Using Absorption Simulation and Gastric pH Modulated Dog Model for Formulation Development To Overcome Achlorhydria Effect

Abstract

Impaired absorption of weakly basic drugs in patients with reduced gastric acidity can lead to loss of efficacy of the therapeutic agent. Hence, a robust formulation which can provide adequate exposure in achlorhydric patients is imperative to achieve the desired efficacy. In this report, formulation development of a weakly basic Merck compound A is described. Compound A shows lower solubility at higher pH and thus is prone to reduced exposure under conditions of achlorhydria, as the compound's solubility increases only in environments of less than pH 2. Several formulations with or without an acidifier were developed and characterized by in vitro dissolution and in gastric pH modified dog model to assess their bioperformance in high gastric pH conditions. To predict the bioperformance of these formulations in humans, a dissolution based absorption model was developed and validated against the observed PPI-interaction data in the clinic and the gastric pH-adjusted dog data. An additional absorption model was developed to allow for incorporation of the dog PK data to provide translation of preclinical to clinical exposure. Based on the in vitro dissolution, in silico absorption modeling and preclinical in vivo data, a citric acid-based formulation (F2) was selected for a human pharmacokinetic study. This study showed that exposures from F2 were not meaningfully different in the presence of proton pump inhibitor (PPI) as compared to non-PPI, thus confirming that the F2 formulation was successful in overcoming the achlorhydria effect. These efforts also highlighted that the complementary use of in vitro/in silico/in vivo (IVISIV) tools may be a helpful strategy in the development of formulations to overcome the achlorhydria effect and achieve adequate exposure in patients with high gastric pH.

Characterization of Supersaturatable Formulations for Improved Absorption of Poorly Soluble Drugs

“…Variability of the stomach pH in human subjects as a result of administering proton pump inhibitor is attributed to cause changes of the level of supersaturation in small intestines, thus resulting in high variability in oral exposure. Similarly, Mitra et al (30) reported that poor absorption of weakly basic drug A in patients with reduced gastric acidity can lead to loss of efficacy of the therapeutic agent. The F1 formulation containing a drug A dosed in beagle dogs under normal (pentagastrin pretreated) and high (famotidine pretreated) gastric pH conditions.…”

IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and overview of results

“…This decision is based on measured in vivo preclinical or in vitro drug efficacy, and predicted human in vivo absorption, first pass intestinal and hepatic extraction, distribution and elimination. It is also used to guide formulation scientists in the first in man (FIM) formulation choice and development, and alert them to possible limitations such as particle size, potential in vivo precipitation or degradation, or permeability limitations, in order to decide on the best formulation strategy and potential impact of certain excipients ( Figure 1) (Willmann et al, 2010;Mitra et al, 2011;Chen et al, 2012).…”

The Use of Modeling Tools to Drive Efficient Oral Product Design

“…Without experimentation to point to the most relevant Tpptn, the modeling exercise is limited to directionally guiding formulation development without truly providing bioperformance understanding. Generating data from mechanistically based biorelevant dynamic pH, in vitro dissolution models like those described in recent publications by Gao et al (12), Bhattachar et al (13), and Mitra et al (16) can be an important step in studying dissolution, supersaturation, and precipitation kinetics for ionizable poorly soluble compounds.…”

“…Recent articles have addressed the in vitro experiment gap by suggesting novel biorelevant methodology to understand the impact of dynamic pH environment on a drugs dissolution profile and its supersaturation potential in the GI lumen (12,13). In pharmaceutics, in silico modeling has been used effectively to assess the need for particle size control and API form comparisons to aid the API AAPS Journal Themed Issue Manuscript-Facilitation oral product development and reducing regulatory burden through novel approaches to assess bioavailability/bioequivalence; based on an AAPS workshop held on October 22-23, 2011. selection process for phase 1 clinical trials (7,(14)(15)(16). The examples illustrate the pharmaceutics-based risk associated with the API and offer insights into the anticipated outcome from clinical studies.…”