Abstract
Background
An 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.
Objectives
The 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.
Methods
This 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).
Results
Of 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.
Conclusions
Plasma 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.
Key words
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Article info
Publication history
Published online: June 21, 2012
Accepted:
May 30,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
