Phoenix winnonlin version 6

From intensive 12‐h serial sampling, pharmacokinetic parameters for TAC and MPA that were directly measured included AUC_0‐12h, ng∙h/mL, C_0h, ng/mL, and C_max, ng/mL. Oral TAC CL L/h was determined using the ratio of dose to AUC_0‐12h. AUC_0‐12h was determined by the linear trapezoidal rule using noncompartmental methods (Phoenix WINNONLIN version 6.3; Pharsight Corp). The C_0h concentration was included in the analysis because this parameter reflects the observed drug administration and the time since study commencement. The TAC therapeutic exposure guide of 100 to 190 ng·h/mL was used for comparisons based upon time post‐transplant.¹⁹Pharmacokinetic parameters for MPA and MPAG included the AUC_0‐12h, C_0h, and C_max. The dose equivalent MPA was utilized. Oral apparent clearance of MPA was calculated as the ratio of MPA dose equivalent to MPA AUC_0‐12h. MPA clearances were adjusted for BMI to assess the impact of standardized body weights. CL and AUC_0‐12h were determined by the linear trapezoidal rule using noncompartmental pharmacokinetic methods (Phoenix WINNONLIN version 6.3; Pharsight Corp). The MPA therapeutic target AUC range of 30 to 60 mg·h/L was utilized as a guide.²²

Blood samples for measurement of plasma ONO-5334 concentration were collected via intravenous cannula over 12 h on day 1 and over 24 h on day 5. Samples were taken once hourly between 1 and 6 h postdose. Sample time-points were relative to the ONO-5334 active dose (either morning or evening) in each treatment period. To minimize overnight disturbance, long-line extension tubing was attached to the cannula, allowing sample collection in another room.
ONO-5334 was extracted from plasma samples using a solid-phase extraction column followed by quantification. Plasma concentrations of ONO-5334 were determined by a validated liquid chromatography–tandem mass spectroscopy method with a lower limit of quantification at 0.02 ng/mL. The assay was performed by Sumika Chemical Analysis Service (Osaka, Japan).
Pharmacokinetic parameters were estimated using noncompartmental methods (Phoenix WinNonlin version 6.1; Pharsight, Mountain View, CA, USA) and included maximum observed concentration (C_max), T_max and area under the concentration–time curve during the dosing interval (AUC_24h).
A scatter plot of individual plasma ONO-5334 concentrations versus serum CTX-I values (% change from baseline, defined as day −1) was produced, and a squared correlation coefficient (R2) value was calculated. All data retrieved on day 5 in both treatment periods were included.