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. 2022 Oct 7;10(4):299-314.
doi: 10.5599/admet.1476. eCollection 2022.

Food effect risk assessment in preformulation stage using material sparing μFLUX methodology

Corinne Jankovsky  1 , Oksana Tsinman  2 , Naveen K Thakral  1   3
Affiliations

Food effect risk assessment in preformulation stage using material sparing μFLUX methodology

Corinne Jankovsky et al. ADMET DMPK. .

Abstract

The intake of food and meal type can strongly impact the bioavailability of orally administered drugs and can consequently impact drug efficacy and safety. During the early stages of drug development, only a small amount of drug substance is available, and the solubility difference between fasted state simulated intestinal fluid and fed state simulated intestinal fluid may provide an early indication about the probable food effect. But higher drug solubility in fed state simulated intestinal fluid may not always results in an increased oral absorption. In the present research, we demonstrated using 11 model compounds that in addition to the drug dissolution in biorelevant media, the evaluation of the diffusion flux of a drug in solution, across artificial lipid coated membrane, where only the unbound drug crosses the membrane, is a reliable way to predict the food effect. Although, the combination of dissolution and diffusion flux may not reliably predict the food effect in case of drugs undergoing intestinal metabolism or when transporters are involved in the drug absorption, the technique generally provides good information about the food effect at very early stages of drug development that may help in designing a clinical plan by adjusting the drug dose in the fed state.

Keywords: Food effect; bioavailability; biorelevant medium; clinical trial; diffusion; flux; permeability; predictive dissolution; solubility.

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Conflict of interest statement

Conflict of interest: All authors declare that they have no conflicts of interest. Oksana Tsinman is an employee of Pion Inc., maker of the instrument used for the current research. Authors or their institutions have never received payment or services from a third party for any aspect of the submitted work.

Figures

Figure 1.
Figure 1.
Furosemide
Figure 2.
Figure 2.
Appearance kinetic of furosemide in the receiver chambers during μFLUX experiment. The corresponding donor chambers of μFLUX pairs were filled with FaSSIF or FeSSIF media. The flux was higher while using FeSSIF medium.
Figure 3.
Figure 3.
Dissolution kinetic of furosemide in donor compartments of μFLUX pairs.
Figure 4.
Figure 4.
Appearance kinetic of fluoxetine in the receiver chambers during μFLUX experiment at dose equivalent to 200 mg of free base. The corresponding donor chambers of μFLUX pairs were filled with FaSSIF and FaSSIF blank media.
Figure 5.
Figure 5.
Solubility ratio, flux ratio, AUC ratio and Cmax ratio for the studied compounds
See this image and copyright information in PMC

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