Kuentz, Martin

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Kuentz
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Martin
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Kuentz, Martin

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2019 - 201912020 - 20212
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Autor:in: Koehl, Niklas × Thema: lipid based formulation ×

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Gerade angezeigt 1 - 3 von 3
  • Vorschaubild
    Publikation
    In Silico, In Vitro, and In Vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax
    (American Chemical Society, 23.04.2021) Koehl, Niklas; Henze, Laura; Bennett-Lenane, Harriett; Faisal, Waleed; Price, Daniel J.; Holm, Rene; Kuentz, Martin; Griffin, Brendan [in: Molecular Pharmaceutics]
    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.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats
    (Springer, 10.06.2020) Koehl, Niklas; Kuentz, Martin [in: Pharmaceutical Research]
    Conclusion: Chase dosed LBF enhanced the in vivo bioavailability of nilotinib. Long chain lipids showed superior performance compared to medium chain lipids. Chase dosing appeared to prolong the absorption phase of the drug. Therefore, chase dosing of LBF is favourable compared to lipid suspensions for 'brick dust' molecules such as nilotinib. Graphical Abstract The potential of bio-enabling lipid vehicles, administered via chase dosing and lipid suspensions, has been evaluated as an approach to enhance oral bioavailability of nilotinib.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    New Insights into Using Lipid Based Suspensions for 'Brick Dust' Molecules: Case Study of Nilotinib
    (Springer, 22.02.2019) Koehl, Niklas; Kuentz, Martin [in: Pharmaceutical Research]
    PurposeLipid suspensions have been shown to be a suitablebio-enabling formulation approach for highly lipophilic or‘grease ball’drug molecules, but studies on‘brick dust’drugsare lacking. This study explored the utility of lipid suspensionsfor enhancing oral bioavailability of the rather hydrophobicdrug nilotinibin vivoin rats.MethodsFour lipid suspensions were developed containinglong chain triglycerides, medium chain triglyceride, longchain monoglycerides and medium chain monoglyceridesandin vivobioavailability was compared to an aqueous suspen-sion. Additionally,in vitrolipolysis and wettability tests wereconducted.ResultsNilotinib lipid suspensions did not show a bioavail-ability increase compared to an aqueous suspension. The bio-availability was lower for triglyceride suspensions, relative toboth monoglyceride and an aqueous suspension. The longchain monoglyceride displayed a significantly higher bioavail-ability relative to triglycerides.In vitrolipolysis results suggestedentrapment of nilotinib crystals within poorly dispersible tri-glycerides, leading to slower nilotinib release and absorption.This was further supported by higher wettability of nilotinibby lipids.ConclusionMonoglycerides improved oral bioavailability ofnilotinib in rats, relative to triglycerides. For‘brick dust’drugsformulated as lipid suspensions, poorly dispersible formula-tions may delay the release of drug crystals from the formula-tion leading to reduced absorption.
    01A - Beitrag in wissenschaftlicher Zeitschrift