Purpose: Warfarin is a poorly soluble weak acid, of which tablets are formulated as a crystalline sodium salt. Warfarin sodium tablet is a commonly prescribed anticoagulant with a narrow therapeutic index (NTI). Substantial concerns over the efficacy and safety have been raised regarding the interchangeability between brand-name and generic warfarin products. No significant difference in pharmacokinetics (PK) or international normalized ratio (INR) has been observed in randomized, small population, well-controlled trials. Nonetheless, large-scale retrospective analysis found that patients who switched warfarin brand products suffer from thrombotic or hemorrhagic events with an over 1.5-fold increase of risk. The reasons for the abnormal outcomes upon switching brands are unclear. The objective of this study is to use physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modelling strategies to examine the impacts of formulation variations among warfarin products on the oral absorption process, and subsequently therapeutic responses.
Methods: The physiologically-based gastrointestinal (GI) tract model was implemented as continuous flux transit through nine GI compartments, each of which had a specific pH, transit time, volume, surface area for absorption and bile salt concentration under fast or fed state. Phase transitions of warfarin molecules were modeled in each GI compartment, including the dissolution of warfarin salt, ionization of warfarin acid, partition into bile-micelle, nucleation and particle growth of unionized warfarin, permeation through the epithelial cells. The dynamic amounts of six states of warfarin, namely undissolved salt, dissolved unbounded or bile-micelle bounded warfarin anion, dissolved unbounded or bile-micelle bounded unionized warfarin, precipitated warfarin, were predicted in different segments of GI tract. The absorbed warfarin amount was used to predict the plasma concentration-time profiles for (S)- and (R)- warfarin respectively by incorporating their PK models. An inhibitory sigmoidal Emax model incorporated with a two-chain transit compartmental model was then integrated with the warfarin PK models to predict the response of the pharmacological target VKORC1 and clinically measured INR. Patient variations in CYP2C9, VKORC1 genotypes and age were accounted for in the model in terms of metabolism and drug response. Sensitivity analysis was conducted to investigate the impact of each formulation attribute on the overall oral absorption process and final clinical performance under various scenarios.
Results: The predicted AUC and Cmax of warfarin sodium tablet are within 15% and 30% deviations of the observed mean AUC and Cmax (Fig.1). The predicted INR for different genotype and age groups are within 15% deviations relative to the clinically measured INR. The high accuracy of the predicted PK and PD data allows the use of our model to assess the role of single formulation variable played on the in vivo performance of warfarin sodium tablet. Herein, fraction of (S)-warfarin and initial particle size are identified as two critical attributes that lead to significant fluctuation of the steady-state INR for various patient groups. Patients are more susceptible to thrombotic or hemorrhagic event when (S)-warfarin fraction is not within 40%-80% of tablet, which is not affected much by the genotypes, age and food effects (Fig. 2). The efficacy of warfarin is predicted to be dramatically decreased when the mean initial particle size is above 150 µm, which largely increases the likelihood of thrombotic risks (Fig 3). Interestingly, fasted groups are more sensitive to warfarin doses with small initial particle size, while fed group are more sensitive to the doses with larger initial particle size. This trend exists in several genotype groups. The diffusion coefficient and solubility of warfarin sodium salt both influence the dissolution rate, and are predicted to fluctuate the INR moderately. Accordingly, these critical quality attributes should be carefully examined during the manufacturing and regulation processes.
Conclusion: Our robust PBPK/PD model identifies the chiral ratio and mean initial particle size as two critical attributes that may be the culprits of adverse effects when switching between warfarin brand products.
Tonglei Li– Purdue University