In vitro–in vivo evaluation of lipid based formulations of the CETP inhibitors CP-529,414 (torcetrapib) and CP-532,623

• We compare the in vitro solubilisation and in vivo exposure of two CEPT inhibitors.
• Digestion of drug loaded SEDDS was simulated using an in vitro digestion model.
• Oral bioavailability was assessed after drug administration in different SEDDS.
• Bioavailability of CETP inhibitors is greatly enhanced by lipid based formulations.
• Nonlinear correlation evident between in vitro solubilisation and in vivo exposure.

The present study investigated the use of lipid based drug delivery systems to enhance the oral bioavailability of the CETP inhibitors CP-532,623 and torcetrapib. A series of self-emulsifying lipid based drug delivery systems (SEDDS) were assembled and examined using an in vitro lipid digestion model to evaluate patterns of drug precipitation under simulated intestinal conditions. Drug exposure after oral administration of the same formulations was subsequently assessed in beagle dogs. CP-532,623 was maintained in a solubilised state during dispersion of most formulations in simulated intestinal fluid, however, solubilisation capacity was reduced to various degrees upon in vitro digestion. Administration of SEDDS formulations to beagle dogs resulted in moderate differences in plasma AUC when compared to the differences in solubilisation observed in vitro. Similar trends were observed for torcetrapib. In all cases, however, in vivo exposure of CP-532,623 was greatly enhanced by administration in lipid based drug delivery systems when compared to a powder formulation. Some correlation between in vitro solubilisation and in vivo drug exposure (AUC) was evident; however, this was not linear. 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 vitro digestion.

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