title: The effect of food on the high clearance drug asenapine after sublingual administration to healthy male volunteers.
abstract: OBJECTIVE
  To determine the effects of food on the pharmacokinetics of sublingual asenapine.
  
  
  METHODS
  Healthy male volunteers (n=26, age 19-53 years) randomly received a single sublingual dose of asenapine 5 mg after ≥ 10 h fasting (Treatment A, reference), after a high-fat meal (Treatment B) and after ≥ 10 h fasting with a high-fat meal at 4 h post-dose (Treatment C). Blood samples were drawn over 72 h to measure asenapine plasma concentrations. Effects of food intake on asenapine pharmacokinetics were assessed using bioequivalence criteria and evaluated using a compartmental modelling analysis.
  
  
  RESULTS
  Compared with the reference, mean asenapine exposure (AUC0-last and AUC0-∞) was approximately 20 % lower after intake of a high-fat meal prior to dosing, whereas Cmax decreased by only about 10 %. When a high-fat meal was taken 4 h post-dose in the fasting state, asenapine concentrations were similar to the reference during the first 4 h post-dose. After the meal intake, asenapine concentrations decreased quickly for several hours. Compartmental modelling indicated that a transient 2.5-fold increase in asenapine clearance after eating could explain the asenapine concentration-time profiles for both food regimens.
  
  
  CONCLUSIONS
  To our knowledge, this is the first study investigating the effect of food upon the sublingual administration of a drug. A high-fat meal taken before or 4 h post-dose of sublingual asenapine indirectly caused a transient increase in liver blood flow that resulted in a temporal increase in asenapine clearance. As the effects on asenapine exposure were small and not clinically relevant, no additional restrictions are required for the timing of food intake in relation to asenapine dosing.
authors.affiliation: Early Stage Development, Merck Sharp & Dohme, PO Box 20, 5340 BH, Oss, The Netherlands, peter.dogterom@merck.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Dogterom
authors.forename: Rik
authors.initials: R
authors.lastname: de Greef
authors.forename: Pierre A M
authors.initials: PA
authors.lastname: Peeters
mesh_terms: D000286:Administration, Sublingual; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003986:Dibenzocycloheptenes; D004041:Dietary Fats / Q000008:administration & dosage*; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D004041:Dietary Fats; D006576:Heterocyclic Compounds, 4 or More Rings; C522667:asenapine