Winnonlin 8

The pharmacokinetics of compound B1 was evaluated by Pharmaron (San Diego, CA) following a single intraperitoneal administration to CD1 mice (two males). A dose of 2.29 mg/kg of the TFA salt of compound B1 in NMP/Solutol/PEG-400/normal saline (v/v/v/v, 10:5:30:55) was prepared just before use. This dose was calibrated due to the compound being a salt form. Plasma was sampled 0.5, 1, 2, and 4 hr post-dose. Mean values from the two animals without dispersion are shown in Figure 12. Tmax (Figure 12) was defaulted to the earliest time point and likely occurred earlier than 0.5 hr. Similarly, Cmax (Figure 12) was recorded as the concentration after 0.5 hr, the first sampling time point. Bioanalytical assays were run using Prominence HPLC and AB Sciex Triple Quan 5500 LC/MS/MS instruments, and a HALO column (90A, C18, 2.7 µm, 2.1 × 50 mm). Snapshot PK results are included in Figure 12. PK parameters were estimated by non-compartmental model using WinNonlin 8.3 (Certara, Princeton, NJ). The lower limit of quantification for plasma sampling was 1.53 ng/mL.

An injection of [¹⁷⁷Lu]Lu-PSMA-R or [¹⁷⁷Lu]Lu-PSMA-617 (7.4 MBq in 150 μL) was administered intravenously via tail into BALB/c male mice (4 groups, 3 mice/group), and a blood sample (5 μL) was taken from mouse orbit at 2, 5, 15, 30, 45, 60 and 120 min post injection. The radioactivity of the blood samples was measured by a γ-counter and the pharmacokinetics data were calculated using the WinNonlin 8.1 software (Certara, Princeton, NJ, USA).

Statistical comparisons were performed with SPSS 19.0 (IBM, United States) software. The difference in the arthritis score between different groups was evaluated using the Mann-Whitney test. The changes in the levels of TNF-α, IL-6, and CRP between different treatment groups were analyzed using one-way analysis of variance (ANOVA). It was considered statistically different when p-value was less than 0.05.
Non-compartmental analysis was performed with WinNonlin 8.1 software (Certara, United States) to calculate the PK parameters of adalimumab including t_1/2, C_max, T_max, AUC_last, AUC_inf, V/F, CL/F, and MRT. The mean and standard deviation of each parameter were calculated for statistical analysis. The difference in T_max between the delanzomib-treated and control groups was analyzed using the Mann-Whitney test. The differences in the level of FcRn and in the PK parameters of adalimumab, including t_1/2, C_max, V/F, and CL/F between two cohorts were calculated using ANOVA. The least significance difference method was used in the post hoc test. It was considered statistically different when p-value was less than 0.05.

Plasma spiramycin concentrations vs. time plots were investigated for each chicken using a non-compartmental approach [11 (link)]. The PK analysis was conducted utilizing WinNonlin 8.3 software (Certara, USA). Following oral administration of spiramycin, the C_max and the T_max¬ were determined. The T_1/2λz was calculated via the equation T_1/2λz = 0.693/λz, where λz, the first order rate constant, was defined from the slope of the terminal phase of the concentration vs. time curve. The linear trepazoidal rule and the linear-up log-down method were used to calculate AUC_0-∞ after IV and oral administrations of spiramycin, respectively. The Cl-obs was determined as Cl-obs = dose/AUC. In addition, the Vz-obs was calculated as Vz = dose/(λz × AUC). The F was obtained by dividing mean AUC_oral by mean AUC_IV.
The concentrations of spiramycin in the collected tissues were utilized to determine preliminary withdrawal times using linear regression approach by applying WT 1.4 software, designed in Germany and licensed by the CVMP of EU as previously reported [64 (link)]. The withdrawal time (WT) was defined to be the time when the upper one-sided tolerance limit (95%) with 95% confidence interval was below the MRL of spiramycin which was determined by CVMP in chicken tissues to be 0.2 µg/g for muscle, 0.3 µg/g for skin and fat, and 0.4 µg/g for liver [29 ].

The pharmacokinetic profile of tiamulin was investigated utilizing the non-compartmental approach [WinNonlin 8.3 software (Certara, USA)] as reported (15 (link), 16 (link)). The values of the highest plasma concentration (C_max) and the time required to attain C_max (T_max) were recorded from the plasma concentration-time plot. The area under the plasma concentration-time curve (AUC_0−∞) was computed using the linear-log trapezoidal method. The elimination half-life (T_1/2λz) was calculated using the equation T_1/2λz = 0.693/λz.
The withdrawal time (WT) was calculated by applying WT 1.4 program which was established in Germany and approved by the CVMP of the EU. It was estimated utilizing the statistical approach (95% tolerance limit and 95% confidence interval) based on the EU MRL for tiamulin in chicken tissues, which were announced by the CVMP to be 0.1 μg/g for muscles, skin, and fat, and 1 μg/g for liver, respectively (24 ).