Winnonlin professional edition

The pharmacokinetic data of the two donepezil/memantine products were analysed by the statistical package integrated into the WinNonLin Professional Edition program, version 8.0 (Pharsight Corporation, Mountain View, CA, USA), with a non-compartmental approach.
The Cmax and time to reach the maximum plasma concentration (Tmax) were obtained directly from raw data. The elimination rate constant (ke) was calculated through linear regression of the log-linear part of the concentration–time plot. Ct is the last measured concentration. The area under the curve (AUC) was calculated from the administration to the last measured concentration (AUCt) by linear trapezoidal integration. The total AUC from administration to infinity (AUC∞) was calculated by adding the sum of AUCt and the residual area (Ct divided by ke). Values of AUC correspond to AUC∞ unless otherwise indicated. T1/2 was calculated by dividing 0.693 by ke.
The total drug clearance adjusted for bioavailability (Cl/F) was calculated by dividing the dose by the AUC∞ and adjusting for weight. The volume of distribution adjusted for bioavailability (Vd/F) was calculated as Cl/F divided by ke. AUC and Cmax were adjusted for dose and weight (AUC/dW and Cmax/dW, divided by the dose-by-weight ratio) and logarithmically transformed.

Pharmacokinetic analysis of ¹²⁷I-CLR1404 mass measurements was performed by Covance Laboratories (Madison, WI), using WinNonlin Professional Edition (Pharsight Corporation, Version 5.2). A nominal dose level of 0.3 mg and actual sampling times were used for PK analysis. For PK calculation purposes, all times were normalized to the start of infusion.

Blood samples for the analysis of GSK2647544 plasma concentration were collected at 15, 30, 60, 120 and 240 min post oral dosing into EDTA-K3 tubes, mixed by inversion and immediately cooled to 2–4 °C. Within 50 min of collection, the samples were centrifuged at 1500 g for 10 min at ~4 °C in a swing bucket centrifuge. Plasma was harvested into uniquely labelled polypropylene screw-cap storage tubes, frozen at −20 °C and shipped on dry ice to GlaxosmithKline (Ware, UK) to determine the plasma concentrations of GSK2647544 using a validated analytical method based on protein precipitation, followed by HPLC/MS/MS analysis [GSK method on file].
Plasma concentration-time data was analysed using WinNonlin Professional Edition (Pharsight Corporation, Mountain View, CA). Calculations were based on the actual sampling times recorded during the study. From the plasma concentration-time data, the maximum observed plasma concentration (C_max) and time to C_max (T_max) were determined.