modeling and Challenges

• Complex due to formulation and physiology
• PBPK Modeling: Physiologically-based, mechanistic approach
• Used for scaling (e.g., rats to humans), drug-drug interactions

Physiologically Based PK (PBPK)

• Represents organs, blood flows
• Scalable across species and populations

PK to PD and Future Topics

• Part two will focus on disease progression, drug impact on PD, quantitative systems pharmacology

Conclusion

• Importance of PK principles
• Invitation to join next session and contact for questions