Dose Proportionality and the Effects of Food on Bioavailability of an Immediate-Release Oxycodone Hydrochloride Tablet Designed to Discourage Tampering and Its Relative Bioavailability Compared With a Marketed Oxycodone Tablet Under Fed Conditions: A Single-Dose, Randomized, Open-Label, 5-Way Crossover Study in Healthy Volunteers

Abstract

BackgroundAn immediate-release oxycodone hydrochloride formulation (IRO-A) indicated for moderate to severe pain was designed (by adding functional excipients) to discourage tampering associated with intranasal and intravenous abuse of prescription opioids. ObjectivesThe primary objective of this study was to determine the dose proportionality of oxycodone in IRO-A tablets under fasted conditions. Secondary objectives were to assess food effects on the pharmacokinetics of IRO-A tablets, to compare the relative bioavailability of oxycodone in IRO-A tablets versus marketed oxycodone hydrochloride (IRO) tablets under fed conditions and to evaluate the single-dose safety profile of the IRO-A tablets in healthy volunteers pretreated with naltrexone. MethodsThis open-label, single-dose, randomized, 5-way crossover study was conducted in healthy adults who received each of the following treatments, separated by a washout period of ≥7 days: IRO-A 1 × 5 mg, 2 × 5 mg, and 2 × 7.5 mg under fasted conditions, and IRO-A 2 × 7.5 mg and IRO 1 × 15 mg after a high-fat, high-calorie breakfast. Naltrexone was administered to minimize untoward pharmacologic effects of oxycodone. Dose proportionality (IRO-A), food effects (IRO-A), and relative bioavailability in a fed state (IRO-A and IRO) were assessed by using bioequivalence criteria (90% CIs between 80% and 125% for Cmax and AUC). ResultsOf the 35 adults enrolled in the study, 33 completed at least 1 dosing period. Most participants were male (54%) and white (69%), with a mean (SD) age of 32.6 (11.1) years and mean weight of 75.5 (12.3) kg. Plasma levels of oxycodone in IRO-A suggested dose-proportional pharmacokinetics; 90% CIs for dose-normalized Cmax, AUC0–last, and AUC0–∞ fell within the 80% to 125% range. Concomitant food intake with IRO-A resulted in an ∼14% reduction in oxycodone Cmax and an ∼21% increase in AUC0–last. The bioavailability of oxycodone from IRO-A tablets in the fed state was comparable with IRO tablets based on AUC parameters, although Cmax was ∼16.5% lower. Reported or observed treatment-emergent adverse events were monitored throughout the study and were similar for IRO-A and IRO tablets. Nausea, headache, abdominal pain, and dizziness were the most common and are consistent with known effects of oxycodone after naltrexone blockade. ConclusionsPlasma levels of oxycodone in IRO-A tablets were compatible with proportional single-dose pharmacokinetics from 5 to 15 mg under fasted conditions. Administration of IRO-A with food suggested increased overall bioavailability relative to fasting conditions and a reduction in peak systemic exposure of oxycodone that is not expected to be clinically significant. When comparing IRO-A tablets with IRO tablets in the fed state, the overall systemic exposure of oxycodone was comparable, and peak systemic exposure was lower. ClinicalTrials.gov identifier: NCT01530542.