Utility of PBPK Absorption Modeling to Guide Modified Release Formulation Development of Gaboxadol, a Highly Soluble Compound With Region-Dependent Absorption

Abstract

Given the complexity of controlled release (CR) formulations, selecting the right preclinical tools is important to enable decision making on the in vivo performance of these formulations during development. In recent years, with the advancements of absorption/physiologically based pharmacokinetic (PBPK) modeling, such computational approaches play an increasing role in guiding formulation development. Development of PBPK models for CR formulations requires additional information compared with immediate release (IR) products. Perhaps the most important aspect is the need to simulate absorption in the lower intestine. Relatively few publications have investigated the use of PBPK models for compounds with region-dependent absorption. In this manuscript, we use gaboxadol as a model compound with region-dependent absorption. We first explored gaboxadol regional absorption in dogs to develop a PBPK model for absorption in the large intestine. Two matrix-based CR formulations were subsequently developed and tested in minipigs and demonstrated distinctly different pharmacokinetic profiles from the IR formulation. A minipig absorption PBPK model successfully predicted the observed plasma concentration data, with the predictions based on the in vitro dissolution being within the observed experimental variability. Finally, we demonstrate the development of an in vitro-in vivo correlation for the preclinical data using the same PBPK model.

The pig as a preclinical model for predicting oral bioavailability and in vivo performance of pharmaceutical oral dosage forms: a PEARRL review

“…The model was subsequently used to extrapolate this data to the fed state, where the elimination of a food‐dependent increase in fenofibrate bioavailability utilising the novel formulation was predicted . Kesisoglou et al . have also used the GastroPlus™ minipig model, in conjunction with modelling of dog and human data, in the formulation development of a modified release preparation of gaboxadol.…”

“…The authors successfully incorporated in vitro dissolution data and preclinical pharmacokinetic data within the PBPK models to guide formulation development. Subsequently, it was possible to use the minipig PBPK model to develop an IVIVC to project formulation performance . Using regional permeability data measured in dogs and clinical pharmacokinetics from human studies, the minipig ACAT model was optimised using an immediate release dry filled capsule as a reference.…”

“…Using this optimised model, the in vivo dissolution was deconvoluted from the simulated plasma profile for two modified release formulations. This in vivo dissolution profile was subsequently plotted against the in vitro release profile resulting in a linear IVIVC …”

Porcine Prediction of Pharmacokinetic Parameters in People: A Pig in a Poke?

“…The food-effect study, however, was shown to be challenging. Kesisoglou et al (2016) developed a PBPK model for the dog to describe absorption in the large intestine for a BCS class I drug dosed via ileal and colonic ports to evaluate regiondependent absorption. A minipig absorption PBPK model was also developed by using the default minipig ACAT model in "Gastro-Plus" and assuming regional absorption differences to be the same as in the dog.…”

Evaluating In Vivo-In Vitro Correlation Using a Bayesian Approach

“…3. Mechanistic models: In silico models are used to describe the in vivo dissolution or absorption of a drug from a dosage form (13,14). A UIR provides the information upon which subject-specific model physiological and pharmacokinetic attributes (system behavior) are defined.…”