Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm

Abstract

Abstract. Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling-(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

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

“…However, for compounds with a significant pH-dependent solubility or a high supersaturation propensity, measured equilibrium solubility at neutral pH may not adequately model dissolved drug concentration throughout the entire absorption window. In these cases, the use of biorelevant dissolution tools along with more sophisticated absorption modeling tools such as MiMBa®, GastroPlus®, STELLA®, or Simcyp® might be better suited [32][33][34][35][36]. The solid form from either undissolved or precipitated material should also be assessed as a change in polymorphic form can affect solubility and dissolution [37].…”

Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine

“…PBPK modeling provides a quantitative and mechanistic methodology that connects a drug’s Critical Quality Attributes (CQAs), which encompass a large variety of modeling parameters such as manufacturing criteria and drug-specific properties, to its in vivo behavior as characterized by its Quality Target Product Profile (QTPP). In recent years, studies hailing from academia as well as industry demonstrated how these models can be implemented within the Quality by Design paradigm [44,45] such that PBPK modeling developed intoa powerful and essential tool to increase mechanistic understanding and provide a holistic description of drug exposure in the body.…”

“…Kesisoglou and Mitra demonstrated how PBPK modeling could be implemented in the rational design of drug product under the Quality by Design (QbD) paradigm with the goal of linking the product critical quality attributes (CQAs) to the quality target product profile (QTPP) [44]. The first study evaluated the effects of gastric pH on absorption of a BCS Class II/IV compound relative to the QTPP, prior to first in human studies.…”

“…The first study evaluated the effects of gastric pH on absorption of a BCS Class II/IV compound relative to the QTPP, prior to first in human studies. Higher gastric pH reduced bioavailability, requiring the drug be formulated in such a way that mitigates pH sensitivity [44]. Since gastric pH is a common source of difference between special populations, this case study provides an example of how a drug may be formulated to accommodate these differences.…”

“…In another study, the optimal drug release rate of a BCS Class II drug from a controlled release tablet was identified to maintain a specified plasma concentration 24 hours after administration and ensure C max did not exceed a given value. An immediate release formulation led to high C max , adverse side effects, and low concentration after 24 hrs whereas controlled release formulations were able to meet this criteria [44]. This example can be used to understand how controlled-release formulations may be adjusted to maintain the desired drug plasma concentration within the therapeutic window of a given population.…”