Confidence Interval Analysis program

Analysis of variance appropriate for a crossover design on the pharmacokinetic parameters using the general linear models procedures of SAS or an equivalent program should be performed, with examination of period, sequence and treatment effects. The 90% confidence intervals for the estimates of the difference between the test and reference least squares means for the pharmacokinetic parameters (AUCo-t, AUCo-inf, Cmax should be calculated, using the two one-sided t-test procedure). 

Methods for acute-to-chronic extrapolations have been developed and are available as computer programs such as the acute-to-chronic estimation (ACE Mayer et al. 1994 Ellersieck et al. 2003) software, which makes use of 3 methods — regression, multifactor probit analysis, and accelerated life testing — to consider the relationship between exposure concentration, degree of response, and time course of response (Mayer et al. 1994 Sun et al. 1995 Lee et al. 1995). All methods produce confidence intervals around the LC and/or EC percentage point estimate. 

Accuracy is estimated from the fixed effects components of the model. If the overall mean is the only fixed effect, then accuracy is reported as the estimate of the overall mean accuracy with a 95% confidence interval. As the standard error will be calculated from a variance components estimate including intermediate precision components and repeatability, the degrees of freedom can be calculated using Satterthwaite s approximation (6). The software program SAS has a procedure for mixed model analysis (PROC MIXED) PROC MIXED has an option to use Satterthwaite s degrees of freedom in calculating the confidence interval for the mean accuracy. An example program and output is shown later for the example protocol. 

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