Population Pharmacokinetics Modeling of Levofloxacin In Rabbit By Intravenous Bolus Injection and Peroral Administration

The population-based approach has been widely applied to describe the pharmacokinetic profile of many drugs. The aim of this current research was to study the implementation of the population-based pharmacokinetics of levofloxacin in rabbits administered by intravenous bolus injection and peroral delivery. Modeling analyses were performed using Monolix, one of the alternative tools for the population-based approach. Monolix works based on the Stochastic Approximation Expectation-Maximization (SAEM) method. The analysis was performed based on the population model using one-compartmental and two-compartmental disposition models. The combination error model was used during the analyses. Modeling appropriateness was determined based on the goodness of fit analyses, i.e., 1) the individual fit, 2) the observed versus population prediction values; and 3) the observed versus individual prediction values Plasma concentration profiles of levofloxacin by intravenous bolus injection and oral administration are better described by an appropriate model using a two-compartmental disposition model. All goodness of fit analyses demonstrates the power of the chosen model. However, the estimated disposition parameter values obtained based on the intravenous bolus injection and peroral administration are different for each subject. To confirm this phenomenon, we performed a simultaneous fitting of all intravenous bolus as well as peroral administration data. The goodness of fit analyses indicates an adequate fitting of all data.

CORRELATIONS OF GIVING DESINFECTION (ALCOHOL SWAB) WHEN GIVING INTRAVEIN INJECTION WITH PHLEBITIS

Introduction: Phlebitis is inflammation of the veins caused by chemical irritations of additives and drugs that are given intravenously. Phlebitis is characterized by the presence of a red and warm area around the area of stabbing or along the vein. This study aims to determine the effect of disinfection (alcohol swab) on intravenous bolus injection with phlebitis. Methods: The research design used in this study is pre-experiment (Static Group Comparison). In this study the population was all patients who received intravenous bolus therapy. The sample in this study were some patients who received intravenous bolus therapy who met the inclusion criteria. Sampling in this study was simple random sampling with a total sample of 52 respondents. Results: From the Chi Square Test x2 = 17,333 and p = 0,00 because p <0. (0,00 <0,05) then H0 is rejected which means there is an influence of disinfection of alcohol swab during intravenous bolus injection with phlebitis occurrence. The number of respondents in the control group who did not / without using alcohol swab almost all respondents had phlebitis (84.6%) and only a small number did not occur phlebitis (15.3%) while respondents who were given alcohol swab during injection via intravenous bolus almost all phlebitis did not occur (92.3%) and a small proportion occurred phlebitis (7.6%). Conclusion: Based on the results of the study, can be concluded that there is an influence of alcohol swab during intravenous injection with the occurrence of plebebitis. The effort that can be done to prevent phlebitis is aseptic technique in the area of insertion and disinfection that is strong in medical devices, observation of signs and symptoms of phlebitis, infusion catheter must be replaced if it is installed > 27 hours.

Pharmacokinetics of Baxter’s Longer Acting rFVIII (BAX 855) in Factor VIII Ko Mice, Rats and Cynomolgus Monkeys

