Probing a Potential In Vivo Drug–Excipient Interaction: Temporal Effects of a Modified β-Cyclodextrin on the Intravenous Pharmacokinetics of a Model High-Affinity Drug Ligand

ABSTRACT:The investigational synthetic ozonide, OZ209, has previously been shown to have high binding affinity for sulfobutylether7–β-cyclodextrin [(SBE)7–β-CD] resulting in altered pharmacokinetics when administered intravenously to rats in a (SBE)7–β-CD aqueous formulation. In the present study, OZ209 and (SBE)7–β-CD have been used to probe whether a modified βCD excipient, on systemic administration, can bind to and alter the pharmacokinetics of a coadministered drug. When (SBE)7–β-CD was administered 60 min after OZ209, a spike in the concentration of OZ209 in blood and plasma was detected within 2 min of the (SBE)7–β-CD infusion, and this was accompanied by a temporary decrease in the whole blood-to-plasma partitioning ratio of OZ209, the duration of which was dependent upon the dose of (SBE)7–β-CD. Administration of (SBE)7–β-CD also resulted in increased urinary excretion of OZ209. By contrast, administration of (SBE)7–β-CD 4 h prior to OZ209 had no pronounced effect on the blood or plasma pharmacokinetics of OZ209, consistent with the (SBE)7–β-CD having been largely eliminated prior to the administration of OZ209. This study is the first to demonstrate an in vivo drug–excipient interaction between a modified β-CD and a coadministered drug, and also demonstrates that such an interaction can be avoided through appropriate consideration of CD pharmacokinetics. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3381–3389, 2012