Use of Pharmacokinetics Modeling & Simulation in the Drug Development:
From Discovery to Development
Joseph Kim, PhD, RPhDirector
Clinical Pharmacology Modeling & SimulationGSK, R&D, Research Triangle Park
High risk R&D investment
12–15 yearsin development
One out of5,000 to 10,000
compounds makesit to patients
>$1 billionper drug
7 out of 10 drugsdon’t cover average
R&D costs0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16
Discovery (2–10 years)Discovery (2–10 years)
Pre-clinical TestingPre-clinical Testing
Phase IPhase I
YearsYears
Agency Review / Agency Review / ApprovalApproval
Phase IIPhase II
Phase IIIPhase III
Discovery FTiH
Drug development process is finding answers to many questions
Approval Trials
POC Dose
SelectionPLE
What is the optimal patient
population?
Do we cease development?
Do we need a new formulation?
What is the 1st indication?
Can we get the optimal dose from
the POC trial?
What’s the probability of
Phase III success?
How do we beat the competition?
Interactions?
Biomarker α Endpoint?
Dose schedule?
Combination Product?
Slide from Jeff Wald, GSK
Effective in animal model?
Safe in animal model?
4 Dis
covery
PHASE 1
PHASE 2
PHASE 3
NDA
MARKET
PRECLINIC
AL
DEVELOPMENT IND
KN
OW
LE
DG
E
(Cer
tain
ty)
0
1
EFFICACY SAFETY- FREQUENT
SAFETY- RARE
At any point in development, there is a need to be able to evaluate whether the realized or anticipated benefits outweigh the potential risks
Bob Powell, ISPOR 2008
Evolution of benefits and risks:Challenges and opportunities
Clinical Pharmacology: Study of drug in humans*
– Pharmacokinetics– Pharmacodynamics– Drug Metabolism and Transport– Optimizing and Evaluating Patient Therapy– Drug Discovery and Development
*Principles of Clinical Pharmacology, 2nd Ed. Arthur Adkison et al.
What is Pharmacokinetics
• What does the body do to drugs– Absorption– Distribution– Metabolism– Elimination
[Dru
g]
Time
Biom
arke
r
[Drug]
Toxicity
Pharmacodynamics: What does the drug do to the body
PK Use in Drug Development• Discovery (pre-clinical)• Phase I – First Time in Human study (FTiH)• Phase I – Non- FTiH study • Phase II – Proof of Concept, Proof of
Mechanism, Dose Finding study• Phase III – Pivotal studies• Phase IV – Post approval commitment,
PLE(Product Line Extension), Country specific registrations
PK Use in Drug Development
• Discovery (pre-clinical)– Allometric scaling> Modeling & Simulation– Predict AUC, Cmax, target dose– Suggest dose strength– Compare human exposure to animal toxicity
(NOAEL- No Observed Adverse Effect Level)
Case #1: Use of Modeling & Simulation with Animal toxicokinetic study
Single dose rat study – no toxicity but some unusual TK profile
Repeat dose rat study initiated – animal dies with 1500mg/kg dose after 3-4 days
Single dose study TK profile reviewed and re-evaluated using modeling & simulation
Case #1– Rat Single Dose Data
Plasma Profi les in Rats Given a Single Oral Dose of GSK570570B in HPMC/ Tween
0
2000
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12000
0 5 10 15 20 25 30 35 40 45 50
Time (hr )
100 mg/kg
1100 mg/kg
1500 mg/kg
Snapshot of 300 mg/kg Dose for SD and Repeat Dose
Plasma Profile of GSK570570A in Rats of R41472 at 300 mg/kg on Days 1 or 7
0
2000
4000
6000
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0 5 10 15 20
Time (hr)
Co
nc.
