Approaches to conducting a physiologically relevant test (PRT) in the study of medicines containing substance IIc of the BCS subclass using sorafenib as an example

Introduction. Sorafenib is an antineoplastic drug belonging to class IIc according to the biopharmaceutical classification system (BCS) due to the presence of both acidic and basic properties. In addition to low solubility, sorafenib is characterized by high variability during clinical trials, in particular bioequivalence studies (BE). To selecting batches that can be recommended for BE studies, the dissolution kinetics test is currently widely used, however, the results of this test are not always sufficient and additional tests, for example, a physiologically relevant test, are advisable. To minimize the risks of obtaining nonequivalent results during the BE study, a physiologically relevant test (PRT) was carried out with further data processing and interpretation of the results of physiologically based pharmacokinetic modeling (PBPK). Aim. The aim of the study is to conduct a physiologically relevant test (PRT) for the purpose of selecting a candidate batch for subsequent BE study of sorafenib drugs using the physiologically based pharmacokinetic model (PBPK). Materials and methods. The objects of the study are Nexavar®, film-coated tablets, 200 mg (Bayer AG, Germany) (one batch) and Sorafenib, film-coated tablets, 200 mg (two batches) (Russia). The physiologically relevant test was performed on the SC PRT-6 device (LLC "Scientific Compliance", Russia). Quantitative analysis was performed by HPLC-UV on the Chromatec-Crystal HPLC 2014 device (CJSC "Chromatec", Russia). The plasma concentration profiles were simulated using PK-Sim® software (Systems Biology Software Suite 11.2, Bayer Technology Services GmbH, Germany). Results and discussion. As part of the study, a method for the quantitative determination of sorafenib was developed and validated, a method for sample preparation was developed, and a method for conducting the PRT for sorafenib, as a representative of the IIc subclass of BCS, was developed. Based on the study results, release profiles were obtained that were used to select a candidate series for the BE study. The series were selected based on the PBPK analysis on a virtual population consisting of 36 healthy volunteers with activated enteropathic circulation, characteristic of sorafenib. Conclusion. The PRT was carried out for the drug sorafenib. Quantitative determination was carried out by HPLC-UV according to the developed and validated method. The test resulted in obtaining data that were subjected to PBPK analysis. It was shown that the studied batches have high risks of non-equivalence during the bioequivalence study.