Winnonlin version 4

Manufactured by Pharsight

Sourced in United States

WinNonlin version 4.0 is a software application designed for pharmacokinetic and pharmacodynamic analysis. It provides tools for modeling and simulation of drug concentration data over time.

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WinNonlin (378 citations) WinNonlin 4.1 (7 citations) WinNonLin professional version 4.1 (2 citations)

8 protocols using winnonlin version 4

Plasma Drug Analysis by HPLC

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Collected blood samples were transferred in EDTA-coated microcentrifuge tubes, centrifuged at 10,000 rpm for 10 min. Plasma separated was stored at -21 °C until drug analysis. After thawing plasma samples were mixed with 4 % phosphoric acid solution in 1:1 ratio to release protein-bound drugs (Vieira et al., 2010[19 ]). The samples were extracted with 3 mL of ethyl acetate. The organic phase was separated by centrifugation at 3,000 rpm for 10 min and evaporated to dryness over a stream of nitrogen gas. The residue was reconstituted with 0.1 mL of mobile phase (methanol: water; 90: 10 %v/v), and analyzed by validated HPLC method.
Pharmacokinetic parameters were calculated by noncompartmental analysis also called as Model independent analysis using WinNonLin version 4.0 (Pharsight Corp., Mountain View, CA). Maximum plasma concentration (C_max), time to reach maximum plasma concentration (T_max), area under the concentration curve from 0-8 hrs (AUC_0-8), area under the concentration curve for 0 to infinity (AUC_0-∞), and mean residence time (MRT) were calculated.

Rauf A., Bhatnagar A., Sisodia S.S., Khar R.K, & Ahmad F.J. (2017). Lungs deposition and pharmacokinetic study of submicron budesonide particles in Wistar rats intended for immediate effect in asthma. EXCLI Journal, 16, 236-244.

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Pharmacokinetic Analysis with WinNonlin

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Non-compartmental method using WinNonlin version 4.0 (Pharsight, Mountain View, CA, USA) was applied for pharmacokinetic parameters calculation. Statistical analysis was applied using unpaired two-tailed Student's t-test for comparison between two groups, or one-way or two-way ANOVA with a post hoc Tukey test for comparison among three or more groups. A P value less than 0.05 was considered as significant. All data are presented as mean values ± standard derivation (SD).

Wu X., Yin C., Ma J., Chai S., Zhang C., Yao S., Kadioglu O., Efferth T., Ye Y., To K.K, & Lin G. (2021). Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo. Acta Pharmaceutica Sinica. B, 11(7), 1885-1902.

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Toxicokinetics and Enzyme Inhibition Study

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Data are expressed as mean ± SD. The Student’s t test was used for the comparison between two groups. The one-way ANOVA followed with a post hoc Bonferroni’s multiple comparison test was used for the comparison among multiple groups. Toxicokinetic parameters were calculated by noncompartmental methods using WinNonlin version 4.0 (Pharsight, Mountain View, CA, United States). The enzyme kinetic parameters were estimated from the best fit line using least-squares linear regression of the inverse substrate concentration versus the inverse velocity (Lineweaver-Burk plots), and the mean values were used to calculate the K_m and V_max. The inhibition constant (K_i) value of GA was determined by the secondary Lineweaver-Burk plots. The statistical significance was set as ^*p < 0.05, ^**p < 0.01 or ^***p < 0.001.

Wang Z., Ma J., Yao S., He Y., Miu K.K., Xia Q., Fu P.P., Ye Y, & Lin G. (2022). Liquorice Extract and 18β-Glycyrrhetinic Acid Protect Against Experimental Pyrrolizidine Alkaloid-Induced Hepatotoxicity in Rats Through Inhibiting Cytochrome P450-Mediated Metabolic Activation. Frontiers in Pharmacology, 13, 850859.

