title: A heuristic model to quantify the impact of excess cyclodextrin on oral drug absorption from aqueous solution.
abstract: The intestinal drug solubilising capacity (Dtot(SC)) of a drug formulated as an aqueous cyclodextrin solution is a recently proposed quantity to predict the cyclodextrin concentration needed to fully solubilise the drug in the intestinal lumen. According to this concept, the cyclodextrin concentration in the drug product must be higher than the amount needed to solubilise the compound, due to the displacement of the drug from the cyclodextrin cavity by bile salts in the intestinal lumen. On the other hand, dosing cyclodextrin at >Dtot(SC) is expected to result in decreased free intestinal drug concentrations and thus potentially a lower fraction absorbed. In this study, data from three previous in vivo studies in rats with fixed concentrations of three compounds (danazol, cinnarizine and benzo[A]pyrene) and various cyclodextrin concentrations >Dtot(SC) were analysed. The model was developed for danazol and applied to the two other compounds. Absorption, as quantified from the area under the plasma concentration-time profile, was predicted by the model to decrease at elevated concentrations of co-administered cyclodextrin in accordance with the in vivo data. In addition, at high cyclodextrin concentrations a delay in Tmax and a decrease in Cmax were predicted, again in accordance with the experimental observations. These observations were rationalised in terms of the free intestinal drug concentration by a chemical equilibrium model for Dtot(SC). This model depends on the quantity termed the dimensionless dose concentration, Dtot(∗)=Do/Pn, given as the fraction of the permeation number (Pn) and dose number (Do). The model provides the formulation scientist with a critical quality attribute for assessing the implication of having excess cyclodextrin in an oral solution.
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark; NSM, Research Unit for Functional Biomaterials, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
authors.forename: Niels Erik
authors.initials: NE
authors.lastname: Olesen
authors.affiliation: NSM, Research Unit for Functional Biomaterials, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Westh
authors.affiliation: Pharmaceutical Science and CMC Biologics, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: rhol@lundbeck.com.
authors.forename: René
authors.initials: R
authors.lastname: Holm
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002936:Cinnarizine / Q000737:chemistry; D003505:Cyclodextrins / Q000737:chemistry*; D003613:Danazol / Q000737:chemistry; D000066506:Heuristics; D007408:Intestinal Absorption; D051381:Rats; D012995:Solubility; D012996:Solutions / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D003505:Cyclodextrins; D012996:Solutions; D014867:Water; D002936:Cinnarizine; D003613:Danazol
keywords: Cyclodextrins; Fraction absorbed; Modelling; Oral absorption; Pharmacokinetics; Rats; Risk analysis