Assessing the Risk of pH-Dependent Absorption for New Molecular Entities: A Novel in Vitro Dissolution Test, Physicochemical Analysis, and Risk Assessment Strategy

Abstract

Weak base therapeutic agents can show reduced absorption or large pharmacokinetic variability when coadministered with pH-modifying agents, or in achlorhydria disease states, due to reduced dissolution rate and/or solubility at high gastric pH. This is often referred to as pH-effect. The goal of this study was to understand why some drugs exhibit a stronger pH-effect than others. To study this, an API-sparing, two-stage, in vitro microdissolution test was developed to generate drug dissolution, supersaturation, and precipitation kinetic data under conditions that mimic the dynamic pH changes in the gastrointestinal tract. In vitro dissolution was assessed for a chemically diverse set of compounds under high pH and low pH, analogous to elevated and normal gastric pH conditions observed in pH-modifier cotreated and untreated subjects, respectively. Represented as a ratio between the conditions, the in vitro pH-effect correlated linearly with clinical pH-effect based on the Cmax ratio and in a non-linear relationship based on AUC ratio. Additionally, several in silico approaches that use the in vitro dissolution data were found to be reasonably predictive of the clinical pH-effect. To explore the hypothesis that physicochemical properties are predictors of clinical pH-effect, statistical correlation analyses were conducted using linear sequential feature selection and partial least-squares regression. Physicochemical parameters did not show statistically significant linear correlations to clinical pH-effect for this data set, which highlights the complexity and poorly understood nature of the interplay between parameters. Finally, a strategy is proposed for implementation early in clinical development, to systematically assess the risk of clinical pH-effect for new molecular entities that integrates physicochemical analysis and in vitro, in vivo and in silico methods.

Mechanistic Study of Belinostat Oral Absorption From Spray-Dried Dispersions

“…Using fiber-optic ultraviolet (UV) probes to measure key attributes governing absorption such as the amorphous solubility (maximum dissolved concentration) of a compound with or without formulation additives, or formulation dissolution performance, presents the opportunity to understand formulation performance in real time with high time resolution and produces high-quality data that can be used as inputs for absorption modeling. 25,26,35 To achieve the goals of this study, an in vivo pharmacokinetic (PK) study was performed with fasted beagle dogs using suspension formulations of belinostat SDDs manufactured using 3 different polymers: the M grade of hydroxypropyl methylcellulose acetate succinate (HPMCAS-M), the K30 grade of polyvinyl pyrrolidone (PVP K30), and the VA64 grade of polyvinyl pyrrolidone vinyl acetate (PVP VA64). All were prepared at a ratio of 25:75 belinostat:polymer (w/w).…”

Prediction of ARA/PPI Drug-Drug Interactions at the Drug Discovery and Development Interface

“…A secondary analysis was conducted, utilizing published ranges for risk assessment of ARA/PPI effects. 32 Namely, a 3-bin risk category was assigned based on the magnitude of the ratio (high <0.5, moderate 0.5-0.8, low >0.8) between the predicted AUC using the fasted pH and elevated pH in the stomach with ARAs/PPIs coadministration. An ARA/PPI DDI effect risk would be considered low at a ratio of >0.8, moderate at a ratio of 0.5 to 0.8, and high at a ratio below 0.5 (Table 8).…”

Commentary: Why Pharmaceutical Scientists in Early Drug Discovery Are Critical for Influencing the Design and Selection of Optimal Drug Candidates

“…Supersaturation is achieved by transferring a compound from a higher energy environment to a lower energy environment [19], such as The supersaturation advantage may be negated by rapid precipitation, and gastrointestinal differences in pH and bile content [20,21] between test animals can lead to different precipitation profiles and oral exposure variability. Precipitation inhibiting formulations and excipients is employed to reduce this variability, but care must be taken that the chemical potential driving force for intestinal increased absorption is not unintentionally lowered through oversolubilization that exceeds supersaturation limits [22].…”