Guiding the Molnupiravir Tablet Formulation Using Physiologically Based Biopharmaceutics Modeling and Successfully Establishing Dissolution Safe Space

Physiologically Based Biopharmaceutics Models (PBBMs) are evolving tools which can be used to aid in drug product quality specifications. PBBMs have gained increased regulatory interest and acceptance over the past 5 years. For molnupiravir, PBBM has been used for: a) calculation of a bioequivalence safe space for capsule formulation and tablets, b) informing of the definitive bioequivalence study (P011) with a target tablet formulation selection designed to be bioequivalent to the capsule formulation, c) selection of a deliberately slower release tablet formulation (beyond f₂ similarity criteria) designed to widen the dissolution knowledge space, d) help select the clinically relevant specification and the dissolution bioequivalence safe space. PBBM data inputs, model development, validation, and application using data from several independent clinical studies are described. Predictive errors for Cmax and AUC were < 25%. The z-factor for dissolution data modeling is described for QC (Quality Control) method(s). The molnupiravir bioequivalence safe space or knowledge space widening is described. The value of the wider dissolution space includes increased potential flexibility with scale-up and post approval changes (SUPAC), including adding or changing a site for a high-volume drug product such as molnupiravir. PBBM is not only important in the development of drug products aiding formulation selection, but can also be a key component toward regulatory flexibility and approval of clinically relevant specifications, such as when the clinical knowledge space has been widened through inclusion of a slow-release variant, as was done for the relative bioavailability study for molnupiravir.