Solid dispersion of alectinib HCl: preclinical evaluation for improving bioavailability and establishing an IVIVC model

Objective: Alectinib HCl (ALB-HCl) is a BCS class IV molecule with low solubility and low oral bioavailability. Owing to its low bioavailability, a high dose of ALB-HCl is recommended with food to meet clinical efficacy. Thus, there is a need for a delivery system to overcome the bioavailability concerns.

Methods: Three solid dispersion (SD) formulations (I, II, and III) were evaluated for in-vitro dissolution and in-vivo pharmacokinetics (PK) study in Wistar rats. An in-vitro and in-vivo correlation (IVIVC) model was developed to establish a relationship between in-vitro dissolution data and in-vivo PK data. The formulations were subjected to stability studies.

Results: All formulations showed enhanced dissolution in all the media except Formulation I in FaSSIF media. In-vivo PK studies displayed that Formulation I was inferior to API alone. Formulations II and III (amorphous SD [ASD]) exhibited two-fold higher C_max and AUC_0-last than API alone. Level A IVIVC model was established for C_max and AUC_0-last with an acceptable % prediction error (PE). When evaluated for external predictability, the model was found validated for C_max (% PE <10%), however, it was inconclusive for AUC_0-last (%PE -14.03). Stability studies showed ASD formulations were stable during storage.

Conclusion: A stable ASD formulation of ALB-HCl was successfully developed with improved bioavailability. Developing an IVIVC model can act as a surrogate to predict in-vivo performance. The selection of formulation components in ASD shall be rationalized for bioavailability and stability before clinical evaluation.