(n
g/m
l)
Day 1
Day 7• Significant accumulation, 4 fold increase in AUClast• Elimination phase has not begun at 24 hrs. on neither day 1 or day 7
Nonparametric superposition prediction – 1500mg QD, assuming t1/2 is 24 hrs starting 48hr after single dose
500
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0 5 10 15 20 25
time
analyte=GSK448960B, dose=100
25000
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0 5 10 15 20 25
time
analyte=GSK448960B, dose=1100
24000
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30000
0 5 10 15 20 25
time
analyte=GSK448960B, dose=1600
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0 5 10 15 20 25
time
analyte=GSK570570B, dose=100
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time
analyte=GSK570570B, dose=1100
19500
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0 5 10 15 20 25
time
analyte=GSK570570B, dose=1500
PK Use in Drug Development
• Phase I – First Time in Human study (FTiH)– Single Dose Study>> Dose escalation– Repeat Dose Study>> Dose escalation– PK data analysis and Modeling & Simulation– Predict AUC, Cmax, target dose– Compare human exposure to animal toxicity
(NOAEL- No Observed Adverse Effect Level) or biological activity (MABEL – Minimum Anticipated Biological Effect Level)
PK Use in Drug Development
• Phase I – After FTiH– Formulation study– Food effect study– Drug Interaction study (perpetrator vs victim) – Renal impairment study– Hepatic impairment study– QTc study– Others (pediatric, elderly population)– Compare human exposure to animal toxicity (NOAEL- No
Observed Adverse Effect Level)
PK Use in Drug Development• Phase II – Proof of Concept, Proof of Mechanism, Dose
Finding study– Modeling & Simulation– Predict target site concentration and needed dose– Use protein binding, receptor occupancy etc.– Suggest dose and regimen for Phase III– Prepare EoP2a meeting with regulatory agency– Predict probability of success with given dose and variability– Compare human exposure to animal toxicity (NOAEL- No
Observed Adverse Effect Level)
16
(Dose mg)
0 250 500 750 1000
HbA
1c w
k 1
2 %
ch
ang
e f
rom
ba
selin
e
-40
-30
-20
-10
0
10
20
30
40
HbA1c Doses (mg)
Placebo 50 100 250 500 1000
Actual data Median
-0.3 -1.1 -1.1 -1.0 -1.1 -1.1
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
0 5000 10000 15000 20000 25000
AUC
0
50
100
250
500
1000
Case #2Phase IIa (POC): Confirming Biologic Activity
Dose-Response Exposure-Response
Some numbers were modified for confidentiality
PK Use in Drug Development
• Phase III – Pivotal studies– Population PK and Modeling & Simulation– Adaptive Design– Ethnopharmacology– Pharmacogenetics– Regulatory filings
Forging the Framework for Biostatistics & Programming ExpertiseForging the Framework for Biostatistics & Programming Expertise
Update the model
StoppingRule
AllocationRule
New Patient
Randomisation
3
Data
1
24
5
6
Continue Stop
Go
STOPfor Futility
STOPfor Efficacy
Patient is randomised in blinded fashion to:
placebo (25%), high dose (25%)
or “optimal” dose (50%)[5, 15, 30, 60, 120, 180]mg
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delete these guides from slide master before printing or giving to the client
7
Logistic Regression Model
Res
po
nse
Rat
e
Dose
ED50
Continual Reassessment Method chooses the “optimal” dose
that will optimise learning about the ED50
Case #3Phase II/III: Adaptive Design Dose Selection
, Slide from Alun Bedding
PK Use in Drug Development
• Phase IV – Post approval commitment, PLE, and Country specific registrations– Population PK and Modeling & Simulation– Bioequivalence study– Foreign country registration– Regulatory filings
20
A model-based continuum provides a quantitative framework for the expected…and unexpected questions
Lalonde, et al., Clinical Pharmacology and Therapeutics, July 2007
LB Sheiner, Clinical Pharmacology and Therapeutics, March 1997
21
Summary
• Drug Development is very high-risk business with big uncertainty and variability
• Public and FDA ask more efficient way of Drug Development
• PK/PD modeling and simulation can answer many questions in every stage of Drug Development
• Model-based drug development/adaptive design approaches are powerful tools to improve clinical drug development, regulatory guidance and the quality of NDA submissions
• USA FDA is aware and willing to accept innovations in New Drug Development Processes
• Choosing the right dose is extremely important
22
Acknowledgements and References
• GSK R&D Colleagues-- Jeff Wald, Patrick Ryan, Alun Bedding
• Bob Powell (formerly at FDA)
