Separate groups of three catheterized guinea pigs each were given: (i) a single dose of L01-Z08 at 20 mg/kg, or L335-M34 at 50mg/kg of body weight; (ii) L01-Z08 at 20 mg/kg and L335-M34 at 50 mg/kg were given together to test for possible drug-drug interactions that might alter the uptake and/or clearance of one or both of the compounds. All drugs were suspended in 1% DMSO, 0.5% DEA, 48.5% PEG 400, 50% water. Blood was collected for analysis of these drugs in plasma pre-dose, and at 1, 4, 8, 24, and 48 hours post-dose. Plasma was separated and stored at −70°C until analysis. Plasma drug concentrations were determined by liquid chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry over the concentration range of 0.005–1 mg/L with dilution to 10 mg/L. Pharmacokinetic variables were calculated from individual drug concentration–time data using non-compartmental methods as implemented in WinNonlin version 5.0 (Pharsight, Mountain View, CA, USA) as described earlier46 (link), 47 (link).
Winnonlin version 5
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WinNonlin Version 5.3 is a software product designed for pharmacokinetic and pharmacodynamic analysis. It provides tools for modeling and simulation of drug concentration data.
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20 protocols using winnonlin version 5
1
Pharmacokinetics of Drug Combinations
2
Pharmacokinetic Analysis of Sorafenib
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All data were subsequently processed using the WinNonlin Version 5.0 program (Pharsight Corporation, Mountain View, CA, USA). The following pharmacokinetic parameters were calculated: half-life (t1/2; min), peak concentration (Cmax; μg/mL), area under the concentration versus time curve (AUC; min μg/mL), clearance (CI; mL/min/kg), apparent volume of distribution at steady state (Vss; mL/kg) and mean residence time (MRT; min). The area under the plasma time to concentration curve from zero to infinity (AUC0−∞) was calculated using the trapezoidal rule, with extrapolation to infinity for the terminal elimination rate constant (Ke) for sorafenib. The significance of the differences was assessed using Student’s t-test. Experimental data and the pharmacokinetic parameters were expressed as the means ± standard deviation.
3
Pharmacokinetic Analysis of Lovastatin
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For drug analysis,
we used the noncompartmental model in the software program WinNonlin
version 5.0 (Pharsight Corporation, Mountain View, CA) to calculate
the relevant pharmacokinetic parameters, including the AUC and Cmax of lovastatin and t1/2 and MRT of lovastatin acid. In terms of statistical analysis
of data, we used the variance function of SPSS 18.0 (SPSS Inc., Chicago,
Illinois) and one-way analysis of variance (one-way ANOVA) to compare
between groups. All data are expressed as the mean ± SD. Significant
differences between the data are expressed as *p <
0.05 or **p < 0.01.
we used the noncompartmental model in the software program WinNonlin
version 5.0 (Pharsight Corporation, Mountain View, CA) to calculate
the relevant pharmacokinetic parameters, including the AUC and Cmax of lovastatin and t1/2 and MRT of lovastatin acid. In terms of statistical analysis
of data, we used the variance function of SPSS 18.0 (SPSS Inc., Chicago,
Illinois) and one-way analysis of variance (one-way ANOVA) to compare
between groups. All data are expressed as the mean ± SD. Significant
differences between the data are expressed as *p <
0.05 or **p < 0.01.
4
Pharmacokinetic Analysis Protocol
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The pharmacokinetic parameters were calculated by non-compartmental analysis using the WinNonlin Version 5.1 software (Pharsight, Certara, NJ, USA). Statistical analysis was performed using SPSS for Windows (version 24.0; IBM Corp., Armonk, NY, USA).
5
Cardiovascular Effects of CMX-2043 in Dogs
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Studies were conducted at Charles River Laboratories, Worcester, MA, USA. Six dogs (3/sex) instrumented with arterial and venous vascular access ports and a telemetry device were given single intravenous infusions (6 mL/kg at a rate of 6 mL/min) of 0.9% sodium chloride (placebo) for injection on day 1 and repeat doses of CMX-2043 (8.5, 20.5 or 60 mg/kg) on days 4, 11 and 18, respectively. Clinical observations were recorded at least once daily starting on day 1, and body-weights were measured before each dose and on day 25. Blood pressure (systolic, diastolic and mean arterial), heart rate, respiratory rate, core body temperature and electrocardiogram were monitored via telemetry from 24 hr before to 24 hr after each dose. Shortly before and at 5, 15 and 30 min. and 1, 4 and 24 hr after dosing, arterial blood samples were collected to measure pH, pCO2, pO2, oxygen saturation (sO2) and bicarbonate ( ). Venous blood samples were collected to measure CMX-2043 concentration and evaluate systemic exposure at pre-dose and at 5, 15 and 30 min. and 1, 4 and 24 hr after dosing on days 1, 8, 15 and 22. Toxicokinetic analysis was performed using WinNonlin version 5.1 (Pharsight, Cary, NC, USA) by the calculation of standard parameters. The animals were returned to the testing facility's telemetry colony at the conclusion of the study.
6
PK Study of PAC-1 and 1541B in Mice
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Ten week old, C57BL/6 female mice
were administered a single intraperitoneal dose of PAC-1 at 125 mg/kg
or 1541B at 17.5 mg/kg, and sacrificed in cohorts of 3 at predetermined
time points (0, 10, 20, 30, 40, 60, 120, 240, 360, 720, and 1440 min).
