钢-MethodstoAdjustDosesBasedonExposure-.pptVIP

Richard Lalonde, CPS Meeting 10-2002 Methods to Adjust Doses Based on Exposure-Response InformationPoints to Consider Richard Lalonde Clinical Pharmacokinetics and Pharmacodynamics Pfizer Global Research and Development Ann Arbor Overall Comment Generally very supportive of the Agency’s attempt to standardize methods for dose adjustments based on E-R data More consistency across sponsors and across therapeutic groups at FDA Once a consensus is reached on some key details, sharing this information as part of a guidance or other means should help sponsors/FDA implement the approach Studies have demonstrated that labels are not very effective at preventing drug interactions (terfenadine, cisapride, mibefradil) What other measures should we (FDA, industry,etc.) consider to increase the effectiveness of the dose adjustments recommended in the label Proposed Decision Tree for Dosing Adjustment Recommendations (Peter Lee et al) Proposed Decision Tree andNo-Effect Boundaries Without adequate PK-PD data, then default to 80 – 125% With PK-PD data, possibly define another boundary The former is typically based on a mean change and the 90% confidence for this estimate The latter is based on the distribution of exposure and E-R relationship in the population Proportion of patients with response above a critical level Includes components of variability that are not included in the usual criterion based on the mean Approach based on distribution of response in the population seems logical Would like to see more examples that include PK variability and E-R variability in setting the no-effect boundary Proposed Standard Outputs of E-R Results (Peter Lee et al) Points to Consider Questions about some practical aspects of the proposed method How to select the critical fraction of patient, while taking into account the selected critical level of response and the risk/benefit for particular drug/therapeutic indication Estimates of tails of distributions less precise than means Bal