Oral delivery of topoisomerase I inhibitors: From biopharmaceutical barriers to clinical translation.

Topoisomerase I (TOP1) inhibitors, derived from camptothecin (CPT), remain integral to the treatment of multiple solid tumours, yet their clinical use is largely confined to intravenous administration. Oral delivery represents a compelling alternative, offering potential advantages in patient convenience, treatment flexibility, and pharmacodynamic optimisation through prolonged exposure. However, development of oral TOP1 inhibitors has been limited, with only topotecan achieving regulatory approval. This review critically examines the biopharmaceutical and translational barriers constraining oral delivery of CPT derivatives. Key limitations include poor aqueous solubility, pH-dependent lactone instability, limited intestinal permeability, active efflux transport, and pre-systemic metabolism, all of which interact dynamically within the gastrointestinal environment and collectively govern oral exposure and contribute to variability. Formulation and prodrug strategies have been extensively explored to address these challenges. Lipid-based systems and polymeric carriers enhance solubilisation, mitigate precipitation, and modulate intestinal transport. Prodrug design further enables stabilisation of the active lactone form and modulation of physicochemical properties, metabolic activation, and biodistribution, including potential engagement of intestinal lymphatic transport pathways. When optimally combined, prodrug and advanced delivery systems can improve toxicity profiles and enhance the risk-benefit balance through controlled activation and targeted exposure. Despite promising preclinical outcomes, these strategies have yet to translate into clinically adopted products, reflecting the challenges in achieving a favourable therapeutic index and demonstrating clear mechanistic advantages over established TOP1 inhibitors. A coordinated, multidisciplinary approach integrating formulation science, prodrug chemistry, and model-informed methods provides the best opportunity to improve translational predictability and facilitates the development of clinically viable oral TOP1 inhibitor therapies.