Blood was collected and centrifuged, and plasma separated for quantification
of PAC-1 or 1541B by HPLC methods (UIUC Metabolomics Center, Urbana,
IL). Pharmacokinetic analyses were performed, using a nonlinear regression
program (Winnonlin, version 5.1, Pharsight Corporation, Cary, NC).
were administered a single intraperitoneal dose of PAC-1 at 125 mg/kg
or 1541B at 17.5 mg/kg, and sacrificed in cohorts of 3 at predetermined
time points (0, 10, 20, 30, 40, 60, 120, 240, 360, 720, and 1440 min).
Blood was collected and centrifuged, and plasma separated for quantification
of PAC-1 or 1541B by HPLC methods (UIUC Metabolomics Center, Urbana,
IL). Pharmacokinetic analyses were performed, using a nonlinear regression
program (Winnonlin, version 5.1, Pharsight Corporation, Cary, NC).
7
Toxicokinetics of Fipronil Desulfinyl in Rats
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Rat in vivo toxicokinetic study of fipronil desulfinyl was performed to show the application of the method. Approval for animal experimentation from the Institutional animal ethics committee was sought and all the animal studies were carried out in accordance with the approved guidelines and regulations. Fipronil desulfinyl was administered intravenously at 1 mg/kg dose in male Sprague Dawley rats (N = 4, weight range 220 to 240 g). Multiple blood samples (volume ~20 μl) were collected serially from rats into heparinised tubes and 10 μl was spotted on the DMPK-C card. DBS samples were spiked with IS and processed as described above. QC samples along with study samples were processed and distributed among the study samples during analysis. Blood concentration–time data was analyzed by non-compartmental method using WinNonlin Version 5.1 (Pharsight Corporation, Mountain View, USA).
8
Quantifying HPβCD in Plasma and CSF
9
Therapeutic Antibody Pharmacokinetics
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All in vivo work was carried out in accordance with UK Home Office ethical and husbandry standards under the authority of an appropriate Project Licence, which was approved by Babraham Institute Animal Welfare and Ethical Review Body (AWERB).
Antibody PK data were determined following intravenous administration of a single dose of the therapeutic antibody in rats or cynomolgus monkeys. Serum samples were prepared from blood collected at various time points. Serum concentrations of MEDI1912 or MEDI1912_STT in Crl:CD (Srague Dawley) rat serum were determined using a sequential flow-through sandwich method using the Gyrolab™ Workstation. The fluorescence-based assay utilised a 3 step capture-analyte-detection Gyrolab™ method in combination with a Bioaffy 200 CD. Commercially obtained mouse anti-human IgG antibodies were used as capture and detection reagents within the assay and labelled with biotin or alexa-647 respectively. Clearance, T max and terminal half-life were determined for MEDI-1912 and MEDI-1912_STT using the validated software package WinNonlin® version 5.3 (Pharsight®).
Antibody PK data were determined following intravenous administration of a single dose of the therapeutic antibody in rats or cynomolgus monkeys. Serum samples were prepared from blood collected at various time points. Serum concentrations of MEDI1912 or MEDI1912_STT in Crl:CD (Srague Dawley) rat serum were determined using a sequential flow-through sandwich method using the Gyrolab™ Workstation. The fluorescence-based assay utilised a 3 step capture-analyte-detection Gyrolab™ method in combination with a Bioaffy 200 CD. Commercially obtained mouse anti-human IgG antibodies were used as capture and detection reagents within the assay and labelled with biotin or alexa-647 respectively. Clearance, T max and terminal half-life were determined for MEDI-1912 and MEDI-1912_STT using the validated software package WinNonlin® version 5.3 (Pharsight®).
10
Vedolizumab Pharmacokinetics in Dose Groups
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Venous blood samples for vedolizumab serum concentration were collected at the following time points for both the 150‐mg and 300‐mg dose groups: on day 1 (first dose) at predose, 2, 6, and 12 hours; on days 2, 3 (applicable only to first 3 patients in step 1), and 8; on day 15 (second dose) at predose, 2, and 6 hours; on days 16 and 29; on day 43 (third dose) at predose, 2, and 6 hours; and during follow‐up (day 44 and weeks 8, 10, 14, 18, 22, 26, 30, and 34). Serum concentrations of vedolizumab were measured by enzyme‐linked immunosorbent assay by QPS Holdings, LLC (Newark, Delaware).
The following main PK parameters were estimated from the serum concentration‐time profile of vedolizumab by noncompartmental analysis (Win‐Nonlin version 5.3; Pharsight Corporation, Cary, North Carolina): after the initial dose (day 1), area under the serum concentration‐time curve (AUC) from week 0 to week 2 (AUCday14), maximum observed serum concentration (Cmax), time of first occurrence of Cmax, apparent terminal elimination half‐life (t1/2z), apparent total body clearance, and volume of distribution during the terminal disposition phase; after the third dose (day 43), AUC from week 0 to week 8 (AUCday56), Cmax, time to Cmax, and t1/2z.
The following main PK parameters were estimated from the serum concentration‐time profile of vedolizumab by noncompartmental analysis (Win‐Nonlin version 5.3; Pharsight Corporation, Cary, North Carolina): after the initial dose (day 1), area under the serum concentration‐time curve (AUC) from week 0 to week 2 (AUCday14), maximum observed serum concentration (Cmax), time of first occurrence of Cmax, apparent terminal elimination half‐life (t1/2z), apparent total body clearance, and volume of distribution during the terminal disposition phase; after the third dose (day 43), AUC from week 0 to week 8 (AUCday56), Cmax, time to Cmax, and t1/2z.
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