What Is PK/PD Modeling?

Introduce pharmacodynamics and understand how exposure becomes response.
Tip

Big picture: PK models describe exposure. PK/PD models explain how exposure becomes response.

Learning Objectives

By the end of this lesson, you will be able to:

  • distinguish pharmacokinetics and pharmacodynamics
  • explain exposure–response relationships
  • understand the idea of multiple endpoints
  • recognize direct and delayed responses
  • explain why PK alone is often insufficient

Key Ideas

  • PK describes concentration
  • PD describes response
  • concentration is not always the final outcome
  • response may occur immediately or with delay

Why Extend PK Models?

Until now, we focused on questions such as:

Dose → Concentration

But real decisions often ask:

  • Did the drug work?
  • Was toxicity observed?
  • Did the biomarker change?

Those questions require pharmacodynamics.

PK/PD extends the workflow:

Dose

↓

Concentration

↓

Response

PK versus PD

Compare the two concepts.

PK → What concentration occurred?

PD → What effect occurred?

Examples:

Question Domain
What exposure occurred? PK
Did blood pressure decrease? PD
Did INR increase? PD
Did concentration change? PK

Interpretation:

PK describes:

Drug → Body

PD describes:

Body → Response

Worked Example 1: Exposure Does Not Equal Response

Suppose two patients have the same exposure.

Same Concentration → Different Response

Possible reasons:

  • biological differences
  • sensitivity differences
  • delayed response
  • variability

This motivates PK/PD modeling.

Worked Example 2: One Subject Can Produce Multiple Endpoints

Earlier we modeled one endpoint.

Conceptually:

Subject → Concentration

PK/PD introduces:

Subject → PK Endpoint + PD Endpoint

Examples:

Endpoint Example
PK concentration
PD biomarker
PD efficacy
PD toxicity

This idea is called:

Multiple Endpoints

Multiple outcomes may come from the same subject.

Worked Example 3: Warfarin Example

Warfarin provides a useful PK/PD example.

INR is a clinical measure related to blood clotting. For warfarin, INR is often used as a response endpoint.

Conceptually:

Dose

↓

Warfarin Concentration

↓

INR Response

Question:

Does concentration immediately determine INR?

Not necessarily.

Response may appear later.

This introduces delayed effects.

Worked Example 4: Immediate and Delayed Response

Some responses occur quickly.

Conceptually:

Concentration → Effect

Other responses appear gradually.

Conceptually:

Concentration → Biological Change → Effect

Examples:

Pattern Example
immediate direct receptor effect
delayed biomarker turnover

Delayed behavior motivates later PK/PD models.

Worked Example 5: What Changes in PK/PD?

Population PK focused on:

Estimate Exposure

PK/PD adds:

Estimate Exposure

↓

Explain Response

Questions become:

  • How much response occurs?
  • When does response occur?
  • Why do subjects differ?

Software Used

We continue using:

library(tidyverse)
library(nlmixr2)
library(nlmixr2data)

No fitting yet.

This lesson focuses on concepts.

Looking Ahead

Next lesson introduces models that connect:

Concentration → Response

We begin with:

  • direct effect
  • saturation
  • Emax relationships

Strategies

  • separate concentration and response
  • identify endpoints
  • think mechanistically

Common Mistakes

  • treating PK as the final goal
  • ignoring delayed effects
  • assuming one endpoint

Practice Problems

  1. What is the difference between PK and PD?

  2. Why is concentration not always sufficient?

  3. Give one PK endpoint and one PD endpoint.

  4. Why can two subjects show different responses?

  5. What does multiple endpoints mean?

Problem 1

PK → concentration

PD → response

Problem 2

Response depends on biology.

Problem 3

Example:

PK → concentration

PD → INR

Problem 4

Response variability exists.

Problem 5

One subject may contribute more than one outcome.

Summary

  • PK describes exposure
  • PD describes response
  • concentration is not always sufficient
  • PK/PD introduces multiple endpoints
  • response may be delayed
  • PK ≠ PD
  • Exposure ≠ response
  • Multiple endpoints matter
  • Delay matters