Pharmacometrics, biostatistics and computational biology postgraduate training:-
How can we integrate courses?
Julie SimpsonHead of Biostatistics Unit
Centre for Epidemiology and BiostatisticsMelbourne School of Population and Global Health
WCoP, 23 August 2016
Population pharmacokinetic modelling2
Kloprogge F et al. Br J Clin Pharm 2015
Population pharmacokinetic modelling:-Let’s unpack the skill set required….
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Pharmacokinetics – absorption, volume of distribution, clearance
Applied mathematics – ordinary differential equations
Population pharmacokinetic modellingLet’s unpack the skill set required….
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• Estimating model parameters • Evaluating how well the model fits the data.
Population pharmacokinetic modelling:-Let’s unpack the skill set required….
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1) Begin with statistical computing (e.g. R), linear regression, statistical inference (confidence intervals – asymptotic or bootstrap),regression diagnostics
Yi= β0 + β1𝑋𝑖 + ε𝑖
120
130
140
150
160
Sys
tolic
Blo
od P
ress
ure,
mm
Hg
30 40 50 60 70Age in years
-20
-10
010
20
Res
idua
ls
-10 0 10Inverse Normal
-20
-10
010
20
Res
idua
ls
130 135 140 145 150Fitted values
Population pharmacokinetic modelling:-Let’s unpack the skill set required….
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2) Progress to linear mixed-effects modelling
Yij= (β0 + 𝑏0𝑖) + (β1 + 𝑏1𝑖)𝑡𝑖𝑚𝑒𝑖𝑗 + ε𝑖𝑗
Population pharmacokinetic modelling:-Let’s unpack the skill set required….
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3) And then on to nonlinear regression
𝐶𝑗 𝑡 =𝑑𝑜𝑠𝑒. 𝛽𝑘𝑎
𝛽𝑉/𝐹𝛽𝑘𝑎 − 𝛽𝐶𝑙/𝐹𝑒−
𝛽𝐶𝑙/𝐹𝛽𝑉/𝐹
𝑡𝑗− 𝑒−𝛽𝑘𝑎𝑡𝑗 + 𝜀𝑗
010
2030
Con
cent
ratio
n (m
g/L)
0 7 14 21 28Time
Population pharmacokinetic modelling:-Let’s unpack the skill set required….
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3) Followed by nonlinear mixed-effects modelling
- NONMEM®, Monolix
𝐶𝑖𝑗 𝑡 =𝑑𝑜𝑠𝑒𝑖𝛽𝑘𝑎𝑖
𝛽𝑉/𝐹𝑖𝛽𝑘𝑎𝑖 − 𝛽𝐶𝑙/𝐹𝑖𝑒−(
𝛽𝐶𝑙/𝐹𝑖𝛽𝑉/𝐹𝑖
)𝑡𝑖𝑗− 𝑒−𝛽𝑘𝑎𝑖𝑡𝑖𝑗 + 𝜀𝑖𝑗
Population pharmacokinetic-pharmacodynamicmodelling:- Further skills required…
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• Identifiability of mathematical systems
• Monte Carlo Markov Chain (MCMC) methods
Systems pharmacology model of the coagulation networkGulati A et. al. CPT PSP 2014
Why is proper training in all these areas important?10
Times Higher Education(THE) Top 16 universities for Clinical, Pre-clinical and Health 2015-16
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Rank Institution Country Master of Biostatistics Master of Pharmacometrics Master of Computational Biology
1 University of Oxford UK √ (MSc Applied Stats) X X
2 Harvard University USA √ X √
3 University of Cambridge UK X X √
4 University College London UK √ X X
=5 University of California, Berkeley USA √ X √ (1st year PhD)
=5 Imperial College London UK X X X
7 Stanford University USA √ (1st year PhD) X √ (1st year PhD)
8 King’s College London UK X X X
9 Johns Hopkins University USA √ X X
10 Columbia University USA √ X X
11 University of Toronto Canada √ X X (undergraduate training)
12 University of Edinburgh UK X X X
13 Karolinksa Institute Sweden X X X
14 Duke University USA √ X √ (1st year PhD)
=15 University of California, Los Angeles USA √ X √ (MSc Biomathematics)
=15 University of Melbourne Australia √ X X
Master of Biostatistics (11 Universities):–Skill set for PK-PD modelling
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0
2
4
6
8
10
12
StatisticalComputing
StatisticalInference
Linear Regression Generalised LinearModels
Linear mixed-effects modelling
Nonlinearregression &
nonlinear mixed-effects modelling
Bayesian methods
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MSc – Pharmacometrics, University of MarylandCurriculum• Basic Pharmacometric Tools
Statistical Computing:- Phoenix, NONMEM and R
• Basic PKPD ModellingFundamentals of PK and PD modelling and hands on training of PK-PD analysis and simulation software
• Statistics for Pharmacometricians I Basic statistical principles required for a pharmacometrician
• Dose-Response Trials Basics of designs such as parallel, cross-over, flexible-dose, titration, withdrawal, adaptive and enrichment trials. Learn how to perform clinical trial simulation.
• Strategic Communication & NegotiationsCommunication & negotiation skills
• Intermediate PKPD Modelling IIntroduction of population analysis concepts.
• Intermediate PKPD Modelling II Nonlinear mixed-effects modelling
• Statistics for Pharmacometricians IILogistic regression, Poisson regression and survival analysis – analysis of real data examples and simulation. 14
Pharmacometrics postgraduate training:-What is the way forward?
Master of Pharmacometrics
• Develop curriculum that includes key subjects from Master of Biostatistics and Master of Computational Biology.
• Online course taught by multiple institutions – Biostatistics Collaboration of Australia (www.bca.edu.au )
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Pharmacometrics postgraduate training:-What is the way forward?
Master of Biostatistics/ Computational Biology –Pharmacometrics stream
Develop subjects – e.g. pharmacokinetics, nonlinear mixed-effects modelling, etc., which are offered as electives.
Pharmacometrics
Computational Biology
Biostatistics