title: Pharmacokinetics, tolerability, and safety of intranasal administration of reformulated OxyContin(®) tablets compared with original OxyContin (®) tablets in healthy adults.
abstract: OBJECTIVE
  Reformulated OxyContin(®) (oxycodone-HCl controlled release) tablets (ORF) became available in the United States in August 2010. The original formulation of OxyContin(®) (oxycodone-HCl controlled release) tablets (OC) used a delivery system that did not provide inherent resistance to crushing and dissolving. The objective of this study was to compare the pharmacokinetics, tolerability, and safety of finely crushed ORF tablets, coarsely crushed ORF tablets, and finely crushed OC tablets.
  
  
  METHODS
  This randomized, single-blind, single-dose, single-center, six-sequence, triple-treatment, triple-period crossover study enrolled eligible healthy adults (aged 18-55 years inclusive). The study evaluated the pharmacokinetics, tolerability, and safety of intranasally administered ORF, both finely crushed and coarsely crushed, as well as finely crushed OC tablets. Plasma oxycodone concentrations were quantified and analyzed to determine the maximum observed plasma concentration (C max), time to maximum plasma concentration (t max), area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration (AUC(last)), and area under the plasma concentration-time curve extrapolated to infinity (AUC(∞)). The abuse quotient (AQ), calculated as C(max)/t(max), served as an index of the average rate of increase in drug concentration from dosing to t max. Intranasal tolerability rating scales (discomfort, itching, burning, pain, runny nose, and stuffiness) and intranasal endoscopy were conducted. Safety assessments included adverse events, vital signs, pulse oximetry (SpO2), and electrocardiograms.
  
  
  RESULTS
  Of 83 subjects screened and enrolled, 30 were randomized to period 1, with 1 subject subsequently discontinuing due to the subject's choice. Mean C max values for finely crushed ORF (17.1 ng/mL) and coarsely crushed ORF (15.5 ng/mL) were lower than that for finely crushed OC (22.2 ng/mL). Median t max for finely crushed OC (1.0 h) was shorter than that for either finely crushed ORF (2.0 h) or coarsely crushed ORF (3.0 h). Mean AQ values were approximately 66 and 80 % lower, respectively, for finely crushed ORF and coarsely crushed ORF than that for finely crushed OC. Finely crushed ORF, coarsely crushed ORF, and finely crushed OC demonstrated similar total oxycodone exposures (AUC(∞)). Insufflation of ORF produced greater nasal discomfort and stuffiness than finely crushed OC, although the latter produced higher runny nose scores. No significant difference was found in other nasal tolerability measures. The overall safety profile was as expected following opioid administration in healthy subjects.
  
  
  CONCLUSIONS
  In contrast to OC, both finely and coarsely crushed ORF retained some control of oxycodone release. Reduced C(max) and increased t max for ORF resulted in lower AQ scores for ORF compared with OC. ORF was associated with greater intranasal irritation than OC. These data suggest that ORF has a lower intranasal abuse potential than OC.
authors.affiliation: Purdue Pharma LP One Stamford Forum, Stamford, CT 06901, USA. Peter.Perrino@pharma.com
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Perrino
authors.forename: Salvatore V
authors.initials: SV
authors.lastname: Colucci
authors.forename: Glen
authors.initials: G
authors.lastname: Apseloff
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harris
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders / Q000517:prevention & control*; D010098:Oxycodone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016037:Single-Blind Method; D013607:Tablets; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D013607:Tablets; D010098:Oxycodone