Evaluation of sampling spacing in pharmacokinetic studies using six sigma method

Key elements of pharmacokinetics (PK) studies include both, the number of sampling points (NSP) as well as the spacing between the sampling points (SSP). Optimization of the SSP is discussed in guidelines of all key regulatory agencies (RA). Those however, provide only very general rules on how to properly distribute the NSPs in proposed PK studies. Here we demonstrate that the six sigma (SX) method can be effectively used to assess the quality of SSPs. We have tested a modified SX method analyzing 466 PK profiles from 16 studies including a total of 368 healthy volunteers. Non-compartmental modeling was used to estimate PK parameters. The arithmetic means of minimum and maximum values of SX obtained for each subject in all studies were 1.97 and 3.83, respectively. The method described here allows comparing quality of studies performed at different centers, even if they cover different chemical entities. We propose that the SX values can be used to assess quality of PK studies, what is consistent with recommendations of the RAs.