Transcript Document

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
• The Pediatrics Knowledgebase (PKB) Project
– Design Issues
– Methotrexate Drug Dashboard
• Vision for the Future
Pharmacotherapy
• Principally concerned with the safe and
effective management 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.
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
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
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
-Pathway(s)
-Sites (GIT, liver,
lung)
Distribution in
Blood Cells
DISTRIBUTION
- Sites (Tissues, fat, etc)
- Binding
Free Drug in Plasma
or Extracellular Fluid
SITE(S) FOR
THERAPEUTIC
EFFECT(S)
SITE(S) FOR
TOXIC EFFECT(S)
ELIMINATION
Excretory
Sites
- Unchanged
drug
- Metabolites
Bound to plasma
proteins
Pharmacologic
Activity
Toxic
Activity
Pharmacotherapy
What’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,
distribution and biotransformation
• Exposure also function of exogenous influences
(diet, concurrent illness)
J. Steven Leeder, Pharm.D., Ph.D.
Pharmacotherapy
What’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
Physiological Function
Gastric pH
Biliary Function
Gastric Emptying Time
Intestinal Motility
Intestinal Surface Area
Splanchnic Blood Flow
Microbial Colonization
Intestinal Metabolism
Intest. Drug Transport
Neonate
Infants
Children
>5
Immature
Irregular
Reduced
Reduced (?)
Reduced
1o aerobes
(?)
(?)
4 to 2
Near adult
Increased
Increased
Near adult
Near adult
Near adult
(?)
(?)
Normal (2-3)
Adult pattern
Slight. increased
Slight. increased
Adult pattern
Adult pattern
1o anaerobes
(?)
(?)
J. Steven Leeder, Pharm.D., Ph.D.
Pediatric Priors
Distribution
Intracellular Water
Extracellular Water
Protein Fat Other
Premature
Newborn
4 mos
12 mos
24 mos
36 mos
Adult
0
20
40
60
80
Percentage of Total Body Weight
100
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
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 concentrationdependent toxicity due to developmentally delayed
drug metabolism (e.g. chloramphenicol, SSRIs)
J. Steven Leeder, Pharm.D., Ph.D.
Pediatric Priors
Metabolism
Liver Mass:Body Weight Change with Age
4.5
Liver Mass
(% Body Weight)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0
5
10
Age (years)
15
20
J. Steven Leeder, Pharm.D., Ph.D.
Pediatric Priors
Activity
Metabolism
Newborn
Toddler
Puberty
Adult
J. Steven Leeder, Pharm.D., Ph.D.
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
•
•
•
•
Discovery
Decision- Pharmacotherapy
Making
Dosing guidance
Patient management of AE / ADRs
Optimize sub-therapeutic response
Rescue therapy
Pediatric Priors
Tools for Prediction
STATA
PLASMA
FLOW
WinSAAM
Epidemiologic
Analysis
PLASMA
Database
Development
Diagnostic
Analysis
Database
HEART
Jet
Engine
HEPATIC ARTERY
AKA
Intermediate
Processing
SPLEEN
Data
Dict.
Data Fitting
and Fit Analysis
Publications
and
Presentations
Excel
Charts
LIVER
SAAM
Reports
BILE
X2
X1
X3
KIDNEY
Dose
0.6
-0.1
0.1
0.5
URINE
-0.2
0.7
Q1
MTX 1
CLMTX
MTX 2
kin
CLCR
0.1
-0.2
MUSCLE
CLM
kout
CARCASS
CLD
Y
BONE
MARROW
Q2
DAMPA 1
DAMPA 2
Pediatric Priors
Electronic Medical Records
• Paper-based records have been in existence for
centuries and their gradual replacement by computerbased 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
• 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
• 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
1. Provide dosing guidance consistent with
formulary standard of care,
2. Examine patient pharmacotherapeutic indices
relative to historical controls derived from the
hospital data warehouse,
3. Explore treatment – diagnoses – drug
correlation in conjunction with utilization and
4. Educate physicians on clinical pharmacologic
principles specific to population and drug
combinations of interest.
Pediatric Knowledgebase (PKB)
Design Issues
Project
Design
Project
Scoping
Steering
Committee
Requirements
Gathering
Charter,
IRB Training
Formation,
Prioritization
Dashboard
Prototype
Data
Warehouse
PKB
Shell
Development
Forecasting
DSS
Access,
Security,
Modeling
SCM Interface
User Interface
Formulary
Testing
Presentation to Therapeutic
Standards Committee (TSC)
Refinement
Training and Implementation
Design Team:
Physician champion for therapeutic area,
Clinical Pharmacologist / Modeler,
Programmer, IT specialist
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
TSC:
Approval for “production use” granted by
Therapeutic Standards Committee
Pediatric Knowledgebase (PKB)
Design Issues - Source Data
Type
Patient-specific
Source
Data Structure
SCM / EPIC
•Demographic, diagnoses, treatment
AE / ADR
Adverse Event DB
Drug Utilization
Accounting DB
Lab Values
SCM / EPIC
Hospital Information
SCM / EPIC
Formulary
Pharmacy DB
Compendial / Static
Lexi-Comp, etc.
PKB Data Mart*
* Under Construction
Oracle Tables
Pediatric Knowledgebase (PKB)
Design Issues – Static Data
Data
Static Sources
Dosing guidance
Compendium Data
Drug substance data
Drug Monograph (Material Safety Data Sheet)
Adult PK
PDR, Literature
Pediatric PK
PDR, Compendiums, Literature
Formulation
Monograph, Compendiums
Clinical Outcomes
Literature, Monograph
References
Literature, Compendiums, Reference
Pediatric Knowledgebase (PKB)
Design Issues – Hospital Computing Environment
Methotrexate Dashboard
•Anti-folate chemotherapeutic agent
•Renal excretion
•Enterohepatic recirculation
•Toxicity at high or prolonged low exposure
Methotrexate Dashboard
Disease
Dose
Route
Leucovorin
ALL
8-15 mg
IT
No
ALL
20 mg/m2
PO
No
ALL
100-300 mg/m2
IV
No
NHL
1 g/m2
IV
Yes
OS
12 g/m2
IV
Yes
Methotrexate Dashboard
•
•
•
•
Dose?
Dose adjustment?
Therapeutic drug monitoring?
Toxicity?
Methotrexate Dashboard
• 12 year-old boy with
osteosarcoma and renal
insufficiency….
• 3 year-old girl with
leukemia and previous
history of
hyperbilirubinemia….
Methotrexate Dashboard
• Percentage of patients
with elevated creatinine
able to get full dose
without toxicity….
• Most common toxicity
in patients with elevated
creatinine….
Methotrexate Dashboard
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 Dashboard
Dose, infusion time
Central
Compartment
Peripheral
Compartment
Dissipation of
Effect
Elimination
from Plasma
Effect
Compartment
Current MTX data
model:
• Patients with normal
renal function
• Patients with
compromised renal
function
• Very young patients
(3 month to 1 year
old)
Serum Creatinine Concentration (mg/dL)
Methotrexate Dashboard
14
12
10
8
6
4
2
0
0
20
40
60
Days Following MTX Dosing
80
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
Methotrexate Dashboard
Methotrexate Dashboard
Methotrexate Dashboard
Methotrexate Dashboard
Methotrexate Dashboard
Methotrexate Dashboard
The PKB Team
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
Mahesh Narayan
Sundarajaran Vijakumar, PhD
Kalpana Vijakumar
Mark Schreiner, MD
Rollie Essex
Arun Muralidharan
Santhanam Srinivasa Raghavan
Theo Zaoutis, MD
Questions?