Abstract 4346 The pharmacokinetic profile of BAX 855, a longer acting PEGylated variant of Baxter’s recombinant FVIII based on the ADVATE™ manufacturing process, was assessed in comparison to ADVATE™ after a single intravenous bolus injection at a target dose of 200 IU/kg BW in mice and rats and 350 IU/kg BW in cynomolgus monkeys. Mean residence time (MRT), terminal half-life (HL), total clearance standardized per kg body mass (Cl), the AUC0-tlast (the area under the concentration vs. time curve from 0 to the last measured time point), the in vivo recovery (IVR) and volume of distribution at steady state (Vss) for FVIII activity (mice and cynomolgus monkey), FVIII antigen (rats) and FVIII-bound PEG were evaluated in all three models. Blood was sampled at baseline and each of the time points after a single intravenous bolus injection of BAX 855 or ADVATE™. A serial sacrifice design was used for the PK in mice. Sixteen FVIII ko mice (B6;129S4-F8tm2Kaz; m/f) for BAX 855 and eight FVIII ko mice for ADVATE™ per time point were bled by cardiac puncture under anesthesia for blood sampling 5 minutes – 48 hours after a single intravenous bolus injection. A single treatment design was used for the single dose PK in Sprague Dawley rats: 8m + 8f for BAX 855 and 4m + 4f for ADVATE™. A single treatment design was also used for the cynomolgus monkeys: 4m + 4f for BAX 855 and 2m + 2f for ADVATE™. Blood samples were drawn from rats and cynomolgus monkeys for citrated plasma (for analysis of baseline FVIII levels) before administration and 5 minutes - 48 hours (rats) and 5 minutes to 96 hours (cynomolgus monkeys) after administration. The citrated plasma samples were analyzed for FVIII activity (chromogenic assay) in mice and cynomolgus monkeys, for FVIII–bound PEG (using a PEG-FVIII ELISA) in all models and FVIII antigen (using a FVIII ELISA) in rats. In all three models a prolongation in MRT of Baxter’s and Nektar’s new BAX 855 compared with ADVATE™ could be demonstrated. FVIII activity analysis showed an increase of MRT in mice from 4.9 to 7.9 hours and in cynomlogus monkeys from 7.5 to 11.5 hours. This prolongation was also reflected in the terminal half-lives (4.3 to 5.9 hours in mice and 5.7 to 9.4 hours in cynomolgus monkeys). According to this prolongation a lower clearance [mL/h/kg] could be observed for BAX 855 than for ADVATE™ (22.1 to 12.2 in mice and 8.1 to 4.9 in monkeys). Similar levels in all PK parameters could be shown when measuring FVIII-bound PEG in all three preclinical models and FVIII antigen analysis in rats. These PK data provide evidence that PEGylation of human rFVIII increases the circulation time. Disclosures: Hoebarth: Baxter Innovations GmbH: Employment. Kubik:Baxter Innovations GmbH: Employment. Wolfsegger:Baxter Innovations GmbH: Employment. Lawo:Baxter Innovations GmbH: Employment. Weber:Baxter Innovations GmbH: Employment. Gritsch:Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment. Schiviz:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Turecek:Baxter Innovations GmbH: Employment. Schwarz:Baxter BioScience: Employment. Muchitsch:Baxter Innovations GmbH: Employment.

Single Dose Pharmacokinetics of a Recombinant FVIIa In Factor VIII KO Mice, Rats, and Cynomolgus Monkeys

Abstract 4655 The purpose of these PK studies was to assess the pharmacokinetic profile of Baxter's rFVIIa in comparison with a commercially available rFVIIa after a single intravenous bolus injection at a target dose of 0.6 mg/kg BW in mice and rats and 2.7 mg/kg BW in cynomolgus monkeys. The AUC0-t last (the area under the concentration vs. time curve from 0 to the last measured time point) was evaluated as primary endpoint. Secondary endpoints were terminal half-life (HL), mean residence time (MRT) and total clearance standardized per kg body mass (Cl) for FVIIa protein and clotting activity. In cynomolgus monkeys only FVIIa clotting activity was evaluated. Blood was sampled at baseline and each of the time points after a single intravenous bolus injection of Baxter's rFVIIa or the commercially available rFVIIa. The citrated plasma samples were analyzed for FVIIa activity and FVII protein (antigen). A serial sacrifice design was used for the PK in mice. Ten FVIII ko mice (B6;129S4-F8tm1Kaz; 5m/5f) per time point were bled by cardiac puncture under anesthesia for blood sampling 5 – 200 minutes after a single intravenous bolus injection. A single animals design was used for the single dose PK in Sprague Dawley rats (5m/5f) and cynomolgus monkeys (2m/2f). In rats and cynomolgus monkeys blood samples for citrated plasma were drawn before administration (for analysis of baseline FVIIa levels) and 5 – 270 minutes (rats) or 5 minutes to 15 hours (cynomolgus monkeys) after administration. Plasma samples were analyzed for FVIIa protein (antigen) using a FVII ELISA calibrated for FVIIa measurement and for FVIIa activity using a FVIIa clotting assay. In all three species bioequivalence of Baxter's rFVIIa and the reference item could be shown for the primary endpoint (AUC0-tlast) for FVIIa activity and antigen (the latter was only tested in mice and rats). Additionally, secondary endpoints of FVIIa activity (terminal half-life, mean residence time and total clearance) were similar for Baxter's rFVIIa and the reference item. In mice, HL was 0.64 h, MRT was 0.80 h and Cl was 245 ml/kg/h for Baxter's new rFVIIa. Values for the secondary endpoints in rats were 1.17 h for HL, 1.29 h for MRT and 102.6 mL/kg/h for Cl. In cynomolgus monkeys, HL was 2.00 h, MRT was 2.45 h and Cl was 33.6 mL/kg/h. In summary, the pharmacokinetic profiles of Baxter's rFVIIa and the commercially available rFVIIa were similar in all species studied. Disclosures: Hoebarth: Baxter Innovations GmbH: Employment. Kubik:Baxter Innovations GmbH: Employment. Wolfsegger:Baxter Innovations GmbH: Employment. Lawo:Baxter Innovations GmbH: Employment. Weber:Baxter Innovations GmbH: Employment. Gritsch:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment.