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Approaching the In Silico Child Jeffrey S. Barrett, PhD, FCP. Outline. Background Pediatric Pharmacotherapy Defined What’s missing? Pediatric Priors – where do they come from? Models for understanding vs prediction The EMR -- leveraging hospital informatics

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slide1
Approaching the In Silico Child

Jeffrey S. Barrett, PhD, FCP

outline
Outline
  • Background
    • Pediatric Pharmacotherapy Defined
    • What’s missing?
  • Pediatric Priors – where do they come from?
    • Models for understanding vs prediction
    • The EMR -- leveraging hospital informatics
  • The Pediatrics Knowledgebase (PKB) Project
    • Design Issues
    • Methotrexate Drug Dashboard
  • Vision for the Future
pharmacotherapy
Pharmacotherapy
  • Principally concerned with the safe and effectivemanagement of drug administration.
  • Implies an understanding of pharmacokinetics (PK) and pharmacodynamics (PD) so that individual dosing guidance, when necessary, can be provided to optimize patient response within their individual therapeutic window.
pharmacotherapy1
Pharmacotherapy
  • 75% prescription drugs in children “off-label”
  • Usage not described in package insert
  • Approved indications
  • Adequate controlled studies
  • Consequences of off label usage
    • Benefit, No effect, Harm
pharmacotherapy2
Pharmacotherapy
  • Unapproved is not improper
  • Decision based on safety/efficacy data
  • Medical literature vs Regulatory Guidance
  • “Best medical judgment”
pharmacotherapy the landscape for predicting exposure
PharmacotherapyThe Landscape for Predicting Exposure

Active/inactive metabolites

Urine, Feces, Expired Air

ABSORPTION

- Site (i.e., GIT, skin, tissue depot)

- First-pass effect (oral)

- Drug properties (i.e., solubility)

METABOLISM

ELIMINATION

  • Pathway(s)
  • Sites (GIT, liver, lung)

- Unchanged drug

- Metabolites

Excretory

Sites

Distribution in Blood Cells

Bound to plasma proteins

Free Drug in Plasma or Extracellular Fluid

SITE(S) FOR THERAPEUTIC EFFECT(S)

Pharmacologic

Activity

DISTRIBUTION

- Sites (Tissues, fat, etc)

- Binding

SITE(S) FOR TOXIC EFFECT(S)

Toxic

Activity

pharmacotherapy what s missing
PharmacotherapyWhat’s Missing?
  • Drug disposition in children is best described using the term “variable”
  • In general, variability is much greater in first 3 months of life and declines to “adult variability”
  • Estimating exposure is challenging due to developmental changes affecting absorption, distributionandbiotransformation
  • Exposure also function of exogenous influences (diet, concurrent illness)

J. Steven Leeder, Pharm.D., Ph.D.

pharmacotherapy what s missing1
PharmacotherapyWhat’s Missing?
  • “Scaling” pediatric from adult dosing data needs to take into consideration:
    • Knowledge of relative contribution of ADME components at each developmental stage
    • For biotransformation, knowledge of fractional contribution of each pathway to total CL
    • Isoform-specific patterns of development
    • Interindividual variability in the rate and pattern of pathway development
    • Age-dependent differences in population variability

J. Steven Leeder, Pharm.D., Ph.D.

pediatric priors absorption
Pediatric PriorsAbsorption

J. Steven Leeder, Pharm.D., Ph.D.

pediatric priors distribution
Pediatric Priors Distribution

Intracellular Water

Protein

Fat

Other

Extracellular Water

Premature

Newborn

4 mos

12 mos

24 mos

36 mos

Adult

20

100

0

40

60

80

Percentage of Total Body Weight

pediatric priors metabolism
Pediatric Priors Metabolism
  • Functional drug biotransformation capacity acquired in isoform-specific patterns
  • Onset in Days: CYPs 2C9, 2D6, 2E1; UGTs 1A and 2B7?
  • Onset in Weeks: CYP3A4
  • Onset in Months: CYP1A2
  • Onset in Years: FMO3

J. Steven Leeder, Pharm.D., Ph.D.

pediatric priors metabolism1
Pediatric Priors Metabolism
  • Time to activity “peaks” also isoform-dependent, but less well characterized
  • In general, in vitro studies indicate that variability is much greater in first 3 months of life and declines to “adult variability”
  • Newborns at particularly high risk for concentration-dependent toxicity due to developmentally delayed drug metabolism (e.g. chloramphenicol, SSRIs)

J. Steven Leeder, Pharm.D., Ph.D.

pediatric priors metabolism2
Pediatric PriorsMetabolism

Liver Mass:Body Weight Change with Age

Liver Mass

(% Body Weight)

Age (years)

J. Steven Leeder, Pharm.D., Ph.D.

pediatric priors metabolism3
Pediatric Priors Metabolism

Activity

Newborn

Toddler

Puberty

Adult

J. Steven Leeder, Pharm.D., Ph.D.

pediatric priors models for understanding vs prediction
Pediatric Priors Models for Understanding vs Prediction

MODEL IMPACT

INFORMATION CONTENT

  • Discovery
  • Define functional relationships
  • PK/PD Data signature
  • Early CUI
  • Decision-making
  • Candidate screening / selection
  • Dose selection
  • Study designs
  • Compound progression
  • Patient Pharmacotherapy
  • Dosing guidance
  • Patient management of AE / ADRs
  • Optimize sub-therapeutic response
  • Rescue therapy

Discovery

Decision-

Making

Pharmacotherapy

pediatric priors tools for prediction
STATA

WinSAAM

Epidemiologic

Analysis

X2

X3

X1

Database

Development

Diagnostic

Analysis

Database

-0.2

0.6

Jet

Engine

-0.1

0.1

0.7

0.5

AKA

Intermediate

Processing

Data Fitting

and Fit Analysis

Data

Dict.

