Effect of Generic Warfarin Sodium Formulation on Its Clinical Steady State Concentrations

Aim: As a BCS class I drug, it is expected that the dissolution profile of warfarin sodium tablet would be able to predict its in vivo performance. The current study aims to evaluate the impact of different generic warfarin sodium tablets in China on its clinical steady state concentrations. Method: We measured dissolution profiles and collected from the literature, physicochemical properties of three generic warfarin sodium tablets in Hong Kong and mainland China market. These included: APO-Warfarin (APO) manufactured by APOTEX INC; IVAX Warfarin Tablet (IVAX) manufactured by IVAX Pharmaceuticals Ireland; Warfarin Sodium Tablet (SINE) manufactured by Shanghai Sine Pharmaceutical Co. Ltd. The dissolution test was conducted using an ERWEKA DT80 dissolution apparatus according to USP pharmacopeia. Samples were analyzed by ESI/MS/MS in the negtive ion mode with MRM monitoring transitions of 307/161 for warfarin. Differential scanning calorimetry (DSC) profiles of the three warfarin sodium tablets generated from Perkin Elmer Pyris 1 differential scanning calorimeter were obtained to provide mechanistic explanations on their dissolution profiles. The in vivo steady state concentrations of the three warfarin sodium tablets were obtained either from clinical patients (for IVAX) or GastroPlus^TM (Simulation Plus Inc.) and compared. Results: All the tablets fully disintegrated within 30 min. It was shown that the dissolution rate of IVAX-warfarin and APO-warfarin at 30 min were significantly higher than that of SINE-warfarin (p<0.05). There was 77.2% of IVAX-warfarin and 67.2% of APO-warfarin dissolved at 30 min of dissolution test, whereas, only 31.5% of SINE-warfarin was dissolved at 30 min of the dissolution test. The physicochemical properties of three warfarin sodium products were investigated by DSC. IVAX-warfarin and APO-warfarin showed an endothermic peak due to their melting at 143.5 ºC and 141.3 ºC, respectively. However, the SINE-warfarin showed no endothermic peak. Comparison of the steady state concentrations of the three tablets indicated that the time to achieve steady state did not differ too much although they demonstrated different dissolution profiles. However, differences between the peak and trough concentrations at the steady state significantly increased for the tablet with the poor dissolution performance, indicating its potential clinical risk. Conclusion: There existed significant different dissolution profiles among the tested generic warfarin sodium tablets, which could be caused by different physicochemical properties of the formulations. Such differences will further increase the variations on the steady state concentrations of warfarin in the patient.