The significance of the distribution of PK and PD variabilities in predicting overall clinical outcome
Airplane versus Human body
Sources of variabilities
PK/PD variabilities
In new drug development, we would like to know the overall probability of response for a given drug and proposed regimen In clinical therapy, we would like to give optimal dose to each individual patient for the particular disease
PK variability and distribution
PD variability and distribution
Tmic = 2.3 (LogCo - Log Cmic) / K
What is the overall probability and distribution of expected response in a population for a given dose and/or regimen ?
Quantal conc.-effect curve
Quantal Tmic-Effect Plot
The effect of increased dose or decreased elimination rate constant on concentration distribution and probability of overall clinical response
Augmentin Example: The distribution of Amoxicillin concentration after single 500mg or 875mg dose
Augmentin Example: The distribution and probability of overall clinical effective response after single 500mg or 875mg dose
Response probability over 24 hours
The distribution of response probability for various MICs
The overall cure rate, for evaluable patient, seen at the later follow-up visit were comparable between the two dose/regimen groups. The q8h dose regimen is slightly better than q12h dose regimen. The overall cure rates are in agreement with the predicted response rate
Application to Emax model
Other clinical factors are also important in determining the final overall response rate. All sources of variabilities should be included in the final prediction
Computational simulation studies
Summary
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