Winnonlin enterprise

The plasma concentration-time data for omecamtiv mecarbil, M3, and M4 were analyzed by noncompartmental methods using WinNonlin Enterprise (version 5.1.1; Pharsight Corporation, Mountain View, CA, USA). Actual dosing and sample collection times were used in this analysis. Plasma concentrations below the lower limit of quantification of 1.0 ng/mL for omecamtiv mecarbil and 0.5 ng/mL for M3 and M4 were set to zero for the data analysis of all analytes.
The pharmacokinetic parameters assessed were plasma concentration-time curve (area under the curve (AUC)) to time of last measureable concentration (AUC_last), AUC to infinity (AUC_∞; calculated using the linear trapezoidal linear interpolation method), C_max, t_max, terminal elimination half-life associated with λ_z (t_1/2,z), apparent plasma clearance (CL/F), the ratios of AUC_last of M3 and M4 to omecamtiv mecarbil, and the ratios of M3 and M4 AUC to the combined AUCs of all analytes (omecamtiv mecarbil, M3, M4 using ng×h/mL). The pharmacokinetic parameters of omecamtiv mecarbil, M3, and M4 were adjusted for each formulation by using their respective potency values where possible: IR = 0.979; MRT-F₁ = 0.999; MRT-F₂ = 0.995; MP = 0.984; SCT-F₁ = 0.914; SCT-F₂ = 0.910.

PK parameters were derived from the plasma concentrations of glycopyrrolate and formoterol fumarate obtained on approximately Day 7 (Day 7 ± 2) of each treatment regimen during Study Parts A and B. In Part A, the PK profiles of glycopyrrolate and formoterol after chronic administration of GFF MDI were compared with those after chronic administration of the monocomponent MDIs. In Part B, the PK profile of formoterol after chronic administration of two dose levels of FF MDI was compared with those after chronic administration of FF DPI. PK samples were collected at pre-dose, at 2, 6 and 20 min, and at 1, 2, 4, 8, 10 and 12 h post-dose. PK analyses were performed by Pharsight Inc using a validated version of WinNonlin^® Enterprise (Version 5.2).

To assess relative bioavailability of each MR vs. the IR formulation, natural log-transformed AUC_∞, AUC_last, and C_max were analyzed separately using a mixed-effect model, with treatment, study period, and sequence as fixed effects, and subject within each sequence as a random effect. Relative bioavailability was analyzed on pharmacokinetic data from all study periods, with the IR formulation as the reference and the MR formulations as the test treatments. To assess the effect of food on the selected MR formulation, natural log transformed AUC_∞, AUC_last, and C_max were analyzed separately using a mixed-effect model, with fasting state as the fixed effect and subject as the random effect. Statistical evaluations were conducted using SAS Software and summary statistics, adjusted parameters, and ratio values were generated using WinNonlin Enterprise (Pharsight Inc., Mountain View, CA, USA) or Microsoft Excel software. Adverse events were described using descriptive statistics. Graphs were prepared using SigmaPlot (version 11.0), (Systat Software Inc., San Jose, CA, USA).