Introduction to PKPD Modelling – Applications
Joe Standing
June 2012UCL Institute of Child Health & Great Ormond
Street Hospital for Children, London
Mycophenolate in Lupus
• Mycophenolic acid: selective noncompetitive inhibitor of ionosine 5’-monophosphate dehydrogenase (IMPDH)
• Blocking this depletes lymphocyte guanosine triphosphate
Mycophenolate in LupusSimplistic statistical analysis
What could model-based approach show?
Summary
• Scaling Pharmacokinetics
• Empirical PKPD models– Accepted PK target– In-vitro correlations– Models of disease score
• Effect site models
• Mechanistic PKPD
• Disease Models
Medicines in Children
• Unlicensed medicines– Prevalence: 36-67% (ICU 90%+) (Turner 1998)
Notterman 1986:
Regulatory Perspective
• Legislation– FDA Modernisation Act 1997– EU Paediatric Medicines Regulation 2006
• All new medicines must be studied
• Old medicines can be licensed for children with appropriate studies
“Children are not small adults”Kearns 2003
VS.
“Children are small adults”Tod 2008 and adults?
7
A typical plot:
8
“Children are small adults”
• CL often better correlated with BSA than wt (Cawford 1950)
• BMR correlated with wt0.75 (Kleiber 1947)
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“Children are small adults”
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Scaling in PK: Tod et al 2008
• MF = maturation function• OF = organ function
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Scaling in PK: Maturation
• Anderson 2010, Midazolam maturation
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Scaling in PK: Size
• Warfarin (Takanashi 2006)
Scaling in PK: Size
• Size matters (Takanashi 2006)
Dose/weight (mg/kg) 0.06 0.06 0.06
Summary
• Scaling Pharmacokinetics
• Empirical PKPD models– Accepted PK target– In-vitro correlations– Models of disease score
• Effect site models
• Mechanistic PKPD
• Disease Models
Aim for accepted target PK
Aim for accepted target PK
Principles of antimicrobial PKPD
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In vitro PKPD
19
20
Principles of antimicrobial PKPD
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Clinical data: Cmax/MICRATE OF CLINICAL RESPONSE VS. CMAX/MIC RATIO
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Clinical data: AUC/MIC
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Clinical data: AUC/MIC
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Clinical data T>MIC
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Clinical evidence lacking…
Be careful …
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Methotrexate (MTX) PKPD
PD marker – disease score
AimsCharacterise MTX PK in osteosarcoma patientsPredict when concentration will fall below
0.2mcmol/LInvestigate relationship between MTX PK and
mucositis scores
Treatment Schedule (EURAMOS 1)
Raw PK Data
943 concentrations from 46 patients on up to 12 occasions
Mucositis Scoring
WHO mucositis scale
0 1 2 3 4
None Soreness± erythema
Erythema,ulcers, andpatient canswallowsolid food
Ulcers withextensiveerythemaand patientcannotswallowsolid food
Mucositisto the extentthat alimentationis not possible
PK VPC
PD VPC
PKPD Relationship
Summary
• Scaling Pharmacokinetics
• Empirical PKPD models– Accepted PK target– In-vitro correlations– Models of disease score
• Effect site models
• Mechanistic PKPD
• Disease Models
Remifentanil PKPD in infants
Remifentanil used to decrease mean arterial pressure (MAP) during craniofacial surgery
Aim:Describe PKPD relationship with remifentanil
and MAP
Data
7 infants (0.3-1y; 6.6-9.6kg)
6 had rich (3 samples/min) PD data
PD data during 1st half hour
PK data during whole operation (before and 5min after changes in rate)
Remifentanil Raw DataIndividual plots (Run 104)
[PKF == 1]
Time
Ob
serv
atio
ns
/ Pre
dic
tion
s
5
10
15
20
25
30
0 50 100 150 200 250
ID:1
0 50 100 150 200 250
ID:2
0 50 100 150 200 250
ID:3
0 50 100 150 200 250
ID:4
0 50 100 150 200 250
ID:5
0 50 100 150 200 250
ID:6
