Multiple Model Dosage Design

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Multiple ModelDosage Design

• Roger Jelliffe, M.D.
• USC Lab of Applied Pharmacokinetics

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Conventional Design of Drug Dosage Regimens

• Use Population Model
• Select single target goal
• Develop the dosage regimen to hit target
• But will it? How precisely?
• How to evaluate the expected precision?

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Optimal Drug Dosage

• Consider the effects of the pop outliers.
• Do a clinical simulation to validate each
  regimen.
• Standard Doses no feedback. Optimize them to
  hit desired targets.
• Cancer Rx, Veterinary Rx.
• Individualized Doses Optimize them also.
• Targets are desired Conc, AUC, etc
• AIDS, Transplants, Cancer, Antibiotics,
  Cardiovascular, etc.

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What is the BEST Pop Model?

• The correct structural PK/PD Model.
• The collection of each subjects exactly known
  parameter values for that model.

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An NPML Population Joint Density, as made by
Mallet
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Multiple Model Dosage Design

• Start with multiple models in pop model
• Best starting tool NPAG joint density.
• Compute regimen having least weighted squared
  error in target goal achievement.

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Continuous IV Vanco. Predictions when regimen
based on means is given to all subjects
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Vanco, continuous IV. Predictions from MM regimen
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MM Optimal Dosage Regimens

• Consider the quantitative effect of outliers.
• A built-in simulated clinical trial each time.
• Achieve target goals with max precision.
• Get the best overall standard dose.
• Best for Vet use, without feedback.
• Best for Patient use, with or without feedback
  - cancer, AIDS, inf. Disease, CV disease.
• Best optimally coordinated combination regimens
  in future.

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Clinical Illustrations

• Planning the initial regimen
• Adjusting it based on TDM data