1) Understanding the relationship between pharmacokinetics (PK) and pharmacodynamics (PD) through preclinical PKPD studies is important for determining effective drug doses and schedules. 2) Successful PKPD study design requires integrating knowledge across disciplines and testing a range of doses, time points, and biological parameters to understand target modulation and optimize efficacy while minimizing toxicity. 3) Case studies demonstrate how PKPD analysis of oncology and respiratory disease models identified optimal dosing schedules, with the oncology study changing from a daily high dose to thrice weekly lower doses to improve efficacy without toxicity.

1. Understanding PKPD using preclinical
models: lessons for efficacy studies
27th May 2020
Jenny Worthington

2. Jenny Worthington – Founder and Director of Science at Axis Bioservices
• Brief background to Axis Bio
• PKPD relationship and why it is important
• Why should we carry out PKPD analysis in preclinical studies
• Factors involved in designing a successful PKPD study
• Case study 1 – Oncology
• Case study 2 – Respiratory
• Round-up
• Questions

3. Axis Bioservices – Who are we?
Oncology
•In Vivo
Pharmacology
•Xenograft
models
•Syngeneic
models for
Immuno-
Oncology
•In vitro
assays/cell
biology
Inflammation
•In Vivo
Pharmacology
•General
Inflammation
models
•Rheumatoid
Arthritis
•Inflammatory
Bowel Disease
•Fibrosis
RespiratoryDisease
•In Vivo
Pharmacology
•Pulmonary
Fibrosis
•Asthma
•COPD
•Emphysema
FACS
•Cell cycle
analysis
•Cytokine
analysis
•BALF analysis
•T-cell, B-cell
tumour
infiltration

4. PKPD Relationship
Understand the
time course of a
pharmacological
effect
Effectiveness
Adverse
effects
Time course
Dose
Concn in
plasma and
tissue
Modulation
of target
PK PD

5. Why conduct preclinical PKPD studies?
1. Quantitative analysis of dose response relationships
2. Predict the time course effects of drug doses (single or multiple)
3. Understand target modulation to enable statistically significant efficacy.
4. Determine optimal dosing regimens with acceptable therapeutic index.

6. Factors involved in successful design of a PKPD study: integration of knowledge
All expertise involved in
design (chemistry,
pharmacology, biology)
Test a range of doses
(modelled from in vitro
and PK data)
Assess different biological
parameters: target
protein, biomarkers,
serum/tissue
Test a range of time
points (around Tmax).
Allow wash out phase
Successful
PKPD study
Optimal dose schedule for efficacy
with minimal toxic effects

7. Case Study 1: Oncology
Understand the
time course of a
pharmacological
effect
Effectiveness
Adverse
effects
Time course

8. 1
10
100
1000
10000
100000
0 5 10 15 20 25
Meanconcentration(ng/ml)
Time (h)
Compound X 2.4 mg/kg Compound X 11.45 mg/kg
PK data
Case Study 1: Oncology
MTD data (14 days dosing)
30 mg/kg is MTD
0
100
200
300
400
11 13 15 17 19 21 23 25
Tumourvolume(mm3)
Treatment time (days)
Vehicle Compound X 30mg/kg
Efficacy data

9. Follow up studies:
• Carried out a PKPD analysis (single dose)
• 3 dose levels – 3, 10 and 30 mg/kg
• Time course – 0, 4, 8, 24, 48, 72, 96h
• Serum exposure levels
• Tumour exposure levels
• Tumour target protein levels by western blot
• Outcome:
• Serum and tumour exposure levels were similar at 10 and 30 mg/kg
• Target protein modulation was similar at 10 and 30 mg/kg
• Target protein expression lowered to 72h post single dose.
• Apoptosis (measured by cleaved caspase expression) remained high out to 96h.
Case Study 1: Oncology
Dosing schedule changed from 30mg/kg QD to 10mg/kg TIW; no
toxicity was observed – good efficacy in tumour model.

10. Case Study 2: Respiratory study
Understand the
time course of a
pharmacological
effect
Effectiveness
Adverse
effects
Time course

11. Case Study 1: Respiratory Study (COPD)
Time scale is an issue for these studies – can last out to 6 months so if its wrong first thing
round there is a serious knock-on effect on project timings.
• PK data from naïve and diseased model
• Tolerability study – diseased model
• Carried out PKPD study – 14 days dosing
• BALF
• Lung histology
• Lung QPCR for specific targets
• Plasma and lung tissue levels
• Complete blood counts and blood chemistry
Able to have full modelling and worked out optimal dosing schedule for full scale
efficacy model

12. Summary/Recommendations
• Factor a PKPD study into your project plans – early!
• Get expert advice to help design these studies
• At least factor some satellite PKPD animals into efficacy studies
• Get as many samples as possible from individual animals
• Work out need-to-know versus nice-to-know information and prioritise
Bottom line: Running a PKPD study does cost £s but gives the opportunity to
maximise efficacy in the short term and plan for success long run.