Pharmacokinetics, Tolerability, and Safety of Intranasal Administration of Reformulated OxyContin^® Tablets Compared with Original OxyContin^® Tablets in Healthy Adults

This was a randomized, single-blind, single-dose, single-center, six-sequence, triple-treatment, triple-period crossover study designed to evaluate the pharmacokinetics, tolerability, and safety of intranasally administered ORF, both finely crushed (10 mg) and coarsely crushed (10 mg), as well as finely crushed OC (10 mg). Coarsely crushed OC was not tested because simple crushing of OC readily produces a fine powder. To minimize variability, tampered tablets were prepared using standardized equipment and techniques.

Study duration was up to 42 days; a 28-day screening phase was followed by a 7-day treatment phase, with follow-up 3–7 days after the last dose of study drug. The treatment phase was divided into three periods (days 1–3, 3–5, and 5–7). The assignment of subjects to treatment sequence was single-blinded. Efforts were made to prevent subjects from making side-by-side comparisons of study drugs, which were similar, but not identical, in appearance.

This study protocol and its informed consent form was submitted to the Western Institutional Review Board (IRB) for review and approval. It was conducted in accordance with regulatory guidelines and the applicable International Conference on Harmonization guidelines of Good Clinical Practice, as consistent with the Declaration of Helsinki. All subjects provided oral and written consent before conduct of any protocol-related procedures. Subjects were informed that they could discontinue the study at any time.

Subjects were healthy men and women (aged 18–55 years inclusive) with no clinically significant medical history or any other concerns that would have jeopardized the study’s safety or validity, as determined by the principal investigator. Special preference for study enrollment was given to recreational drug users who had experience with opioid use on at least five occasions, and to subjects who reported at least three occasions of intranasal opioid use for the purpose of abuse/misuse within the past year. Subjects were excluded if they had significant obstruction of either naris, or clinically important changes in the intranasal cavity that would interfere with the study procedures or data integrity or compromised the safety of the subject. Subjects with piercings through the nose or a perforated nasal septum were given a lower priority than those without these findings.

Other conditions warranting exclusion from participation were use of any medication/herbal product [except paracetamol (acetaminophen) (2 g/day), vitamin or mineral supplements, birth control, and hormone replacement] within 7 days of study drug administration or for the study duration.

A physical examination, biochemistry tests, and urinalysis were conducted for each subject at screening. Subjects abstained from consuming alcoholic beverages for 48 h prior to initial study drug administration (day 1) and for the duration of the study (i.e., through to the end of study procedures). They were confined to a nonsmoking study facility the day prior to administration of the study drug and throughout all three periods of the study. Subjects abstained from caffeine or xanthine entirely during confinement. While confined at the study site, they received meals at scheduled times that did not conflict with other study-related activities. The same standard meal timing was employed over corresponding study days in each period, but the content of meals varied.

Subjects were randomized to a treatment sequence on the morning of day 1 and received treatments on days 1, 3, and 5 of the treatment phase, with a minimum washout period of 48 h between dose administrations. For each treatment period, subjects completed a 10-h overnight fast before sitting in an upright position and intranasally insufflating a dose of finely crushed ORF (10 mg), coarsely crushed ORF (10 mg), or finely crushed OC (10 mg) through a short thin straw. Dosing was carefully observed by the site staff, and the weight of any drug not successfully insufflated during the 5-min administration period was recorded, with significant amounts of nonadministered drug potentially resulting in subject discontinuation from the study. Subjects continued fasting for 4 h subsequent to dosing and were to remain upright, unless a procedure required that they be in the supine position. They remained confined to the study site throughout all three treatment periods and abstained from strenuous exercise or physical exertion. Treatment procedures were identical for all three treatment periods, with subjects receiving single intranasal doses of study drug in alternating nares (e.g., left-right-left). Telephone follow-ups were conducted 3–7 days after the last dose or following early discontinuation.

During each treatment period, blood samples for determining oxycodone plasma concentrations were obtained for each subject just prior to dosing and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10, 12, 16, 24, 28, 32, 36, and 48 h postdose. For each sample, venous blood (4 mL) was drawn via an indwelling catheter or direct venipuncture into tubes containing potassium ethylenediaminetetraacetic acid anticoagulant. A validated liquid chromatography tandem mass spectrometric method quantified plasma concentrations of oxycodone (lower limit of quantitation was 0.1 ng/mL).

Relative bioavailability was determined by comparison to the reference treatment (finely crushed OC). Pharmacokinetic metrics were calculated, whenever possible, based on the plasma concentrations of oxycodone according to the model independent approach. Pharmacokinetic calculations were performed using WinNonLin (Pharsight Corporation, St. Louis, MO, USA; Version 5.2). Noncompartmental analysis of plasma oxycodone concentrations generated values for: 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), area under the plasma concentration–time curve extrapolated to infinity (AUC_∞), and half-life (t _1/2). These pharmacokinetic metrics permit assessment of the rate and extent of drug absorption (bioavailability). AUC_∞ is an index of total drug exposure and C _max is an index of maximum or peak exposure to treatment. The AQ, calculated as C _max/t _max, is a measure of the average rate of rise in concentration between dosing and t _max [12]. Because more rapid exposure to higher opioid concentrations correlates with greater drug-liking, higher AQ scores predict greater abuse potential [6, 11, 12].

Pharmacodynamic measurements were assessed by evaluating intranasal tolerability. Subjects rated intranasal discomfort, itching, burning, pain, runny nose, and stuffiness on numeric scales ranging from 0 (none) to 10 (worst I can imagine). Ratings measured only the naris used for drug administration. Intranasal tolerability rating scales were evaluated at predose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10, and 12 h postdose. At approximately 5 and 24 h after each dosing, subjects provided a written response to the question, “What effects (if any) did snorting this drug cause to the inside of your nose?” Additionally, a specialist in ear, nose, and throat procedures performed intranasal endoscopies. These were conducted at predose, and as close to 0.5 h postdose as possible, but not later than 2 h postdose.

Safety assessments included reports of adverse events (AEs), clinical laboratory test results, vital signs results, pulse oximetry (SpO₂), physical examinations, and electrocardiograms (ECGs). Reported AEs were coded according to the Medical Dictionary for Regulatory Activities (version 9.1) by preferred term and system organ class. AEs reported herein are those that emerged, reemerged, and/or worsened in severity during treatment and were classified as treatment-emergent AEs.

Subjects who were randomized, received study drug, and had at least one postdose safety assessment were included in safety analyses; subjects who were randomized, received study drug, and had at least one valid pharmacokinetic metric were included in pharmacokinetic analyses. For pharmacokinetic data, a mixed-model analysis of variance was used to compare logarithmic-transformed (base e) values for C _max, AUC_last, and AUC_∞ of oxycodone, with fixed effects for treatment, period, and sequence, as well as random effects of subject within sequence.

For pharmacokinetic data, bioequivalence was indicated if the 90 % confidence intervals (CIs) for oxycodone for a given measure fell entirely within the 80–125 % range. Intranasal tolerability rating scales used descriptive statistics for raw data and for differences from predose for each time point and treatment. The maximum response over time was tabulated and an analysis of covariance model was conducted to assess differences among treatments related to maximum response. This pharmacodynamic model included a covariate for the predose assessment, fixed effects for treatment, period, and sequence, and a random effect of the subject within sequence.