title: Single-dose pharmacokinetics of 2 or 3 tablets of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) under fed and fasted conditions: two randomized open-label trials.
abstract: BACKGROUND
  Biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) 7.5/325-mg tablets are formulated with gastroretentive ER drug delivery technology that has been associated with clinically meaningful food effects in other approved products. Two phase 1 studies evaluated potential effects of food on single-dose pharmacokinetics of IR/ER HB/APAP tablets.
  
  
  METHODS
  These were single-center, open-label, randomized, single-dose, 3-period crossover studies in healthy volunteers (aged 18-55 years). IR/ER HB/APAP was administered as a single 2-tablet dose (study 1) or 3-tablet dose (study 2) under fed (high- and low-fat) and fasted conditions. Area under the plasma concentration-time curve from 0 h to time t (AUC0-t) and from time 0 extrapolated to infinity (AUC0-inf) and maximum observed plasma concentration (Cmax) of hydrocodone and APAP under fed versus fasted conditions were compared using analysis of variance. A 90% confidence interval of the geometric least squares mean ratio fully contained within 80 to 125 % indicated no treatment difference. Safety and tolerability were assessed.
  
  
  RESULTS
  Forty of 48 participants in study 1 and 21 of 30 in study 2 completed all treatments. In both studies, under fed (high- or low-fat meal) versus fasted conditions, 90% CIs for AUC0-t and AUC0-inf for both hydrocodone and APAP were entirely contained within the bioequivalent range (80-125%), indicating that high- and low-fat meals did not affect the extent of exposure. In both studies, a high-fat meal did not affect the Cmax for hydrocodone. Hydrocodone Cmax was not affected by a low-fat meal in study 1 but increased by approximately 19% in study 2. A high-fat meal decreased APAP Cmax by approximately 20 % (study 1) and 13 % (study 2); a low-fat meal decreased APAP Cmax by 22% (study 1) and 21% (study 2). Approximately 50% of participants in both studies reported ≥1 treatment-emergent adverse event (TEAE), with no notable difference based on food intake. There were no serious or severe AEs. The most common TEAEs were nausea, vomiting, and dizziness.
  
  
  CONCLUSIONS
  Pharmacokinetic and safety findings were similar regardless of food intake. TEAEs were consistent with those reported with low-dose combination opioids. IR/ER HB/APAP can be administered without regard to food.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02561650 and NCT02561741 .
authors.affiliation: Department of Clinical Pharmacology, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA. krishna.devarakonda@mallinckrodt.com.|Department of Clinical Pharmacology, Mallinckrodt Inc., 675 James S. McDonnell Blvd, Hazelwood, MO, 63042, USA. krishna.devarakonda@mallinckrodt.com.
authors.forename: Krishna
authors.initials: K
authors.lastname: Devarakonda
authors.affiliation: Independent Pharmaceuticals Professional, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA. kenneth.kostenbader@mallinckrodt.com.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kostenbader
authors.affiliation: Research and Development, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA. michael.giuliani@mallinckrodt.com.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Giuliani
authors.affiliation: Clinical Affairs and Program Management, Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA. jim.young@mallinckrodt.com.
authors.forename: Jim L
authors.initials: JL
authors.lastname: Young
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000493:pharmacokinetics*; D004435:Eating; D005215:Fasting; D005260:Female; D006261:Headache / Q000139:chemically induced; D064368:Healthy Volunteers; D006801:Humans; D006853:Hydrocodone / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009294:Narcotics / Q000009:adverse effects / Q000493:pharmacokinetics; D009325:Nausea / Q000139:chemically induced; D013607:Tablets; D055815:Young Adult
chemical_list: D018712:Analgesics, Non-Narcotic; D003692:Delayed-Action Preparations; D009294:Narcotics; D013607:Tablets; D000082:Acetaminophen; D006853:Hydrocodone