title: Development of level A, B and C in vitro-in vivo correlations for modified-release levosimendan capsules.
abstract: The aim of this study was to investigate the possibility of developing different levels of correlation between in vitro release and in vivo absorption rate for four modified-release levosimendan capsule formulations. Differences and similarities in the in vitro dissolution curves were compared with pharmacokinetic parameters describing absorption rate. Formulations F, G, H and I differed in the amounts of the delaying excipients alginic acid and HPMC. In vitro release rate was studied by the USP basket method using the following conditions: pH 5.8 or 7.4 and a rotation speed of 50 or 100 rpm. In vivo bioavailability was tested in nine healthy male volunteers and the fractions absorbed were calculated by the Wagner-Nelson method. Dissolution conditions pH 5.8 and a rotation speed of 100 rpm predicted best the similarities and differences in absorption rates among different formulations, and levels C and B correlation coefficients were 0.85 and 0.97, respectively. For formulation H level A correlation (r=0.997) was found when in vitro lag time was 0.2 h and time scale factor 1.9. This study indicated that dissolution tests developed can be used as a surrogate for human bioequivalence studies, for development processes of final commercial products, to ensure batch to batch bioequivalence and in the future in possible scale-up and post approval change cases for modified-release levosimendan formulation H.
authors.affiliation: Orion Pharma, PO Box 65, FIN-02101, Espoo, Finland. hanna.kortejavi@orionpharma.com
authors.forename: H
authors.initials: H
authors.lastname: Kortejärvi
authors.forename: J
authors.initials: J
authors.lastname: Mikkola
authors.forename: M
authors.initials: M
authors.lastname: Bäckman
authors.forename: S
authors.initials: S
authors.lastname: Antila
authors.forename: M
authors.initials: M
authors.lastname: Marvola
mesh_terms: D000328:Adult; D000465:Algorithms; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D005079:Excipients; D005260:Female; D005780:Gelatin; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D008297:Male; D008954:Models, Biological; D011724:Pyridazines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D000077464:Simendan; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013810:Therapeutic Equivalency
chemical_list: D000889:Anti-Arrhythmia Agents; D002214:Capsules; D003692:Delayed-Action Preparations; D005079:Excipients; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan; D005780:Gelatin