Physiologically Based Biopharmaceutics Modeling to Demonstrate Virtual Bioequivalence and Bioequivalence Safe-space for Ribociclib which has Permeation Rate-controlled Absorption

A physiologically based biopharmaceutics model (PBBM) was developed to support formulation development of ribociclib, an orally bioavailable selective CDK4/6 inhibitor. Ribociclib is a weak base with moderate permeability and complete in vitro dissolution under stomach pH. GastroPlus™ was used to simulate the pharmacokinetics (PK) in healthy volunteers after capsule dosing. Simulations showed rapid, complete dissolution in human stomach without intestinal precipitation and with permeation-controlled absorption. Permeability was identified as controlling the systemic exposure. PBBM predicted bioequivalence (BE) between capsule and tablet in healthy volunteers, despite non-similarity between in vitro dissolution kinetics (f2<50). BE was verified in a clinical study. Then virtual bioequivalence (VBE) simulations predicted comparable PK in cancer patients between capsule and tablet of commercial batch, which was also confirmed in a clinical study. Finally, virtual trial simulations using virtual batches with slower dissolution were used to define an in vitro BE safe-space for tablets, where BE is expected. PBBM can identify drugs with permeability-controlled absorption for which formulation optimization can focus more on manufacturability rather than dissolution. PBBM can be used to predict BE study outcomes, define clinically relevant specification and BE safe-space, superseding dissolution similarity f2 criteria.