Assay%20and%20Error%20issues%20in%20Pop%20modeling%20and%20TDM

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Assay and Error issues in Pop modeling and TDM

• Irina Bondareva, Ph.D.
• Institute for Physical-Chemical Medicine

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InTER-Individual Variability

• Usually a single number (SD, CV) in parametric
  population models
• But there may be specific sub- populations
• eg, fast, slow metabolizers, etc.
• How describe all this with one number?
• A good question!

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InTRA-Individual Variability

• Assay error pattern, plus
• Errors in Recording times of samples
• Errors in Dosage Amounts given
• Errors in Recording Dosage times
• Structural Model Mis-specification
• Unrecognized changes in parameter values during
  data analysis.
• How describe all this with one number?
• Why describe interoccasional variability only
  with one number?

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Determining the assay error pattern how
credible is it?What do we mean by
credibility?What is a good MEASURE of
credibility?
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Fisher Information

• Fisher Info 1/Varx
• So need to know, or have a good estimate, of the
  SD of every TDM serum level
• Var SD2
• Weightx 1/Varx

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Determining the Assay SD polynomial

• Measure blank, low, medium, high, and very high
  samples in at least quadruplicate.
• Get mean SD for each sample.
• Fit a polynomial to the mean and SD data.
• SD A0C0 A1C1 A2C2 A3C3
• Then can weight each measurement by the
  reciprocal of its variance (Fisher Info)
• No lower detectable limit for PK work!

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Assay CVSD

• Concentration

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Assay CV versus weight, Fisher Information

• Assume, for example, 10 assay CV
• If conc 10, SD 1, var 1, weight 1
• If conc 20, SD 2, var 4, weight ¼
• So a constant error (the assay CV) is NOT the
  correct measure of the error!
• As conc approaches zero, CV approaches infinity
• But assay SD, var, weight always finite. Fisher
  info is the correct measure of assay error.
• Therefore, NO LOQ for PK work!

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Other environmental errors

• Gamma a multiplier of the assay error
  polynomial
• Overall error Gamma(assay error polynomial)
• Lamda an additive term
• Overall error Lamda (assay error polynomial)