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?

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A typical plot:

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“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

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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

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serv

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/ Pre

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s

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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]

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0 5 10 15 20

ID:1

0 5 10 15 20

ID:2

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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

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0 5 10 15 20

ID:1

0 5 10 15 20

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ID:4

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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

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Individual predicted MAP (mmHg)

Ob

serv

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MA

P (

mm

Hg

)

a.) Linear Model

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20 30 40 50 60 70 80 90 100

Individual predicted MAP (mmHg)

Ob

serv

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MA

P (

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Hg

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c.) Sigmoidal Emax Model (final)

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Individual predicted MAP (mmHg)

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MA

P (

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Individual PD Fits

b.) Subject 1

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0 1 2 3 4

Time (min)

MA

P (

mm

Hg

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b.) Subject 2

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0 1 2 3 4 5 6 7 8 9 10 11 12

Time (min)

MA

P (

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Hg

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b.) Subject 4

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P (

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0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 190

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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

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b.) Subject 5

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Time (min)

MA

P (

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Hg

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b.) Subject 6

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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

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MA

P (

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b.) Subject 7

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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

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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

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HIV viral load/CD4

HIV viral load/CD4

Summary

• Scaling Pharmacokinetics

• Empirical PKPD models

• Effect site models

• Mechanistic PKPD

• Disease Models