title: Randomized Comparative Bioavailability of a Novel Three-Dimensional Printed Fast-Melt Formulation of Levetiracetam Following the Administration of a Single 1000-mg Dose to Healthy Human Volunteers Under Fasting and Fed Conditions.
abstract: BACKGROUND
  Rapidly disintegrating or 'fast-melt' oral formulations have been developed recently to facilitate drug intake among patients. Even though these formulations have helped to improve therapy adherence, some of their limitations include: the dissolution time, their facility to be swallowed, and the dosage strengths that may be accommodated. To overcome these limitations, a novel, porous, quickly disintegrating, and easier-to-swallow fast-melt formulation based on powder-liquid, three-dimensional printing (3DP) technology has been developed.
  
  
  OBJECTIVE
  To determine and compare the relative bioavailability of a novel 3DP fast melt containing levetiracetam in healthy male and female subjects.
  
  
  METHODS
  This study included 33 subjects in a three-way crossover design. The 3DP fast-melt formulation was compared against the conventional immediate-release tablet of levetiracetam (Keppra(®)) after a single 1000-mg dose administration under fasting conditions following the bioequivalence criteria used by the US Food and Drug Administration. This study also evaluated the food effect on the bioavailability of the levetiracetam 3DP fast melt. A small sip of liquid was used to administer the fast-melt formulation.
  
  
  RESULTS
  The novel 3DP fast melt showed rapid oral disintegration (mean duration of 11 s from a sip of water to completion of swallowing) following its administration, and did not affect the pharmacokinetic profile of levetiracetam. A lower absorption peak was observed after administration of the 3DP fast melt under fed conditions, as expected. In addition, time of maximum measured plasma concentration was delayed by approximately 3.5 h under fed conditions. These effects are unlikely to be of clinical significance with long-term administration, and may help reduce the adverse events and facilitate compliance. Finally, no change in the oral mucosa was observed with the 3DP fast melt while being as safe and well tolerated as the standard levetiracetam tablet.
  
  
  CONCLUSIONS
  This study quantified the rapid disintegration of the 3DP levetiracetam fast melt and confirmed its equivalent rate and extent of absorption to the conventional immediate-release tablet in the fasted state, using standard bioequivalence criteria.
authors.affiliation: Algorithme Pharma Inc., 575 Blvd. Armand-Frappier, Laval, QC, H7V 4B3, Canada. sboudriau@algopharm.com.
authors.forename: Sophie
authors.identifier: http://orcid.org/0000-0001-8235-0079
authors.initials: S
authors.lastname: Boudriau
authors.affiliation: Algorithme Pharma Inc., 575 Blvd. Armand-Frappier, Laval, QC, H7V 4B3, Canada.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Hanzel
authors.affiliation: Algorithme Pharma Inc., 575 Blvd. Armand-Frappier, Laval, QC, H7V 4B3, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Massicotte
authors.affiliation: Algorithme Pharma Inc., 575 Blvd. Armand-Frappier, Laval, QC, H7V 4B3, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Sayegh
authors.affiliation: Algorithme Pharma Inc., 575 Blvd. Armand-Frappier, Laval, QC, H7V 4B3, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Algorithme Pharma Inc., 575 Blvd. Armand-Frappier, Laval, QC, H7V 4B3, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Lefebvre
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004339:Drug Compounding / Q000379:methods*; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000652:urine; D066330:Printing, Three-Dimensional; D013607:Tablets; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D013607:Tablets; D000077287:Levetiracetam; D010889:Piracetam