Development of an automated appendix generation system (ARGUS) for clinical study reports

Data handling and tabulation are a time-consuming job when writing appendices for clinical study reports. The authors have developed an automated appendix generation system (ARGUS) conforming to the CDISC/SDTM standard using SAS (version 9.3) and R (version 3.3.1: for PK plot generation). It consists of the one main program and three subprograms. The program runs to convert a database file into an appendix document with about 100 tables and plots in MS Word format within one min after pressing the submit button under common desktop environments. We found that tasks of constructing appendices for a typical 2×2 crossover design study that have taken our team about 8 days were completed within 6 or 7 hours using the ARGUS system.

Mixed?effects analysis of increased rosuvastatin absorption by coadministered telmisartan

The Cmax and AUC of rosuvastatin increase when it is coadministered with telmisartan. The aim of this study was to explore which of the pharmacokinetic (PK) parameters of rosuvastatin are changed by telmisartan to cause such an interaction. We used data from drug–drug interaction (DDI) studies of 74 healthy volunteers performed in three different institutions. Rosuvastatin population PK models with or without telmisartan were developed using NONMEM (version 7.3). The plasma concentration–time profile of rosuvastatin was best described by a two-compartment, first-order elimination model with simultaneous Erlang and zero-order absorption when given rosuvastatin alone. When telmisartan was coadministered, the zero-order absorption fraction of rosuvastatin had to be omitted from the model because the absorption was dramatically accelerated. Notwithstanding the accelerated absorption, the relative bioavailability (BA) parameter estimate in the model demonstrated that the telmisartan-induced increase in BA was only about 20% and the clearance was not influenced by telmisartan at all in the final PK model. Thus, our model implies that telmisartan may influence the absorption process of rosuvastatin rather than its metabolic elimination. This may be used as a clue for further physiologically based PK (PBPK) approaches to investigate the mechanism of rosuvastatin–telmisartan DDI.