Winnonlin

The corresponding simulations of INR levels over first 10 days of treatment with warfarin were performed for each participant using a Jusko-type Indirect Response Model (IRM) for an inhibitory effect, based on their individual CYP2C9 genotype data and population average parameters. Analyses were conducted through WinNonlin® (WinNonlin® professional software, version 2.1, Pharsight Inc., 1997, NC, USA). Pharmacokinetic (PK) of warfarin was described by a one-compartment model, with first-order absorption and linear elimination rate while the pharmacodynamic (PD) response was simulated by an indirect model that accounts for delay in anticoagulation response. A schematic representation of the indirect pharmacokinetic-pharmacodynamic (PK-PD) model to be employed in the simulation is depicted in Figure 5.
Initial warfarin doses (mg/day) used in the simulation procedures was determined by a previously developed pharmacogenetic-driven algorithm in Puerto Ricans. The average IC₅₀ value for warfarin inhibition of Vitamin K recycling was set at 1.5 mg/L for all cases, which are the plasma warfarin concentration required to reach a 50% reduction in synthesis/activation of prothrombin-related, calcium-dependent clotting factors (i.e., factors II, VII, IX, X, protein Z and C) and a corresponding doubling of the INR level.

The data obtained with a single subcutaneous injection of 1.25, 2.5, 5 and 10 mg/kg marbofloxacin were analyzed separately using WinNonlin version 5.2 (Pharsight Corporation). Marbofloxacin concentration-time data were best described using the noncompartment model with extravascular input. According to dose proportionality from the obtained PK parameters, we used them to estimate the AUC_0-24h, C_max for each tested mabofloxacin dosing for which no kinetics were determined. The PK/PD analysis was performed by using the inhibitory effect E_max model. This model is described by the following equation: E = E_max-(E_max-E₀)*(C/(EC₅₀ + C)), where E is the change in log₁₀CFU/lung after 24 h in treated mice compared to the initial log₁₀CFU/lung in untreated control mice; E_max is the log change in CFU per lung, comparing 0 and 24 h in the untreated control mice; E₀ is the change in log₁₀CFU/lung between the treated mice with untreated mice after the 24 h period of the study, when the detection limit is reached; C is the PK/PD parameter (e.g. fAUC/MIC, fCmax/MIC, fT_>MIC); EC₅₀ is the C value at which 50 % of the maximal antibacterial effect is produced. These PD parameters were calculated using the nonlinear regression program (WinNonlin, Pharsight Corporation).