title: Effect of food intake and co-administration of placebo self-nanoemulsifying drug delivery systems on the absorption of cinnarizine in healthy human volunteers.
abstract: Positive food effects may be observed for low aqueous soluble compounds, these effects could potentially be circumvented using lipid based formulations. However, as all compounds are not chemically stable in lipid based systems, alternative dosage regimes could be investigated to evade the stability issue. The two aims for this present study were therefore; i) to investigate if a nutritional drink, Fresubin Energy®, could induce food effect in humans for the poorly soluble compound cinnarizine; and ii) to investigate if co-administration of a self-nano-emulsifying drug delivery systems (SNEDDS) with a conventional cinnarizine tablet could reduce the observed food-effect. A commercial conventional cinnarizine tablet was dosed to 10 healthy volunteers in a cross-over design in both fasted and fed state, with and without co-administration of a SNEDDS, with a one week wash-out period between dosing. The fed state was induced using a nutritional drink (Fresubin Energy®) and gastric emptying was assessed by administration of paracetamol as a marker. The pharmacokinetic analysis showed that the nutritional drink delayed the uptake and increased the fraction of absorbed cinnarizine, indicative of a food effect on the compound. This was in agreement with a previous dog study and indicates that the nutritional drink can be used for inducing the same level of food effect in humans. Though not statistically significant, the co-administration of SNEDDS exhibited a tendency towards a reduction of the observed food effect and an increased absorption of cinnarizine in the fasted state; based upon the individual ratios, which was not reflected in the mean data. However, the co-administration of SNEEDS in the fasted state, also induce a slower gastric emptying rate, which was observed as a delayed tmax for both cinnarizine and paracetamol.
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: martinlauchristiansen@gmail.com.
authors.forename: Martin Lau
authors.initials: ML
authors.lastname: Christiansen
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark; Pharmaceutical Science and CMC biologics, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
authors.forename: Rene
authors.initials: R
authors.lastname: Holm
authors.affiliation: AstraZeneca R&D, 431 83 Mölndal, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Abrahamsson
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Jette
authors.initials: J
authors.lastname: Jacobsen
authors.affiliation: Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, DK-2300 Copenhagen S.
authors.forename: Jakob
authors.initials: J
authors.lastname: Kristensen
authors.affiliation: University of Copenhagen, Department of Nutrition, Exercise and Sports, Rolighedsvej 30, 1958 Freriksberg, Copenhagen, Denmark.
authors.forename: Jens Rikardt
authors.initials: JR
authors.lastname: Andersen
authors.affiliation: University of Copenhagen, Faculty of Health and Medical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark; Bioneer:FARMA, Department of Pharmacy, University of Copenhagen.
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002936:Cinnarizine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D016503:Drug Delivery Systems; D004655:Emulsions; D005215:Fasting; D018565:Food-Drug Interactions; D005746:Gastric Emptying; D064368:Healthy Volunteers; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D013607:Tablets; D055815:Young Adult
chemical_list: D002121:Calcium Channel Blockers; D004655:Emulsions; D006634:Histamine H1 Antagonists; D013607:Tablets; D002936:Cinnarizine
keywords: Cinnarizine; Enabling formulations; Food effect; Humans; Low soluble compounds; Oral absorption; SNEDDS