In Silico, In Vitro, and In Vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax
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Authors
Koehl, Niklas
Henze, Laura
Bennett-Lenane, Harriett
Faisal, Waleed
Price, Daniel J.
Holm, Rene
Griffin, Brendan
Author (Corporation)
Publication date
23.04.2021
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Type
01A - Journal article
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Parent work
Molecular Pharmaceutics
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Volume
18
Issue / Number
6
Pages / Duration
2174-2188
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Publisher / Publishing institution
American Chemical Society
Place of publication / Event location
Washington
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Abstract
The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico–in vitro–in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug–excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.
Keywords
precipitation inhibitor, lipid based formulation, venetoclax, SEDDS, SNEDDS, SMEDDS, lipid suspension, polymers, super-SNEDDS, supersaturation
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ISBN
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1543-8384
1543-8392
1543-8392
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
Peer review of the complete publication
Open access category
Gold
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Citation
Koehl, N., Henze, L., Bennett-Lenane, H., Faisal, W., Price, D. J., Holm, R., Kuentz, M., & Griffin, B. (2021). In Silico, In Vitro, and In Vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax. Molecular Pharmaceutics, 18(6), 2174–2188. https://doi.org/10.1021/acs.molpharmaceut.0c00645