RE : Sample size

From rene.BRUNO@rhone-poulenc.com Thu Jun 26 08:14:10 1997 Subject: RE : Sample size Sampling times : I basically agree with the proposal of Ene to compute optimal times and then randomly allocate those times to patients. It is exactly what we did for docetaxel to assess population PK eraly during its development and it worked. This approach could well be done again for new studies. However, we have now a "validated" population PK model drawn from 547 patients (see JPB 24(2), 153-172, 1996). We recently used this information to reassess optimal sampling times and demonstrated that it was possible to get unbiased and precise estimates of docetaxel CL from 2 points (5 min prior to the end of the 1 hour infusion and 5 hours after) (Clin. Cancer Res. in press). I believe that this sampling strategy could be used for further studies with minimal disturbance of the clinical trial. I can of course provide you with the priors to be used for Bayesian estimation using NONMEM. Sample size : In our studies using data from 640 patients we were able to demonstrate that docetaxel exposure at first cycle was a predictor of first hematologic toxicity (incidence of Grade 4 neutropenia and febrile neutropenia, logistic regression models). Such a huge sampling size was probably not required for Grade 4 neutropenia which was quite frequent; however it was definitely required for febrile neutropenia which was, fortunately, much less frequent. In this model CL/AUC were better predictors than time over any threshold level. First cycle exposure was also a predictor (to a lesser extent however) of the time to onset of fluid retention (Cox model). Regarding efficacy endpoints we did not found any predictive power of exposure for response rate and time to first response in breast and NSCLC. However, the sampling size was less (< than 200 patients) and I believe that a larger sample size would be required because systemic exposure is much less directly related to tumor shrinkage. The idea of Ene to perform a simulation study is a good one to assess sampling size for the PK study; however, I don't see how it would work to assess sample size for PK/PD and particularly efficacy since I believe it would require the use on at least a preliminary PK/PD model. But may be I am wrong I have no experience with simulation. For the analysis of time to event variables, you need to use a model for survival analysis (e.g. COX model or any other parametric model such as exponential Weibull ...). Rene Bruno Rhone-Poulenc Rorer Drug Metabolism and Pharmacokinetics Pharmacometry unit ****