Correlating in Vitro Solubilization and Supersaturation Profiles with in Vivo Exposure for Lipid Based Formulations of the CETP Inhibitor CP-532,623.

  title={Correlating in Vitro Solubilization and Supersaturation Profiles with in Vivo Exposure for Lipid Based Formulations of the CETP Inhibitor CP-532,623.},
  author={Claire L. McEvoy and Natalie L. Trevaskis and O. Feeney and G. Edwards and M. Perlman and C. Ambler and C. J. Porter},
  journal={Molecular pharmaceutics},
  volume={14 12},
Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro… Expand
Effects of Lipid Digestion and Drug Permeation/Re-Dissolution on Absorption of Orally Administered Ritonavir as Different Lipid-Based Formulations.
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Interaction with biliary and pancreatic fluids drives supersaturation and drug absorption from lipid-based formulations of low (saquinavir) and high (fenofibrate) permeability poorly soluble drugs.
The data show that rapid dilution of LBFs with biliary and pancreatic secretions at the absorptive site in the upper small intestine drives transient supersaturation, that supersaturation is a significant driver of drug absorption for both low and high permeability drugs, and that PPIs delay drug precipitation, enhance supersaturation and promote drug absorption in a drug and formulation specific manner. Expand
Drug supersaturation during formulation digestion, including real-time analytical approaches.
  • M. Kuentz
  • Computer Science, Medicine
  • Advanced drug delivery reviews
  • 2018
A main focus is mechanisms by which supersaturation is triggered from gastro-intestinal processes, as well as analytical techniques that are promising from a research and development perspective, which lays the groundwork for better in vitro to in vivo correlations. Expand
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Current Status of Supersaturable Self-Emulsifying Drug Delivery Systems
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Effects of Hydrophilic Carriers on Structural Transitions and In Vitro Properties of Solid Self-Microemulsifying Drug Delivery Systems
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In vitro-in vivo evaluation of lipid based formulations of the CETP inhibitors CP-529,414 (torcetrapib) and CP-532,623.
The data suggest that for highly lipophilic drugs such as CP-532,623 in vitro digestion data may be a conservative in vitro indicator of utility and that good exposure may be evident even for formulations that result in significant drug precipitation during in vivo digestion. Expand
Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine.
The potential utility of in vitro digestion models to assess and rank order the in vivo performance of lipid solution and suspension formulations of poorly water-soluble drugs such as Hf is demonstrated. Expand
Toward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 3: Understanding Supersaturation Versus Precipitation Potential During the In Vitro Digestion of Type I, II, IIIA, IIIB and IV Lipid-Based Formulations
The maximum supersaturation ratio (SRM) provides an indication of the supersaturation ‘pressure’ exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro and may also prove effective in discriminating the in vivo performance of LBFs. Expand
A new in vitro lipid digestion – in vivo absorption model to evaluate the mechanisms of drug absorption from lipid-based formulations
Drug absorption for rapidly absorbed drugs such as fenofibrate may occur even when drug precipitation is apparent during in vitro digestion, suggesting simple in vitro lipid digestion models may underestimate the potential for absorption from LBFs. Expand
Rapid determination of drug solubilization versus supersaturation in natural and digested lipids.
A simple equilibrium approach based on solubility in lipids and their corresponding digestion media to estimate a maximum drug supersaturation ratio (SRmax) provides an early risk assessment of drug precipitation for LBFs. Expand
Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion.
Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M) attained on initiation of digestion, which may prove to be an effective tool in discriminating between LBFs based on performance. Expand
Biopharmaceutical Modeling of Drug Supersaturation During Lipid-Based Formulation Digestion Considering an Absorption Sink
Biopharmaceutical modeling is a valuable approach for predicting LBFs performance in vivo in the absence of in vitro tools simulating absorptive conditions, and modeling strategies should be further considered. Expand
Increasing the Proportional Content of Surfactant (Cremophor EL) Relative to Lipid in Self-emulsifying Lipid-based Formulations of Danazol Reduces Oral Bioavailability in Beagle Dogs
A rank-order correlation was observed between the patterns of solubilisation obtained during in vitro digestion and the in vivo performance of self-emulsifying formulations of danazol. Expand
Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems.
The data suggest that digestion acts as a "trigger" for enhanced supersaturation and that solubilization/precipitation behavior is correlated with the degree of supersaturation on dispersion (S(M)DISP) or digestion (S (M)DIGEST). Expand
Susceptibility to Lipase-Mediated Digestion Reduces the Oral Bioavailability of Danazol After Administration as a Medium-Chain Lipid-Based Microemulsion Formulation
In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations, and Digestion of microemulsion preconcentrate formulations based on medium- Chain lipids may limit in vivo utility whenCompared with similar formulations based with long chain lipids. Expand