title: 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 sulfobutylether(7)-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 β-CD 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.
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Mannila
authors.forename: Julia
authors.initials: J
authors.lastname: Morizzi
authors.forename: Thuy Tien
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Michelle P
authors.initials: MP
authors.lastname: McIntosh
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005079:Excipients / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D006571:Heterocyclic Compounds / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D007275:Injections, Intravenous; D008024:Ligands; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013678:Technology, Pharmaceutical / Q000379:methods; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C503429:1,2,4-trioxane; D005079:Excipients; D006571:Heterocyclic Compounds; D008024:Ligands; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin