The Effects of Dose Volume and Excipient Dose on Luminal Concentration and Oral Drug Absorption
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Mini-Review The Effects of Dose Volume and Excipient Dose on Luminal Concentration and Oral Drug Absorption Bruce J. Aungst1,2
Received 18 May 2020; accepted 17 July 2020 Abstract. Excipient concentrations in the gastrointestinal luminal fluids can influence the absorption of poorly water-soluble drugs when dosed orally with solubilizing excipients, and poorly permeable drugs when dosed with permeation-enhancing excipients. This report examines how dose volume, excipient dose level, volume of water chaser, and gastric fluid volume influence luminal excipient concentrations, and how these could differ from preclinical species and humans. Gastric concentrations of excipient resulting immediately after dosing typical formulations containing a solubilizing excipient are estimated in preclinical species and humans. Examples of the effects of excipient dose and dose volume on drug absorption are illustrated using cases in the literature. When estimating human absorption potential of poorly soluble drug candidates from solubility data, in vitro dissolution models, physiologically based pharmacokinetic models, or preclinical pharmacokinetic data, it may be useful to consider the dose volume and excipient dose, and it is recommended to include estimated luminal excipient concentrations as a factor. There is a need for further studies collecting data on excipient concentrations in luminal fluids and evaluating the effects on drug absorption. KEY WORDS: absorption; dose volume; excipient; solubilization.
INTRODUCTION In preclinical pharmacokinetic studies, oral doses are typically administered as liquids, and poorly water-soluble compounds are given the best chance to demonstrate oral bioavailability when the compound is dosed in solution. Therefore, preclinical studies with poorly water-soluble compounds are commonly performed using solubilizing excipients that may include cosolvents, surfactants, complexing agents, and/or lipid vehicles [1]. Preclinical pharmacokinetic studies, particularly in rodents, often use dose volumes and excipient doses that would be impractical for humans. Dose volume and excipient dose levels influence the excipient concentration and therefore drug solubility in the gastrointestinal lumen, which is a main factor determining the oral bioavailability of poorly water-soluble compounds. As developmental compounds transition from preclinical pharmacokinetic studies to the identification of a formulation for early clinical studies, it is important to understand how dose volume, excipient dose, and the dilution of drug and excipients in the GI lumen could influence oral absorption, so that preclinical assessments of oral absorption are most predictive of humans. The objective of this report is to 1 2
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examine these factors and their possible effects on oral absorption, focusing on potential differences between preclinical species and humans. For poorly soluble compounds, it
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