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Related Concept Videos

Factors Influencing Drug Absorption: Physicochemical Parameters01:22

Factors Influencing Drug Absorption: Physicochemical Parameters

The physicochemical characteristics of drugs play a crucial role in formulating stable and bioavailable drug products. The solubility of a drug, governed by the varying pH along the GI tract and its dissociation constant (pKa), is pivotal in determining its ionization state and absorption rate. Notably, weak acids and bases remain unionized and are absorbed more rapidly.
Enhanced drug absorption can be achieved by reducing particle sizes and increasing surface areas, thereby facilitating...
Drug Absorption: Factors Affecting GI Absorption01:19

Drug Absorption: Factors Affecting GI Absorption

The process of oral drug absorption can be influenced by several factors. Weakly acidic drugs tend to be absorbed more readily from the stomach due to their nonionized state. However, absorption may be less efficient in the upper intestine, where drugs are often ionized. Interestingly, despite the stomach's apparent advantage for drug absorption, its mucous layer can hinder diffusion. Its surface area is also smaller than the intestine's, which can further slow down the absorption rate.
In...
Methods for Studying Drug Absorption: In situ01:09

Methods for Studying Drug Absorption: In situ

In situ experiments, such as the Doluisio method and Single-Pass Perfusion technique, provide critical insights into drug uptake by simulating in vivo conditions for drug absorption.
The Doluisio method involves perfusing a prepared segment of a rat's small intestine with a solution of radiolabeled drug and a non-absorbable marker. This helps to differentiate between absorbed and non-absorbed drug concentrations. The intestinal segment is connected at both ends using tubing and syringes,...
Factors Affecting Dissolution: Drug pKa, Lipophilicity and GI pH01:21

Factors Affecting Dissolution: Drug pKa, Lipophilicity and GI pH

Drug absorption within the gastrointestinal (GI) tract is a complex process influenced by several critical factors, including the site pH, the drug's dissociation constant (pKa), and the drug's lipophilicity. The GI tract exhibits a pH gradient, with an acidic environment in the stomach and a more alkaline environment in the small intestine. This pH variation directly affects the ionization state of drugs.
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles in drug...
Methods for Studying Drug Absorption: In vitro01:16

Methods for Studying Drug Absorption: In vitro

In vitro experiments are crucial for understanding the transport and absorption of drugs through biological materials. These studies employ varied methods such as the diffusion cell method, the everted sac technique, and the everted ring technique.
The diffusion cell method uses a two-compartment cell, including a donor compartment with the drug solution, which simulates the environment where the drug is applied, and a receptor compartment with a buffer solution, which simulates the environment...
Factors Influencing Drug Absorption: Anatomical Parameters01:23

Factors Influencing Drug Absorption: Anatomical Parameters

Drug absorption involves the movement of drugs from the point of administration into the systemic circulation. Initially, Gastrointestinal (GI) motility propels the drug through the digestive tract and into the stomach. However, the stomach's high acidity and limited surface area restrict its role in drug absorption for most drugs. The drug then moves from the stomach to the small intestine via gastric emptying, which can be slowed by various factors, including interactions with other...

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Using absorption simulation and gastric pH modulated dog model for formulation development to overcome achlorhydria

Amitava Mitra1, Filippos Kesisoglou, Martyn Beauchamp

  • 1Biopharmaceutics, Product Value Enhancement, Pharmaceutical Sciences and Clinical Supply, Merck Sharp & Dohme Corp., West Point, Pennsylvania, United States. amitava_mitra@merck.com

Molecular Pharmaceutics
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Summary

Developing a new drug formulation successfully overcomes reduced drug absorption in patients with low stomach acidity. This ensures therapeutic efficacy by maintaining adequate drug exposure, even with proton pump inhibitor use.

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Area of Science:

  • Pharmaceutical Sciences
  • Drug Delivery
  • Pharmacokinetics

Background:

  • Reduced gastric acidity (achlorhydria) impairs the absorption of weakly basic drugs, potentially leading to therapeutic failure.
  • Drug solubility is often pH-dependent, with many weakly basic compounds exhibiting poor solubility at higher gastric pH levels.
  • Achieving adequate drug exposure in patients with achlorhydria requires specialized formulation strategies.

Purpose of the Study:

  • To develop and characterize a robust formulation for a weakly basic drug (Compound A) that ensures adequate systemic exposure in patients with reduced gastric acidity.
  • To evaluate the bioperformance of various formulations under simulated achlorhydric conditions using in vitro and in vivo models.
  • To establish and validate predictive models for translating preclinical data to human pharmacokinetics.

Main Methods:

  • Formulation development of Compound A, including strategies with and without acidifiers.
  • In vitro dissolution testing and biopharmaceutical assessment in a gastric pH-modified dog model.
  • Development and validation of dissolution-based absorption models using clinical and preclinical data, including proton pump inhibitor (PPI) interaction studies.

Main Results:

  • A citric acid-based formulation (F2) demonstrated robust performance in overcoming pH-dependent solubility challenges.
  • In vitro, in silico, and in vivo (IVISIV) data predicted successful formulation performance in achlorhydric conditions.
  • Human pharmacokinetic studies confirmed that Formulation F2 provided comparable drug exposure with and without PPI co-administration, indicating successful mitigation of achlorhydria effects.

Conclusions:

  • A citric acid-based formulation (F2) effectively overcomes the challenges of impaired drug absorption in patients with reduced gastric acidity.
  • The integrated use of in vitro, in silico, and in vivo (IVISIV) tools is a valuable strategy for developing formulations to manage achlorhydria.
  • The developed formulation ensures consistent therapeutic efficacy by achieving adequate drug exposure in patients with high gastric pH.