In silico, in vitro, and in vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax

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Koehl, Niklas J.
Henze, Laura J.
Bennett-Lenane, Harriet
Faisal, Waleed
Price, Daniel J.
Holm, René
Kuentz, Martin
Griffin, Brendan T.
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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.
Precipitation inhibitor , Lipid based formulation , Venetoclax , SEDDS , SNEDDS , SMEDDS , Lipid suspension , Polymers , Super-SNEDDS , Supersaturation , Super-SMEDDS , Supersaturating drug delivery systems
Koehl, N.J., Henze, L. J., Bennett-Lenane, H., Faisal, W., Price, D. J., Holm, R., Kuentz, M. and Griffin, B. T. (2021) 'In silico, in vitro, and in vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax', Molecular Pharmaceutics, 18(6), pp. 2174-2188. doi: 10.1021/acs.molpharmaceut.0c00645
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