Dr. Kunihiro Sasahara, Ph.D.
Dr. Russell Wada, Ph.D.
Dr. Yuying Gao, M.D., Ph.D.
Modeling & Simulation: A
Tool to Enable Efficient
Clinical Drug Development
JSPS
Agenda
•
Overview of Clinical Trial Simulations
•
The Pharsight Trial Simulator
™software
•
Application to the efficient approval of etanercept in pediatric patients with
rheumatoid arthritis
3
2005 03 29 Pharsight Copyright
Population pharmacokinetic modeling and exposure-response
modeling are essential ingredients in drug development today.
PK PD
Dose Efficacy/Safety
Pop PK (FDA Guidance: 1999)
Exposure-Response (FDA Guidance: 2003)
Cp
How can we incorporate these models into clinical trial
simulations?
In 1999, the CDDS developed “good practices” for simulations in drug
development, with three guiding principles: clarity, completeness, and
parsimony.
Simulation in Drug Development: Good Practices
Draft Publication of the Center for Drug Development Science (CDDS) Draft version 1.0, July 23, 1999
Copyright: CDDS, 1999
Editors: Holford NHG, Hale M, Ko HC, Steimer J-L, Sheiner LB, Peck CC Contributors : Bonate P, Gillespie WR, Ludden T, Rubin DB, Stanski D
• CLARITY: The report of the simulation should be understandable in terms of scope and conclusions by intended users such as those responsible for committing
resources to a clinical trial.
• COMPLETENESS: The assumptions, methods and critical results should be described in sufficient detail to be reproduced by an independent team.
• PARSIMONY: The complexity of the models and simulation procedures should be no more than necessary to meet the objectives of the simulation project…
5
2005 03 29 Pharsight Copyright
Here’s an example using clinical trial simulations to avoid a
Phase 3 trial studying dose-intensification of docetaxel in
NSCLC patients with high
α
1-acid glycoprotein levels.
Veyrat-Follet CPT 2000; 68:677-87
•
Docetaxel was approved at a dose of 100 mg/m2 in patients with non-small-cell lung cancer.•
Patients with high α1-acid glycoprotein levels (AAG) had shorter time toprogression and death.
•
Exposure-response analysis of 151Phase 2 patients showed that cumulative dose, first cycle AUC and AAG were
predictive of progression and survival.
•
125 mg/m2 was selected as the optimaldose because of dose-limiting hematologic toxicity.
•
Clinical trial simulations demonstrated a slight survival benefit that had a 6% likelihood to be significant in Phase 3.Here’s an example of using Phase 3 data to demonstrate
similar clinical outcome for weight-based vs. fixed-dose
regimens of ARANESP, an erythropoietin stimulating protein.
7
2005 03 29 Pharsight Copyright
Agenda
•
Overview of Clinical Trial Simulations
•
The Pharsight Trial Simulator software
•
Application to the efficient approval of etanercept in pediatric patients with
rheumatoid arthritis
Before using Trial Simulation, equations describing population
variability must be determined using modeling.
30% Variability 1.071 (m2) Population Mean BSA Clearance/F 29% Variability 0.077 ± 0.005 (L/h) 0.058 ± 0.003 (L/h) Population Mean ± SE Male Female
CL/F = (Population Mean ± SE) × (BSA/1.071)1.41 × exp(η)
Variability due to BSA Variability(unexplained) Variability due to
uncertain parameter estimates
9
2005 03 29 Pharsight Copyright
The trial simulator software organizes the clinical trial
simulation into seven sections.
The drug model is organized using a graphical model editor.
Formulations
Responses
11
2005 03 29 Pharsight Copyright
Demographic variables and pharmacokinetic parameters are
viewed by “opening” the blocks.
Monte-Carlo simulations generate distributions of patient
characteristics. These virtual patients are enrolled into a
clinical trials, and drug response is determined.
ID SEX BSA (m2) CLF (L/h) 1 F 0.84 0.057 2 M 0.82 0.03 3 F 1.62 0.114 4 M 1.64 0.124 5 F 0.91 0.058 6 F 0.9 0.029 7 M 1.04 0.056 8 F 0.8 0.028 9 M 0.72 0.035 10 F 0.91 0.041 0.0 0.05 0.10 0.15 0.20 0 1500 Clearance (L/h) Count Male, BSA=1.071 m2 0.0 0.05 0.10 0.15 0.20 0 1500 Clearance (L/h) Count Male 0.0 0.05 0.10 0.15 0.20 0 1500 Clearance (L/h) Count Female 0.0 0.05 0.10 0.15 0.20 0 1500 Clearance (L/h) Count All Children 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0 500 1000 1500 BSA (m2) Count
13
2005 03 29 Pharsight Copyright
Dosing schedules are specified and displayed in a graphical
user interface.
