Prediction On The BA/BE Of Drugs And Their Formulations Using In Silico/in Vitro Model Based On BCS

The prediction of oral bioavailability is very important both for screening the lead candidates in the early stage of new drug discovery, and for choosing candidate compounds into the clinical test and drug formulations research. However, the oral absorption of drug is very complex. The different predictive method should be used in the different stage of new drug discovery and formulation research. In silico, in vitro, and in silico/in vitro coupling advanced compartment absorption and transit (ACAT) models were established to predict the bioavailability of drugs and their formulations, based on biopharmaceutical classification system (BCS). The biowaiver of BCS class Ⅲ drugs was also studied. Specific content as follows:1) A structure-based in silico predictive model of Peff was successfully developed to facilitate in silico BCS classification in the early stage of drug discovery, even before the compound was synthesized. The quantitative structure-Peff relationship for30drugs was constructed based on seven structural parameters. Then the model was built by the multiple linear regression method and internally validated by the residual analysis, the normal Probability-Probability plot and Williams plot. For the entire data set, the R2and adjusted R2values were0.782and0.712, respectively. The results indicated that the fitted model was robust, stable and satisfied all the prerequisites of the regression models. As for102tested drugs, the predicted Peff values had a good correlation with the experimental human absorbed fraction (Fa). This model was also used to perform high/low Peff classification for57drugs which have been classified according to BCS, and72%of drugs can be classified correctly, indicating that the developed model can be used for rapid BCS classification in the early stage of drug discovery.2) The oral bioavailability (BA) and concentration-time curve of nine drugs were predicted using in silico/in vitro coupling ACAT model. The value of hepatic clearance, volume of distribution and permeability obtained by QSPR model were inputted to ACAT model to predict the oral bioavailability, Cmax、AUCo-t and Tmax. The predicted bioavailability residual of77.78%drugs is within20%. However, Cmax、AUCo-t and Tmax were not predicted accurately. It maybe because that the inputted hepatic clearance and volume of distribution were not accurate enough for predicting concentration-time curve accurately. Above all, in silico/in vitro coupling ACAT model predicted the BA accurately. However, it cannot predict Cmax、AUCo-t and Tmax accurately.3) The impact of cyclodextrin on the solubility and permeability was studied using progesterone as model drug, and the oral bioavailability of three formulations were predicted by ACAT model. The in situ rat jejunal perfusion experiment indicated that the permeability of progesterone decreased with the increasing of cyclodextrin concentration. Moreover, in order to simulate the effect of bile salt on the permeability and oral absorption of progesterone, sodium taurocholate and lecithin were added in to perfusion. The results indicate sodium taurocholate can displace drug molecular which complexing with cyclodextrin, and enhance the permeability of progesterone. At last, BA, Cmax、AUCo-t and Tmax of three formulation were predicted by ACAT model, and validated by rat in vivo pharmacokinetic experiment. The results indicate that this model is accurate and can be used to choose the dosage of cyclodextrin in the formulation.4) Dynamic dissolution ASD model was established to simulate the in vivo dissolution process. The pH value in the two compartment chambers is similar with in vivo pH value at intestine. This model was used to predict bioavailability of formulations which active pharmaceutical ingredients is weak acid/weak base and insoluble. Using itraconazole as model drug, the area under the drug concentration-time curve of three itraconazole formulation in simulated jejunum compartment is49.96±10.17,12.94±0.52�'�34.50±5.58μg*h/mL, the in vivo AUCo-t is7.63±4.29、6.86±5.52and6.11±4.13μg*h/mL. The result indicated the model predicted the bioavailability of formulations accurately.5) The objective of this study was to assess the effects of site-specific absorption, low absorbed fraction (Fa) and gastric emptying rate on the biowaiver extension of BCS class Ⅲ drugs. The oral absorption of BCS class Ⅲ drugs nadolol, acebutolol and atenolol which are P-gp substrates, was simulated using ACAT model with physiological parameters reflecting site-specific and site-independent absorption. Then, the simulation results were compared with the experimental data in literature. Simulation with different dissolution rate (T85%=15to180min) was performed to predict absorption (Cmax and AUCo-inf) of the above model/virtual drugs (Fa:81-80.14%). The results of this study indicated that the site-specific absorption and low Fa magnify the effect of dissolution rate on Cmax and AUCo-inf. Based on the results of this study, we suggested that for BCS class III drug with high Fa(about>80%), the biowaiver would extend to rapid dissolution (T85%=30min), and30%of Fa as the boundary of intermediate permeability class (30%<Fa<90%).