A Point of Consider on Credible and Efficient Dose Selection Based on the Exposure-Response Relationship

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A major goal of evaluating the exposure-response relationship in a dose-response study is to optimize the dose selection both in the next confirmatory trials and in the clinical use after approval as a new drug. While sample size, cost, time and human resource to conduct a confirmatory trial has been currently increasing, the success rate is less than 50%. Therefore, to realize credible and efficient dose selection is thought to be essential for the current clinical development of new drugs. In this article, how to use a quantitative exposure-response relationship given by dose-response study for dose selection strategy is proposed with the basic concept on causal relationship among dosing intervention, pharmacokinetic information, pharmacokinetic covariates and efficacy/safety response.<BR>Classical pharmacokinetic and pharmacodynamic models were excellent tools to adjust a timedependent variability between drug concentration in the biological fluid and the correspondent pharmacodynamic variable. On the contrary, our proposed pharmacokinetics-response correlation approach makes an inter-patient variability adjustable with pharmacokinetic covariates.<BR>In this approach, first each patient's dose-dependent pharmacokinetic parameters (i.e., C<SUB>max</SUB>., AUC) are estimated, secondly the most sensitive pharmacokinetic parameter is searched for inter-patient variability on the primary endpoint, and finally the effect size at the optimized dose is predicted using statistical simulation techniques. A highly reliable and efficient dose-selection strategy is expected to be produced from this approach including a pharmacokinetic covariate-based study design.

A Point of Consider on Credible and Efficient Dose Selection Based on the Exposure-Response Relationship

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