Intravenous administration of poorly soluble new drug entities in early drug discovery: the potential impact of formulation on pharmacokinetic parameters.
Currently, in early drug discovery, compounds that are formulated for first-animal experiments are increasingly characterized as being lipophilic and poorly water-soluble. Typical examples of intravenous formulations for these compounds include aqueous solutions at non-physiologically high or low pH, co-solvent solutions, solutions in cyclodextrins (CDs), surfactant-based solutions, mixed micellar solutions, parenteral fat emulsions or nano- and microsuspensions. Experiments designed to determine the intrinsic pharmacokinetic behavior of a new drug entity (NDE) are complicated as, depending upon the formulation, disposition in the organism can be affected. This may be due to slow or incomplete dissolution of injected particles, precipitation in the bloodstream, delayed release from the dosing vehicle, competition between compound and formulation ingredients for transport and metabolism mechanisms, or altered binding to blood components. The most important determinant for the successful development of a 'non-interfering' dosing vehicle is the required dose. Provided the analytical technique used to determine drug concentration in the body is sensitive enough to allow compound administration at low doses, screening formulations at comparatively low concentrations may be feasible. In this way, formulation approaches that may potentially impact the pharmacokinetic behavior of the compound of interest can be avoided.
Bittner
Beate
B
F Hoffmann-La Roche Ltd, Pharmaceuticals Division, DMPK Discovery Support, CH-4070, Basel, Switzerland. beate.bittner@roche.com
Mountfield
Richard J
RJ
D000465:Algorithms; D004339:Drug Compounding; D004655:Emulsions; D005079:Excipients; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008823:Micelles; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D010599:Pharmacokinetics; D012995:Solubility; D012997:Solvents; D013501:Surface-Active Agents
D004655:Emulsions; D005079:Excipients; D008823:Micelles; D004364:Pharmaceutical Preparations; D012997:Solvents; D013501:Surface-Active Agents