Publications

and

Presentations

Excel

0.1

-0.2

SAAM

Charts

Reports

Y

Pediatric Priors Tools for Prediction

PLASMA

FLOW

PLASMA

HEART

HEPATIC ARTERY

SPLEEN

LIVER

BILE

KIDNEY

URINE

BONE

MARROW

MUSCLE

CARCASS

pediatric priors electronic medical records
Pediatric Priors Electronic Medical Records
  • Paper-based records have been in existence for centuries and their gradual replacement by computer-based records has been slowly underway for over 20 years.
  • The penetration of electronic medical records (EMRs) may have reached over 90% in primary care practices in Norway, Sweden and Denmark (2003), but has been limited to 17% of physician office practices in the USA (2001-2003).
  • The EMR systems that have been implemented have been used primarily for administrative rather than clinical purposes.
electronic medical records chop environment
Electronic Medical Records CHOP Environment
  • EpicCare and EpicWeb – ambulatory computerized medical record.
  • Sunrise Clinical Manager – impatient clinical order entry, charting, charging, and documentation.
  • Wellsoft – Emergency Department patient management, clinical documentation, and reporting.
  • ChartMaxx – legal medical record for impatient, emergency, ambulatory surgery.
  • IDX Rad – radiology patient management and transcription.
  • Meditech – laboratory information system
pediatric knowledgebase pkb concept
Pediatric Knowledgebase (PKB)Concept
  • A physician-designed informatics system which surfaces the “most relevant” data to guide individual patient pharmacotherapy
  • Construction of individual “drug dashboards” which provide quantitative prediction (as requested) relative to historical and comparative patient metrics.
pediatric knowledgebase pkb project aims
Pediatric Knowledgebase (PKB)Project Aims
  • Provide dosing guidance consistent with formulary standard of care,
  • Examine patient pharmacotherapeutic indices relative to historical controls derived from the hospital data warehouse,
  • Explore treatment – diagnoses – drug correlation in conjunction with utilization and
  • Educate physicians on clinical pharmacologic principles specific to population and drug combinations of interest.
pediatric knowledgebase pkb design issues
Pediatric Knowledgebase (PKB)Design Issues

Project Design

Requirements Gathering

Project Scoping

Charter,

IRB Training

Steering Committee

Formation,

Prioritization

Design Team:

Physician champion for therapeutic area, Clinical Pharmacologist / Modeler, Programmer, IT specialist

Dashboard

Prototype

Development

Forecasting

DSS

Data

Warehouse

Access, Security, Modeling

PKB

Shell

SCM Interface

User Interface

Formulary

Metrics

Questionnaire

Clinical and operational benefit

Steering Committee:

Clinical Care Attending (Chair), Members: IRB head, external pharmacometrician, 3 physicians, project sponsor, IT specialist, business manager, hospital pharmacist

Testing

Presentation to Therapeutic Standards Committee (TSC)

TSC:

Approval for “production use” granted by Therapeutic Standards Committee

Refinement

Training and Implementation

methotrexate dashboard
Methotrexate Dashboard
  • Anti-folate chemotherapeutic agent
  • Renal excretion
  • Enterohepatic recirculation
  • Toxicity at high or prolonged low exposure
methotrexate dashboard2
Methotrexate Dashboard
  • Dose?
  • Dose adjustment?
  • Therapeutic drug monitoring?
  • Toxicity?
methotrexate dashboard3
Methotrexate Dashboard
  • 12 year-old boy with osteosarcoma and renal insufficiency….
  • 3 year-old girl with leukemia and previous history of hyperbilirubinemia….
methotrexate dashboard4
Percentage of patients with elevated creatinine able to get full dose without toxicity….

Most common toxicity in patients with elevated creatinine….

Methotrexate Dashboard
methotrexate dashboard6
Methotrexate Dashboard
  • Underlying model accounts for combined elements of methotrexate therapy
    • Dose characteristics (amount, duration)
    • Covariates (age, weight, gender, disease state, etc.)
    • Pharmacokinetics (plasma concentration)
    • Pharmacodynamics (creatinine clearance)
  • Applied to individual patient data for TDM
methotrexate dashboard7
Methotrexate Dashboard

Dose, infusion time

Central Compartment

Peripheral Compartment

Dissipation of Effect

Effect Compartment

Elimination from Plasma

methotrexate dashboard8
Current MTX data model:

Patients with normal renal function

Patients with compromised renal function

Very young patients (3 month to 1 year old)

Methotrexate Dashboard
methotrexate dashboard9
Methotrexate Dashboard
  • Provide predictions of:
    • MTX concentrations at later time
    • Creatinine clearance at later time
    • Time to reach threshold plasma concentration
  • Guidance for dose titration
  • Diagnosis of delayed MTX clearance due to acute nephrotoxicity
  • Guidance of rescue therapy in response to renal toxicity
the pkb team
The PKB Team

Mahesh Narayan

Sundarajaran Vijakumar, PhD

Kalpana Vijakumar

Mark Schreiner, MD

Rollie Essex

Arun Muralidharan

Santhanam Srinivasa Raghavan

Theo Zaoutis, MD

Athena Zuppa, MD

Jeffrey Skolnik, MD

John Mondick, PhD

Kelly Wade, MD

Peter C. Adamson, MD

Garret Brodeur, MD

Manish Gupta, PhD

Di Wu, PhD

Bhuvana Jayaraman

Dimple Patel

Dominique Paccaly, PharmD

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