0 50 100 150 200 250
ID:7
DV IPRE PRED
Individual plots (Run 104)[PKF == 0]
Time
Ob
serv
atio
ns
/ Pre
dic
tion
s
30
40
50
60
70
80
0 5 10 15 20
ID:1
0 5 10 15 20
ID:2
0 5 10 15 20
ID:4
0 5 10 15 20
ID:5
0 5 10 15 20
ID:6
0 5 10 15 20
ID:7
DV IPRE PRED
PK Data: Remifentanyl concentration vs time (min)
PD Data: MAP vs time (min)
PD Model
Individual plots (Run 104)[PKF == 0]
Time
Ob
serv
atio
ns
/ Pre
dic
tion
s
30
40
50
60
70
80
0 5 10 15 20
ID:1
0 5 10 15 20
ID:2
0 5 10 15 20
ID:4
0 5 10 15 20
ID:5
0 5 10 15 20
ID:6
0 5 10 15 20
ID:7
DV IPRE PRED
Remifentanil Results
Final model - Sigmoidal Emax
Target concentration for 30% MAP reduction = 14ng/mL
b.) Emax Model
20
30
40
50
60
70
80
90
100
20 30 40 50 60 70 80 90 100
Individual predicted MAP (mmHg)
Ob
serv
ed
MA
P (
mm
Hg
)
a.) Linear Model
20
30
40
50
60
70
80
90
100
20 30 40 50 60 70 80 90 100
Individual predicted MAP (mmHg)
Ob
serv
ed
MA
P (
mm
Hg
)
c.) Sigmoidal Emax Model (final)
20
30
40
50
60
70
80
90
100
20 30 40 50 60 70 80 90 100
Individual predicted MAP (mmHg)
Ob
serv
ed
MA
P (
mm
Hg
)
Individual PD Fits
b.) Subject 1
20
30
40
50
60
70
80
0 1 2 3 4
Time (min)
MA
P (
mm
Hg
)
b.) Subject 2
20
30
40
50
60
70
80
90
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (min)
MA
P (
mm
Hg
)
b.) Subject 4
20
25
30
35
40
45
50
55
60
65
70
0 1 2 3 4 5 6 7 8 9
Time (min)
MA
P (
mm
Hg
)
0
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 190
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 240
2
4
6
8
10
12
14
16
0 1 2 3 4 5
b.) Subject 5
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Time (min)
MA
P (
mm
Hg
)
b.) Subject 6
20
30
40
50
60
70
80
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time (min)
MA
P (
mm
Hg
)
b.) Subject 7
20
25
30
35
40
45
50
55
60
65
0 1 2 3 4 5
Time (min)
MA
P (
mm
Hg
)
Defined Concentration/Effect Relationship
Summary
• Scaling Pharmacokinetics
• Empirical PKPD models– Accepted PK target– In-vitro correlations– Models of disease score
• Effect site models
• Mechanistic PKPD
• Disease Models
Modelling hematological toxicity
• Relationship between drug exposure and myelosuppression
• Myelosuppression dose-limiting
• Typically: Logistic (Emax) model
0
1
2
3
4
5
6
7
8
9
10
0 5 10 15 20Time (Days)
Leu
kocyte
s (
x1
09/L
)
AUC
% D
ecre
ase a
t n
ad
ir
CirculatingProliferative
MTT
Transit Transit Transitktrktrktrktr
Slope · Conc
Feedback = CirculatingCirc0
Model of myelosuppression:
Estimated parameters - Leukocytes
*=Unbound concentrations
Circ0
(109/L)
IIVCirc0
(CV%)
MTT
(hours)
IIVMTT
(CV%)
Slope
(µM-1)
IIVSlope
(CV%)
Docetaxel 7.12 35 90.4 14 0.175 6.39 47
Paclitaxel 7.21 33 124 17 0.239 28.9* 42
Etoposide 7.07 39 135 14 0.189 0.0710 45
DMDC 7.50 34 123 22 0.121 0.660 44
CPT-11 8.10 26 125 31 0.147 0.892 40
Vinflunine 6.74 35 112 24 0.157 0.0020 40
Neutrophil model example
• CP-690,550 new oral DMARD• Inhibitor of Janus kinase• T and Bcell depression, causes neutropenia• Phase 2a study, 264 subjects, placebo, 5, 15
and 30mg bd dosing
Gupta et al PD model
Model simulation properties:Visual Predictive Check
Gupta et al PD model
Maintenance ALL treatment
Maintenance ALL
• Prevents recurrence in sanctuary sites
• 3 monthly intrathecals
• Monthly: vinc, dex
• Weekly: MTX
• Daily: 6-MP
• Target neuts: 0.75 – 1.5 *109/L
Retrospective data• 31 children, 2-13 y
Research question
• Does dose affect neutrophil counts?
• How should doses be adjusted?
Method
• Fitted Friberg model
• Drug effects as logistic decrease in proliferation
• Dexamethasone effect – increase Ktr
• Estimate baseline
Summary
• Scaling Pharmacokinetics
• Empirical PKPD models– Accepted PK target– In-vitro correlations– Models of disease score
• Effect site models
• Mechanistic PKPD
• Disease Models
Diabetes Platform Models
Extension to diabetes model
Antiviral PKPD
60
HIV viral load/CD4
HIV viral load/CD4
Summary
• Scaling Pharmacokinetics
• Empirical PKPD models
• Effect site models
• Mechanistic PKPD
• Disease Models