title: Bioequivalence of a New Oral Levosulpiride Formulation Compared With a Standard One in Healthy Volunteers.
abstract: A monocentric, single-dose, open-label, 2-way, crossover randomized study was conducted by the San Matteo Phase I Clinical Trial Unit and Experimental Therapy (Pavia, Italy) to assess the bioequivalence and the systemic tolerability of a new oral formulation of levosulpiride (tablet 25 mg: test) versus a commercially available formulation on the Italian market (tablet 25 mg: reference).
  
  
  
  Thirty-five healthy adult volunteers, men (n = 19) and women (n = 16), aged between 18 and 55 years were screened and 32 of them were enrolled in the study. After having signed the written informed consent, each subject received a single oral dose of Test or Reference product with 250 mL of natural mineral water, in fasting conditions, interspersed with a 6-day washout period Blood samples were collected up to 36 hours after drug administration: the drug plasma levels were determined by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The pharmacokinetic parameters included peak plasma concentration (Cmax), time corresponding to Cmax (tmax), area under the plasma concentration-time curve from zero to infinity (AUC0-∞) or to the last sampling time assessment (AUC0-36), the elimination rate constant (ke), and the terminal half-life (t1/2). Safety was measured by pre- and post-treatment specific biochemical investigations, physical examination, electrocardiogram, occurrence of adverse events, and any information on patients' withdrawal.
  
  
  
  The geometric mean ratio Test/Reference (90% confidence interval) for levosulpiride was 103.0% (95.8-110.8) for AUC0-36, 103.6% (95.9-111.9) for AUC0-∞, and 104.3% (94.9-114.6) for Cmax. ke and t1/2 were 0.07 (SD: 0.02) and 9 hours (8-12) for both the formulations. Clearance (L/h) was 29.6 (±13.5) and 30.7 (±14.2) for the test and the reference product, respectively.
  
  
  
  Because the acceptance criteria required by the drug regulatory agency (European Medicines Agency, EMA) for bioequivalence prescribe limits of 80%-120% for untransformed data and 80%-125% for "ln" transformed data, we can confirm that the 2 formulations are bioequivalent, in terms of the rate and extent of absorption.
authors.affiliation: *Clinical and Experimental Pharmacokinetics Unit, Fondazione IRCCS Policlinico San Matteo. Dr. Michelini is now with the Eurofins Biolab Srl, Milano, Italy; †San Matteo Phase I Clinical Trial Unit and Experimental Therapy, Fondazione IRCCS Policlinico San Matteo; ‡Biometry and Clinical Epidemiology Unit, Fondazione IRCCS Policlinico San Matteo; and §Department of Respiratory Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: De Gregori
authors.forename: Laura
authors.initials: L
authors.lastname: Cipollina
authors.forename: Annalisa
authors.initials: A
authors.lastname: De Silvestri
authors.forename: Marianna
authors.initials: M
authors.lastname: Ventura
authors.forename: Roberta
authors.initials: R
authors.lastname: Michelini
authors.forename: Monica
authors.initials: M
authors.lastname: Morosini
authors.forename: Michela
authors.initials: M
authors.lastname: Montagna
authors.forename: Carmine
authors.initials: C
authors.lastname: Tinelli
authors.forename: Mario
authors.initials: M
authors.lastname: Regazzi
authors.forename: Mariadelfina
authors.initials: M
authors.lastname: Molinaro
authors.forename: Roberto
authors.initials: R
authors.lastname: Imberti
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D018592:Cross-Over Studies; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D013469:Sulpiride / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D013607:Tablets / Q000008:administration & dosage; D053719:Tandem Mass Spectrometry / Q000379:methods; D013810:Therapeutic Equivalency
chemical_list: D013607:Tablets; D013469:Sulpiride; C078143:levosulpiride