The Study Of Preclinical Pharmacokinetics Of The Sustained-release And Controlled-release Preparation Of Levetiracetam And Fenofibrate In Beagle

The sustained-release and controlled-release preparation is a new kind ofdosage form in water or a predetermined medium, which could slow and controlpharmacal release after administration on purpose in order to obtain bettertherapeutic effect. The sustained-and-controlled release preparations couldreduce dosing frequency, improve the patient’s compliance, improve the clinicalefficacy, reduce side effects and enhance the bioavailability of the drug. Thus inrecent years, the sustained-and-controlled release preparation has been greatlydeveloped. The purpose of this research was to study the pharmacokineticcharacteristics of the sustained-and-controlled release preparation, fenofibratenano tablet and levetiracetam sustained-release tablet in vivo of theexperimental animals, to summarize the characteristics and laws of thepharmacokinetic parameters and to provide the basis for clinical studies.1. The establishment of analytical method of determination the drug contentin plasmaA quick and easy HPLC-MS/MS method was established for determinationthe concentration of fenofibric acid and levetiracetam. Pretreatment of thesample was performed with ethylether: ethyl acetate(1:1， v/v) liquid-liquidextraction method. A good linearity was obtained in the plasma concentrationrange5~1000ng·mL-1of fenofibric acid and levetiracetam. The precision ofintra-assay and inter-assay for fenofibric acid was evaluated by analysis ofvariance with the results of2.52%~7.81%and7.77%~13.14%and the accuracy is-0.78%~3.52%. Simultaneously, the precision and accuracy of levetiracetamare respectively5.85%~13.96%(intra-assay),8.42%~9.35%(inter-assay), and-6.76%~-0.23%. The extraction recoveries rates of fenofibric acid andlevetiracetam had no significant difference. Meanwhile, the specificity of themethod was satisfactory, and there were no matrix effects, no dilution effectsand the stabilities were satisfactory too.2. The pharmacokinetic evaluation after single oral administration withfenofibric acid and levetiracetamBeagles fasted for12h before administration, following a single oraladministration with fenofibrate nano tablet (test preparation) and Tricor(reference preparation) and performed cross-over experiments. The eliminationhalf-lives (t1/2) of fenofibrate nano tablet and Tricor were8.58±3.41h、8.02±2.08h, respectively. The Tmaxof fenofibrate nano tablet and Tricor were1.50±1.16h,1.94±2.48h, respectively. The differences between thepharmacokinetic parameters of fenofibrate nano tablet and Tricor were notstatistically significant by student’s t-test. ANOVA results showed that therewere no statistically significance between periods and preparations. AUC ratioof the mean relative bioavailability of the test preparation and referencepreparation was96.0%. According to the results of bioequivalence, the90%confidence interval of AUC of fenofibrate nano tablet was out of the rangebetween80%and125%, then it couldn’t get the conclusion of bioequivalence.The reason may be related to the differences between individuals. And it couldreach bioequivalence by increasing the numbers of experimental animals.Beagles were randomly divided into two groups and fasted for12h beforeadministration, following a single oral administration with levetiracetamsustained-release tablet (test preparation) and Keppra XR (reference preparation)and performed cross-over experiments. The elimination half-lives (t1/2) oflevetiracetam sustained-release tablet and Keppra XR were4.32±1.61h、3.76±0.89h, respectively. The Tmaxof levetiracetam sustained-release tablet andKeppra XR were3.88±1.64h、3.38±1.69h, respectively. There were nostatistically significant differences between the two preparations by t Test,suggesting that the two preparations were almost the same. AUC ratio of themean relative bioavailability of the test preparation and reference preparationwas121.0%. According to the results of bioequivalence, the90%confidence interval of AUC of levetiracetam sustained-release tablet was between102.95%~142.49%, slightly beyond bioequivalence requirements of80%~125%. The reason may due to differences between the individuals andsmall sample sizes, also may related to the bioavailability of the testformulation was slightly better than the reference formulation.3. The effect of diet on the absorptive evaluation of fenofibrate nano tabletBeagles had a single oral administration with fenofibrate nano tablet afterdiet or limosis, then compared the pharmacokinetic parameters and analyzed theeffect of diet on the absorbtion of fenofibrate nano tablet. The elimination ofhalf-lives (t1/2) of after-diet and limosis were8.21±1.51h,8.58±3.41h,respectively. The Tmaxwere separately1.34±0.55h and1.50±1.16h. Thedifferences between the pharmacokinetic parameters of after diet and limosiswere not statistically significant by student’s t-test. The result indicated that dietcould not affect the absorption of fenofibrate nano tablet in beagle dogs.