An In Silico Model-Based Feasibility Assessment of Erlotinib Long-Acting Injectable Formulation for the Management of Metastatic Non-Small Cell Lung Cancer

Erlotinib is an orally administered tyrosine kinase inhibitor used in the treatment of EGFR-positive non-small cell lung cancer. However, poor tolerability and suboptimal patient adherence often limit its clinical efficacy. Furthermore, lower doses are recommended for elderly patients, those with EGFR-sensitising mutations, and cutaneous toxicities. A PLGA-based long-acting injectable formulation may offer significant advantages for metastatic NSCLC by enhancing treatment compliance. This study aims to develop a physiologically based pharmacokinetic model to support dose selection, optimisation of release profiles, and dosage form design.The semimechanistic ERL PBPK model was first developed and validated for oral formulations and subsequently extended to intramuscular depots. The IM model was used to determine the optimal dose and release profile to maintain plasma drug concentrations above the IC50 and Css min targets.A monthly dose of 750 mg with an intermediate-release profile able to maintain the drug concentration above the Css, min. When targeting the IC₅₀, the prototype formulations required a monthly dose of 300 mg and a three-month dose of 1200 mg, both with intermediate-release profiles.The semimechanistic PBPK model successfully predicted the optimal dose and release profile. The results provided valuable insights for polymer grade selection and drug-to-polymer ratio optimisation.