title: Effect of food on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended release formulation of oxycodone with sequestered naltrexone.
abstract: ALO-02 is being developed as an abuse-deterrent formulation of extended-release oxycodone hydrochloride with naltrexone hydrochloride sequestered in the core of pellets contained in capsules. The primary objective of this study was to assess the effects of administration of ALO-02 capsule whole under fed conditions or sprinkling the pellets from ALO-02 capsule on applesauce under fasting conditions on the pharmacokinetics (PK) of oxycodone, naltrexone and 6-ß-naltrexol compared with ALO-02 capsule administered whole under fasting conditions. The plasma naltrexone and 6-ß-naltrexol concentrations were used to assess the sequestration of naltrexone in the ALO-02 formulation. The secondary objective was to evaluate the safety and tolerability of single 40 mg doses of ALO-02 in healthy volunteers.
  
  
  
  This was an IRB-approved, open-label, single-dose, randomized, 3-period crossover study in 24 healthy adult volunteers, aged 18-55 years. Each subject was assigned to receive single 40 mg doses of ALO-02 administered whole (intact capsule) under fasting conditions, administered whole under fed conditions (high-fat breakfast ∼ 950 calories), or sprinkling the contents of the ALO-02 capsule (pellets) over applesauce and swallowing the dose without chewing under fasting conditions. Each treatment was separated by a 7-day washout interval. Plasma samples were analyzed just before dosing through 48 hours postdose for oxycodone, and through 120 hours postdose for naltrexone and its major metabolite, 6-ß-naltrexol. Pharmacokinetic parameters included maximum plasma concentration [Cmax ], area under the plasma concentration-time profile from time 0 to infinity [AUCinf ] and to the last quantifiable concentration [AUClast ], time to Cmax [Tmax ], and terminal half life [t1/2 ]. Adverse events, vital signs, and laboratory parameters were monitored for safety assessment.
  
  
  
  The t1/2 and Tmax values for oxycodone were similar for all 3 treatments. There was a lack of effect of food (whole capsule, fed vs. fasted) or of sprinkling on applesauce (pellets vs. whole capsule, fasted) on oxycodone bioavailability. The Test/Reference ratios of adjusted geometric means for oxycodone AUCinf , AUClast , and Cmax were 99.2%, 100%, and 107%, respectively, for the effect of food; and 101%, 101%, and 97.5%, respectively, for the effect of sprinkling on applesauce. The 90% confidence intervals contained entirely within the bioequivalence limits of 80% to 125% for each comparison. Naltrexone remained sequestered during each treatment, based on the sporadic and low measurable plasma concentrations of naltrexone and 6-ß-naltrexol. Single doses of ALO-02 40 mg were well tolerated, and adverse events were mild, with no apparent difference in frequency for all 3 treatments.
  
  
  
  Results indicate that ALO-02 can be administered without regard to food. Also, the contents of ALO-02 can be sprinkled over applesauce and consumed without chewing as an alternative treatment option by subjects with difficulty swallowing. Naltrexone remained sequestered in the ALO-02 formulation under all 3 treatments.
authors.affiliation: Pfizer Inc., New York, NY, USA.
authors.forename: Kuan
authors.initials: K
authors.lastname: Gandelman
authors.affiliation: Pfizer Inc., Cary, NC, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lamson
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Salageanu
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: Candace
authors.initials: C
authors.lastname: Bramson
authors.affiliation: Pfizer Inc., Collegeville, PA, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Matschke
authors.affiliation: Pfizer Inc., New York, NY, USA.
authors.forename: Bimal
authors.initials: B
authors.lastname: Malhotra
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D002214:Capsules; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D004339:Drug Compounding; D005215:Fasting / Q000097:blood; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009271:Naltrexone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010098:Oxycodone / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019518:Postprandial Period; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D002214:Capsules; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D009292:Narcotic Antagonists; C000608978:oxycodone naltrexone combination; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; D010098:Oxycodone
keywords: ALO-02; applesauce; extended release; food effect; naltrexone; oxycodone; pharmacokinetics