Enabling clinical development of an HIV attachment inhibitor through innovative pharmaceutical development: novel extended‐release delivery of prodrug

Abstract

BackgroundHIV‐1 attachment inhibitors are a new class of viral entry inhibitors which target viral gp120 preventing attachment of virus to its host cell receptor CD4. This class presents major challenges for development based upon low solubility and short half‐lives. For progression into clinical studies, requirements include reliable and reproducible absorption from a tolerable and convenient oral dosing regimen.MethodsA series of highly soluble prodrugs were designed to overcome the poor absorption caused by the low solubility of the active compounds. A regional absorption study was conducted to assess the uptake of active throughout the gastro‐intestinal tract following oral prodrug delivery. An extended‐release (ER) strategy was subsequently devised to optimise tolerability, decrease peak to trough ratios and reduce frequency of dosing. In silico absorption modelling was used to verify feasibility and drive in vitro testing leading to dosage form development and selection. The performance of the ER dosage form was verified in vivo prior to use in clinical studies.ResultsPhosphonooxymethyl prodrugs with aqueous solubilities in excess of 250 mg/mL were synthesised and shown to be readily converted to parent compound via alkaline phosphatase in vitro. Results of regional absorption studies for the selected compound, BMS‐663068, confirmed the rapid absorption but short half‐life of active following oral administration of prodrug. Delivery to specific regions throughout the GI tract showed absorption of active to be subject to regional variation with an extent of colonic absorption of approximately 40% of intestinal absorption. Incorporation of this data into an in silico model guided development of an ER tablet which releases prodrug over 24 hours and achieves the required exposure, pharmacokinetics and reproducibility in vivo.ConclusionsThe novel approach of combining prodrug synthesis and ER formulation has enabled clinical evaluation of a promising new class of therapeutic entity into Phase 2b studies.