Progress 11/01/06 to 12/31/07
Outputs
OUTPUTS: In a two-phase pharmacokinetic and bioavailability study, a cross-over design was utilized to compare 5 mg/kg i.v. and 15 mg/kg p.o. doses in the same population, with 12 samples per time point. A 20 mg/kg p.o. dose was studied simultaneously in a smaller population, 5 samples per time point. In the first phase, birds were randomly assigned to one of the three treatment groups and to 0.08, 0.17, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h sampling times; with 6 birds per sampling time in the 5 mg/kg i.v. group, 6 birds per sampling time in 15 mg/kg p.o. group, and 2 birds per sampling time in the 20 mg/kg p.o. group. After a washout period of two weeks, the birds were reassigned to 5 mg/kg i.v. and 15 mg/kg p.o. treatment groups according to the crossover design, 6 per sampling time. Birds from the 20 mg/kg p.o. group received the same treatment but were assigned to different sampling times. The 24 h sampling time after 5 mg/kg i.v. administration was eliminated in the second phase and additional birds were enrolled in the study in order to assign 3 birds per sampling time to the 20 mg/kg p.o. treatment group. Four different control birds in each phase were sampled but not treated. A total of 159 quail (76 females, 83 males) were used in this part of the study in order to limit blood sampling to one time per bird per phase. For i.v. dosing, a sterile 1.25% orbifloxacin injectable formulation was prepared by the drug manufacturer (Schering-Plough Research Institute, Summit, NJ, US) and was administered via 1 cc syringe and 25 gauge needle into the right or left jugular vein. For p.o. dosing, orbifloxacin tablets were crushed and suspended in distilled water at 5.7 mg/mL in one batch for each phase, and volumes of suspension were administered according to dose via 1 cc syringe into the crop. Venous blood samples were taken at the assigned times, and plasma separated and stored in the same manner as in the pilot study. Sample analysis Analysis of plasma samples followed a previously described method {Davis et al. 2006}. Pharmacokinetic analysis Recoveries of orbifloxacin in each p.o. suspension or i.v. solution determined by mean HPLC results (recovery = actual concentration / nominal concentration) were used to calculate estimated doses (Destimated = Dintended x recovery) delivered by each formulation. Plasma concentration data were then transformed to normalize each dose group to the intended dose, according to the formulation each quail received (adjusted concentration = observed concentration / recovery). Adjusted plasma concentrations and a naive pooled data approach were used in compartmental and noncompartmental analyses of orbifloxacin pharmacokinetics within each dose group with the program WinNonlin (Pharsight Corporation, Mountain View, CA, US). A one-compartment open model was applied to the i.v. dose group, and a one-compartment open model with first-order input was applied to each p.o. dose group. The inverse square of predicted plasma concentration was used as a weighting factor to improve the fit of the compartmental model in each dose group. PARTICIPANTS: Nothing significant to report during this reporting period. TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Analysis of orbifloxacin preparations used to dose the quail revealed discrepancies between actual and nominal concentrations in some of the p.o. suspensions, requiring calculation of an estimated dose for each individual. In the two batches of suspension per dose prepared for the pilot study, estimated doses were 3.8 and 4.6 mg/kg for the 5 mg/kg p.o. group, 7.0 and 7.2 mg/kg for the 7.5 mg/kg p.o. group, and 9.4 and 9.7 mg/kg for the 10 mg/kg p.o. group. For the 15 mg/kg p.o. group in the main study, estimated doses were 15.4 mg/kg during the first phase and 16.0 mg/kg in the second. For the 20 mg/kg p.o. group receiving the same suspensions, the corresponding doses were 20.5 and 21.3 mg/kg, respectively. For the 5 mg/kg i.v. dose group, estimated doses from the same solution were 5.14 mg/kg in the first phase and 5.09 mg/kg in the second. Estimated doses were used to transform the plasma concentration data, allowing pharmacokinetic analyses to better reflect the nominal doses. Pharmacokinetic parameters for the larger groups (n = 12 per time point) receiving the 5 mg/kg intravenous and 15mg/kg p.o. doses are presented in Table 1. Analyses of the 5, 7.5, 10, and 20 mg/kg p.o. doses in smaller groups (n = 5 per time point) are presented in Table 2. The transformed plasma concentration data from individual quail and predicted concentration-time curves are plotted in Figures 1, 2, 3, and 4. The 15 mg/kg p.o. dose appeared to be completely absorbed with 102% bioavailability and an area under the curve to dose ratio (AUC/D) very similar to the 5 mg/kg i.v. dose. Comparing the area under the curve parameter over the five p.o. doses by linear regression produced a high coefficient of determination (R2 = 0.981, Figure 5), indicating linear pharmacokinetics. However, AUC/D was skewed lower in the 5, 7.5, and 10 mg/kg p.o. groups (74-76% of the i.v. value) and higher in the 20 mg/kg group (117% of the i.v. value). Terminal elimination rates (lambda z) and were similar between i.v. and p.o. dose groups, not correlated with p.o. dose level (R2 = 0.041), and rapid (mean 0.405 +/- 0.058 h-1). The harmonic mean across the dose groups of the corresponding terminal half-lives (T1/2 lambda z) was 1.71 h. Cmax was obtained 0.5-2 h after p.o. administration, with high 9-39% coefficients of variation (CV = [SD / mean] x 100%) among individual concentrations at these time points. Tmax values predicted by the compartmental models varied little across p.o. treatment groups (1.20 +/- 0.09 h) and model-predicted peak concentrations fell within +/- 1 SD of each dose-adjusted Cmax . Observed concentrations in the 20 mg/kg dose group dipped at 1 h before rising markedly at 2 h, however. Variation in non-compartmental Tmax between doses generally reflected the variability of individual concentrations in the 0.5-2 h range of each treatment group, and small sample size in the 5, 7.5, 10, and 20 mg/kg p.o. treatment groups.
Publications
- No publications reported this period
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