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.
Mannila, A. H., Morizzi, J., Nguyen, T. T., Charman, S. A., McIntosh, M. P., & Shackleford, D. (2012). 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. Journal of Pharmaceutical Sciences, 101(9), 3381 - 3389. https://doi.org/10.1002/jps.23177