In Silico, In Vitro, and In Vivo Evaluation of Precipitation Inhibitors in Supersaturated Lipid-Based Formulations of Venetoclax.

Niklas J Koehl,Martin Kuentz,Daniel J Price,Harriet Bennett-Lenane,René Holm,Waleed Faisal,Brendan T Griffin,Laura J Henze

doi:10.1021/acs.molpharmaceut.0c00645

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.

Highlights

Favorable solubility in gastrointestinal fluids and intestinal permeability is a prerequisite for the high oral bioavailability of any drug
Drug discovery approaches such as high throughput screenings, modifications during lead optimization, as well as the noticeable therapeutic target shift toward intracellular targets deliver more drugs, displaying low aqueous solubility and beyond rule-of-five properties.[1−3] These drug candidates have sub-optimal biopharmaceutical properties, which typically create a need for bioenabling formulation approaches
For drugs with a low aqueous solubility, a high lipophilicity and/or bioavailability that is increased by the coingestion of fatty meals, lipid-based formulations (LBF) can offer particular formulation advantages.[4−6] The most convenient and conventional LBFs are lipid solutions, where the drug is dissolved in the lipid vehicle and most widely applicable for drugs that show high lipid solubility

Summary

Introduction

Favorable solubility in gastrointestinal fluids and intestinal permeability is a prerequisite for the high oral bioavailability of any drug. Drug discovery approaches such as high throughput screenings, modifications during lead optimization, as well as the noticeable therapeutic target shift toward intracellular targets deliver more drugs, displaying low aqueous solubility and beyond rule-of-five properties.[1−3] These drug candidates have sub-optimal biopharmaceutical properties, which typically create a need for bioenabling formulation approaches. The design of such formulations includes strategies to generate and maintain high concentrations or supersaturation in intraluminal fluids. For drugs which display low solubility in lipid vehicles, strategies to increase dose loading in the lipid vehicles may be required such as lipid suspensions,[7−9] supersaturated LBFs (sLBF),[10−13] lipophilic salts,[14−16] or lipid−hybrid systems.[17−19]

Objectives

Methods

Results

Discussion

Conclusion