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Pharmacokinetics of First-Line Anti-TB Drugs

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The total (protein-bound plus unbound) plasma concentrations of isoniazid, acetyl-isoniazid, rifampicin, desacetyl-rifampicin (the main metabolite of rifampicin), pyrazinamide and ethambutol were assessed by validated HPLC methods as described before.²⁷ (link)
Pharmacokinetic evaluations were performed using standard non-compartmental methods in WinNonLin Version 4.1 (Pharsight Corp., Mountain View, CA, USA) as described before,¹⁹ (link)^,²⁷ (link) to assess the total exposure (AUC_0–24), C_max with the corresponding T_max, the apparent clearance (CL/F; in which F is bioavailability), the apparent volume of distribution (Vz/F) and the elimination half-life (t_½).
Reference ranges for C_max values were 3–6 mg/L for isoniazid, 8–24 mg/L for rifampicin, 20–50 mg/L for pyrazinamide and 2–6 mg/L for ethambutol.²⁹ (link)
The acetylator status for isoniazid was determined phenotypically, either by assessing the elimination half-life of isoniazid (with participants with a t_½ of >130 min being classified as slow acetylators and those with t_½ <130 min being classified as fast/intermediate acetylators) or by calculation of the ratio of acetyl-isoniazid to isoniazid at 3 h after the dose (using this approach, patients with a ratio <1.5 were considered slow acetylators and those with a ratio >1.5 were fast/intermediate metabolizers³⁰ (link)).

Mtabho C.M., Semvua H.H., van den Boogaard J., Irongo C.F., Boeree M.J., Colbers A., Burger D.M., van Crevel R., van der Ven A.J., Kibiki G.S., Tostmann A, & Aarnoutse R.E. (2019). Effect of diabetes mellitus on TB drug concentrations in Tanzanian patients. Journal of Antimicrobial Chemotherapy, 74(12), 3537-3545.

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Metformin Pharmacokinetics in Sprague-Dawley Rats

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Female Sprague-Dawley rats were administered metformin (150 mg/kg BW/day) by gavage for 14 days. Plasma samples were collected on Days 1 and 14. Metformin concentrations in plasma were determined using an LC/MS/MS method as modified from Tucker et al (26 (link)) (See Supplementary Materials). Plasma concentration-time data were analyzed by non-compartmental methods using the program WinNonlin Version 4.1 (Pharsight Corporation, Mountainview, CA). Additional materials can be found in the supplemental information (e.g. Supplementary Fig 1).

Thompson M.D., Grubbs C.J., Bode A.M., Reid J.M., McGovern R., Bernard P.S., Stijleman I.J., Green J.E., Bennett C., Juliana M.M., Moeinpour F., Steele V.E, & Lubet R.A. (2015). Lack of Effect of Metformin on Mammary Carcinogenesis in Non-Diabetic Rat and Mouse Models. Cancer prevention research (Philadelphia, Pa.), 8(3), 231-239.

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Pharmacokinetic Analysis of GSK933776

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First-Time-in-Human Study. Blood samples were obtained by venipuncture at screening, days 1, 2, 3, 8, 15, 22, 29, 43, 64, and follow-up visit in part A and at screening, days 1, 2, 3, 4, 8, 15, 22, 29, 30, 31, 36, 43, 50, 57, 58, 59, 64, 71, 78, 91, 105, 119, 140, 182, and follow-up in part B. Samples were collected into 2-mL EDTA tubes and centrifuged at 2000g at 4°C for 15 minutes. Plasma was stored below—70°C until analysis. Plasma GSK933776 concentrations were measured by validated immunoassay detecting free GSK933776 antibody (defined as the sum of bivalent and monovalent unbound forms; lower and higher limits of quantification, 100 and 5000 ng/mL). Pharmacokinetic parameters for GSK933776 were determined by noncompartmental modelling (WinNonlin version 4.1; Pharsight, Cary, NC). Additionally quantitative population analysis was performed using nonlinear mixed effect modelling approach using NONMEM (version VII) software. The best model in terms of goodness of fit was a two-compartment model with two different pharmacokinetic parameter sets: one for dose 0.1 mg/kg (in single and repeat dose), the other for all remaining doses: 1, 3, and 6 mg/kg repeat dose.

