Probing a potential in vivo drug-excipient interaction: Temporal effects of a modified beta-cyclodextrin on the intravenous pharmacokinetics of a model high-affinity drug ligand

Anne Hannele Mannila, Julia Morizzi, Tien Thuy Nguyen, Susan Ann Charman, Michelle Paula McIntosh, David Shackleford

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Abstract

The investigational synthetic ozonide, OZ209, has previously been shown to have high binding affinity for sulfobutylether 7-I?-cyclodextrin [(SBE) 7-I?-CD] resulting in altered pharmacokinetics when administered intravenously to rats in a (SBE) 7-I?-CD aqueous formulation. In the present study, OZ209 and (SBE) 7-I?-CD have been used to probe whether a modified I?-CD excipient, on systemic administration, can bind to and alter the pharmacokinetics of a coadministered drug. When (SBE) 7-I?-CD was administered 60min after OZ209, a spike in the concentration of OZ209 in blood and plasma was detected within 2min of the (SBE) 7-I?-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-I?-CD. Administration of (SBE) 7-I?-CD also resulted in increased urinary excretion of OZ209. By contrast, administration of (SBE) 7-I?-CD 4h prior to OZ209 had no pronounced effect on the blood or plasma pharmacokinetics of OZ209, consistent with the (SBE) 7-I?-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 I?-CD and a coadministered drug, and also demonstrates that such an interaction can be avoided through appropriate consideration of CD pharmacokinetics.
Original languageEnglish
Pages (from-to)3381 - 3389
Number of pages9
JournalJournal of Pharmaceutical Sciences
Volume101
Issue number9
DOIs
Publication statusPublished - 2012

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