A Comparative Study of Some Approaches for Estimating Tolerance Limits

In a dose finding study the aim is to come up with a safe and efficient drug administration. By comparing the estimated tolerance limits of the concentrations with a predetermined desired interval, that is, the therapeutic window, one may be able to adjust the drug dosage to attain a large proportion of the population within the window. For drugs with a therapeutic window situated at high concentrations close to toxic levels, one has to achieve a balance between attaining a large proportion of the population at efficiently high levels on one hand and the risks of an overdose on the other hand. In such cases, it is important to use the proper estimation approach for the upper tolerance limit. Here, the conservative estimation approach intended for a drug with potentially adverse side effects is compared with the expectation approach intended for a drug with harmless side effects. It is shown in an example that the expectation approach can be considerably more efficient when used in the latter case, an advantage that is rarely discussed when proposing estimators.