title: Sex- and smoke-related differences in gastrointestinal transit of cyclosporin A microemulsion capsules.
abstract: The aim of this work was to study the effect of the sex and the smoking status on the pharmacokinetics and the bioequivalence assessment of a branded and a generic cyclosporine A microemulsion formulation in soft-gelatin capsule. Sixteen healthy volunteers (eight women and eight men) participated in a CyA bioequivalence study, with nine of the volunteers being smokers. Sandimmun Neoral® (brand formulation; Reference) and Sigmasporin Microral® (generic formulation; Test) were administered under fasting conditions. Pharmacokinetic parameters were calculated through non compartmental analysis. Bioequivalence was declared based on the 90% confidence intervals (90% CI) for the T/R ratio of the geometric means for each parameter. In vitro determination of the capsules opening time was performed in simulated gastric fluid without enzyme with USP Apparatus 2. The extent of absorption was similar between both products for all subjects or each sex-group. The absorption rate was similar for both products when considering all subjects, whereas a significant difference in the TMAX between the two products was observed for the male subjects only, which relates to its slower capsule opening time observed in vitro (12.4 versus 6.0 min). No differences were observed in women that could relate to their slower gastric emptying. Differences in drug exposure were observed between smokers and non-smokers. Sex- and smoke-related differences in the gastrointestinal transit should be considered when the on-set time would be determinant for the treatment success of a drug.
authors: Department of Pharmaceutical Sciences - Faculty of Chemistry, Bioavailability and Bioequivalence Center for Medicine Evaluation, Universidad de la República, Uruguay. Electronic address: pfagioli@fq.edu.uy.
authors: Pietro
authors: P
authors: Fagiolino
authors: Department of Pharmaceutical Sciences - Faculty of Chemistry, Bioavailability and Bioequivalence Center for Medicine Evaluation, Universidad de la República, Uruguay.
authors: Marta
authors: M
authors: Vázquez
authors: Department of Pharmaceutical Sciences - Faculty of Chemistry, Bioavailability and Bioequivalence Center for Medicine Evaluation, Universidad de la República, Uruguay.
authors: Manuel
authors: M
authors: Ibarra
authors: Department of Pharmaceutical Sciences - Faculty of Chemistry, Bioavailability and Bioequivalence Center for Medicine Evaluation, Universidad de la República, Uruguay.
authors: Laura
authors: L
authors: Magallanes
authors: Department of Pharmaceutical Sciences - Faculty of Chemistry, Bioavailability and Bioequivalence Center for Medicine Evaluation, Universidad de la República, Uruguay.
authors: Natalia
authors: N
authors: Guevara
authors: Department of Pharmacy and Pharmacology, Faculty of Science, University of Bath, United Kingdom.
authors: Nikoletta
authors: N
authors: Fotaki
mesh_terms: D065567:Absorption, Physiological; D000293:Adolescent; D000328:Adult; D002214:Capsules; D016572:Cyclosporine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004655:Emulsions; D005260:Female; D005746:Gastric Emptying; D005772:Gastrointestinal Transit; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D012727:Sex Characteristics; D012737:Sex Factors; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000378:metabolism*; D013810:Therapeutic Equivalency; D013997:Time Factors; D055815:Young Adult
chemical_list: D002214:Capsules; D004655:Emulsions; D012906:Smoke; D016572:Cyclosporine
keywords: Bioequivalence; Cyclosporine; Gastrointestinal transit; Microemulsion; Sex; Smoking