Agenda
•
Overview of Clinical Trial Simulations
•
The Pharsight Trial Simulator software
•
Application to the efficient approval of etanercept in pediatric patients with
rheumatoid arthritis
– This example is based on a recent publication by Yim et al, Journal Clinical Pharmacology, 2005; 45:246-256.
– It was selected because it illustrates clearly how clinical trial simulations bridge from data to new trials using models.
15
2005 03 29 Pharsight Copyright
Development strategy
•
Tumor necrosis factor alpha is elevated in synovial joints in rheumatoid
arthritis.
•
Etanercept inactivates tumor necrosis factor alpha
– Received FDA approval in adults for RA, psoriatic arthritis, ankylosing
spondylitis and polyarticular course of juvenile rheumatoid arthritis
and psoriasis in adults.
– Recommended dose in JRA patients was 0.4 mg/kg SQ twice weekly
•
Etanercept has a 5-day half-life, so a doubled dose of a once-weekly
injection was sought.
•
Key Question
– Using PK data from twice-weekly SQ injections in JRA patients, could
population PK models and clinical trial simulations be used to support
the approval of the once-weekly regimen?
Description of patients studied with twice-a-week dosing used
in the modeling.
17
2005 03 29 Pharsight Copyright
Simulation strategy
•
Develop demographic model and population PK based on 69 juvenile RA
patients.
•
Trial simulations
– 100 subjects per BIW and QIW regimen.
– 100 trial replications of the trial
– Display graphically the mean, median, 5
thand 95
thpercentile
concentration values at each time point.
– Compare BIW vs. QIW regimens
•
Utilize previously developed exposure-response model for efficacy in
adults, and dose-response information for safety in juveniles and adults.
Population PK model parameters
19
2005 03 29 Pharsight Copyright
Here is an overlay of measured and predicted concentrations.
Simulations of BIW and QIW dosing show 11% greater peak
concentrations and 18% lower trough concentrations on QIW
dosing.
Yim et al, Journal Clinical Pharmacology, 2005; 45:246-256.
21
2005 03 29 Pharsight Copyright
Conclusions of the clinical trial simulation
•
“Concentration simulations for the 0.4 mg/kg twice-weekly and 0.8 mg/kg once weekly dose regimens showed overlapping profiles that support interchangeability between the dosing regimens.”•
It is possible that the increased peak concentrations by 11% may cause a safety risk.•
“On the basis of simulation analysis, FDA approved the dosing regimen ofetanercept 0.8 mg/kg SC once weekly for pediatric patients with JRA along with 50 mg SC once weekly in adults.”
•
Key “Bridging” Assumptions– Twice-weekly pharmacokinetics is predictive of once-weekly pharmacokinetics in pediatrics
– Exposure-response relationships in JRA are similar between pediatrics and adults
Agenda
•
Overview of Clinical Trial Simulations
•
The Pharsight Trial Simulator software
•
Application to the efficient approval of etanercept in pediatric patients with
rheumatoid arthritis
23
2005 03 29 Pharsight Copyright
Clinical trial simulation bridges from existing data to new trials
using models. The predictability depends on the strength of
the key assumptions.
•
Phase 2 NSCLC to Phase 3 NSCLC for docetaxel– Phase 2 population is similar to phase 3 population
– Exposure-response relationship extends to higher doses
•
Phase 3 weight-based vs. fixed doses of ARANESP– The effects of weight on hemoglobin response are captured in pharmacokinetics
•
Twice-a-week to once-a-week dosing of etanercept in juvenile RA – Once-a-week PK predicts twice-a-week PK– Exposure-response similar in adults and children
•
When assumptions are strong, clinical trial simulations can be used to support regulatory interactions. When assumptions are weaker, clinical trial simulations support internal decisions.Other “bridging” applications of clinical trial simulations
•
From immediate release to extended release formulations
•
From approved statins to new statins in hypercholesteremia
– Similar relationship between LDL reduction and cardiovascular risk
reduction
•
For PPAR gammas to PPAR alphas in diabetes
– Animal models for glucose lowering are relevant to humans
•
For novel neuroprotective Parkinson’s drugs
– Animal models of neuroprotection are relevant to humans
25
2005 03 29 Pharsight Copyright
Model-based drug development was broadly discussed by
industry and FDA at the 2005 American Society of Clinical
Pharmacology and Therapeutics Meeting.
Conclusions
•
Modeling and clinical trial simulation is a tool that is being used by
pharmaceutical companies and FDA to improve the efficiency of drug
development.
•
Clinical trial simulation bridges from existing data to new trials using
models.
•
Pharsight’s Trial Simulator™ is capable of implementing most Clinical