Pharmaco Metrics

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PHARMACOMETRICS


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INTRODUCTION

Clinical trial

Expensive, time consuming, inefficient.

Data rich & knowledge poor.( hidden,undiscovered)

Necessary to develop a new toolkit with

powerful technical models, computerbased models, newer clinical evaluation

techniques.


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PHARMACOMETRICS

Pharmacometrics is the science of developingand applying mathematical and statisticalmethods to

(a) characterize, understand, and predict a

drugs pharmacokinetic and pharmacodynamicbehavior,

(b) quantify uncertainty of information about thatbehavior and

(c) rationalize data-driven decision making in thedrug development process andpharmacotherapy.


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PHARMACOMETRICS

Involves the development or estimation ofpharmacokinetic, pharmacodynamic,

pharmcodynamicoutcomes linking & disease

progression models.

Aid in understanding the impact of varying

dosing strategies, patient selection criteria,

differing statistical methods & different

study endpoints. to customize patient drug therapy through

therapeutic drug monitoring and improved

population dosing strategies.


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2)PharmacodynamicsInclude all of the pharmacological

actions, pathophysiological effects and

therapeutic responses, both beneficial or

adverse, of active drug ingredient and/or itsmetabolite(s) on various systems of the body

from sub-cellular effects to clinical outcomes.

1) Pharmacokinetics (parameters)

A,D,M,E

Volume of distributionBioavailability

Area under curve


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Provide a basis for selecting lead compounds

for development and can contribute knowledge

about clinical pharmacology.

3) Biomarkers

Characteristic that is objectively

measured and evaluated as an indicator ofnormal biological processes, pathogenic

process or pharmacologic responses to a

therapeutic intervention.

Biomarkers can identify patients at risk for a

disease, predict patient response, predict

the occurrence of toxicity, and predict

exposure to the drug.


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4) PK/PD Link Modeling

- Sequential models- Simultaneous PK/PD model

5) Population Modeling


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6) Clinical trial simulation

- Simulation of clinical trials within a computer

and can be used to design powerful, robust,informative, and efficient clinical trials.

- provide convincing objective evidence of the

merits of a proposed study design and

analysis.- Offers a useful tool for evaluating and

understanding the consequences of different

study designs.

Eg. Monte Carlo simulation, Bayesian simulation.

7) Learn-confirm-learn process


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8) Pharmacometric Knowledge Discovery

9) Pharmacometric Knowledge

Creation


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10) AppropriatenessofModel

State the problem to be solved

Describe how the model will be used to solve the problem

Categorize the model as descriptive or predictive

Identify the model using sound approaches

Execute model evaluation or validation in a manner

consistent with the intended use of the model

Apply the model to solve the problem

Communicate the application


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- Preclinical Development (PBPM models)

- Clinical Development- Phase 1 Studies

- Phase 2 Studies

- Phase 3 Studies

- Phase 4 Studies

ROLE OF PHARMACOMETRICS IN

DRUG DEVELOPMENT


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Progamming the tasks.

Writing scripts, codes & programs.

Customising existing code/ minor modifications

in order to create a program.

Developing complex software projects.

Interacting with management, information

technology group & regulatory group responsiblefor the software validation process.

A Pharmacometrician plays a role in


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Set of objectives with respect to the quality of scientific

programs:

(a) program correctness.

(b) reproducibility of results.

(c) program readability (critical for code reviews)

(d) maintainability (bug fixing and minor changes to the

program)(e) ease of configuration change (eg. parameter values

and the constants used in the program)

(f) portability and extensibility (ability to run the program on

different systems and ability to link the program withother programs)

(g) performance (speed and disk space requirements).


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Steps involved in the development of a

scientific program.

- Mathematical Formulation of the Scientific

Problem.

- Algorithm Design.- Design and Documentation of the Computer

Code.

- Design of Test Cases.

- Program Implementation.- Program Verification and Correction.

- Program Refinement and Optimization.


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Software designs:ADAPT IINONMEM

S-Plus

Matlab

WinNonlin

SAS

PK/PD Software: Kinetica, WinNonMix.


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Also..

The term pharmacometrics first appeared

in the literature in 1982 in the Journal of

Pharmacokinetics and Biopharmaceutics.

The FDA has promoted the role of

pharmacometrics in the drug approval

process.

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