Andreasen N., Simeoni M., Ostlund H., Lisjo P.I., Fladby T., Loercher A.E., Byrne G.J., Murray F., Scott-Stevens P.T., Wallin A., Zhang Y.Y., Bronge L.H., Zetterberg H., Nordberg A.K., Yeo A.J., Khan S.A., Hilpert J, & Mistry P.C. (2015). First Administration of the Fc-Attenuated Anti-β Amyloid Antibody GSK933776 to Patients with Mild Alzheimer’s Disease: A Randomized, Placebo-Controlled Study. PLoS ONE, 10(3), e0098153.

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Quantifying OX1R Occupancy in Rat Brain

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Experiments were performed as previously described (Dugovic et al., 2009 (link)) in male Sprague-Dawley rats (300–400 g, Charles River Laboratories, San Diego, CA, United States). The animals were euthanized using carbon dioxide and decapitated at different time points after drug administration (n = 3 per time point or dose regimen). Brains were rapidly frozen on powdered dry ice and stored at -80°C before sectioning. Plasma samples were also collected for bioanalysis (LC–MS/MS). Twenty micron thick tissue sections at the level of the tenia tecta were prepared for autoradiography. OX1R radioligand binding autoradiography was determined at room temperature with 5 nM [³H]SB-674042. Sections were incubated for 10 min to minimize dissociation. Non-specific binding was determined in the presence of 10 μM SB-674042. Ex vivo receptor labeling was expressed as the percentage of receptor labeling in corresponding brain areas (i.e., tenia tecta) of vehicle-treated animals. The percentage of receptor occupancy was plotted against time or dosage using GraphPad Prism (GraphPad Software, San Diego, CA, United States). Percentage of receptor occupancy was also plotted against drug plasma or brain concentration. Pharmacokinetic parameters were analyzed using a non-compartmental model using the software package WinNonlin Version 4.0.1 (Pharsight, Palo Alto, CA, United States).

Bonaventure P., Dugovic C., Shireman B., Preville C., Yun S., Lord B., Nepomuceno D., Wennerholm M., Lovenberg T., Carruthers N., Fitz S.D., Shekhar A, & Johnson P.L. (2017). Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation. Frontiers in Pharmacology, 8, 357.

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Pharmacogenetics of Irinotecan Metabolism

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Genomic DNA was extracted from 2 mL of peripheral blood in each patient. The UGT1A1*6, UGT1A1*7, UGT1A1*27, and UGT1A1*29 gene polymorphisms were detected via the PCR direct DNA sequencing method. The UGT1A1*28 gene polymorphism was detected using the polyacrylamide gel electrophoresis method. The drug concentrations of irinotecan, SN‐38, and SN‐38G were evaluated at 0, 1, 3, and 24 hours after the administration of irinotecan therapy by analyzing 3 mL blood samples. Venous blood samples were collected on day 1 in 5 mL glass tubes containing heparin before the administration of irinotecan, as well as at 0 and 1, 3, and 24 hours after the first infusion of irinotecan, for pharmacokinetic analysis. The plasma concentrations of irinotecan, SN‐38, and SN‐38G were determined via high‐performance liquid chromatography, and AUC values were calculated using the trapezoidal method in WinNonlin version 4.01 (Pharsight Corporation, Mountain View, CA, USA). Drug toxicity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.21 Before the first cycle, a blood cell count, urinalysis, and biochemistry tests were performed to assess renal and hepatic function and electrolyte levels. These tests were repeated during treatment, while other examinations of marker levels were repeated as necessary.

Fukuda M., Okumura M., Iwakiri T., Arimori K., Honda T., Kobayashi K., Senju H., Takemoto S., Ikeda T., Yamaguchi H., Nakatomi K., Matsuo N., Mukae H, & Ashizawa K. (2017). Relationship between UGT1A1*27 and UGT1A1*7 polymorphisms and irinotecan‐related toxicities in patients with lung cancer. Thoracic Cancer, 9(1), 51-58.

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