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Purpose The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone. Methods The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2 mg/kg). Results Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo. Conclusions Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodone.

Abstract Objective. To evaluate the abuse potential of ALO-02, an abuse-deterrent formulation comprising pellets of extended-release oxycodone hydrochloride surrounding sequestered naltrexone hydrochloride. Design. Randomized, double-blind, placebo-/active-controlled, 6-way crossover study, with naloxone challenge, drug discrimination, and treatment phases. Subjects. Nondependent, recreational opioid users. Methods. Oral administration of crushed and intact ALO-02, crushed immediate-release (IR) oxycodone, and placebo. Primary endpoints were Drug Liking and High measured on visual analog scales and reported as maximum effect (Emax) and area-under-the-effect-curve from 0 to 2 hours (AUE0-2h). Other pharmacodynamic, pharmacokinetic and safety assessments were included. Results. Drug Liking and High (Emax) for crushed oxycodone IR 40 mg were significantly higher compared with placebo, confirming study validity (P < 0.0001). Drug Liking and High (Emax, AUE0-2h) for crushed ALO-02 (40 mg/4.8 mg and 60 mg/7.2 mg) were significantly lower compared to corresponding doses of crushed oxycodone IR (40 and 60 mg; P < 0.0001). Likewise, Drug Liking and High (Emax and AUE0-2h) for intact ALO-02 60 mg/7.2 mg were significantly lower compared with crushed oxycodone IR 60 mg (P < 0.0001). Secondary pharmacodynamic endpoints and plasma concentrations of oxycodone and naltrexone were consistent with these results. Fewer participants experienced adverse events (AEs) after ALO-02 (crushed or intact: 71.1–91.9%) compared with crushed oxycodone IR (100%). Most common AEs following crushed ALO-02 and oxycodone IR were euphoric mood, pruritus, somnolence, and dizziness. Conclusions. The results suggest that ALO-02 (crushed or intact) has lower abuse potential than crushed oxycodone IR when administered orally in nondependent, recreational opioid users.

Purpose This study aimed to investigate the effect of antivirals ritonavir and lopinavir/ritonavir on the pharmacokinetics and pharmacodynamics of oral oxycodone, a widely used opioid receptor agonist used in the treatment of moderate to severe pain. Methods A randomized crossover study design with three phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg, or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioral effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis. Results Ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-fold (range 1.9- to 4.3-fold; P <0.001) and 2.6-fold (range 1.9- to 3.3-fold; P <0.001). The mean (± SD) elimination half-life increased after ritonavir and lopinavir/ritonavir from 3.6 ± 0.6 to 5.6 ± 0.9 h (P <0.001) and 5.7 ± 0.9 h (P <0.001), respectively. Both ritonavir (P <0.001) and lopinavir/ritonavir (P <0.05) increased the self-reported drug effect of oxycodone. Conclusions Ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse effects.

Objective We investigated the effect of voriconazole on the pharmacokinetics and pharmacodynamics of oxycodone. Methods Twelve healthy subjects ingested either voriconazole or placebo for 4 days in a randomized, cross-over study. On day 3, they ingested 10 mg oxycodone. Timed plasma samples were collected for the measurement of oxycodone, noroxycodone, oxymorphone, noroxymorphone and voriconazole up to 48 h, and pharmacodynamic effects were recorded. Results When voriconazole was taken at the same time as oxycodone, the mean area under the plasma concentration-time curve (AUC₀₋[infinity]) of oxycodone increased 3.6-fold (range 2.7- to 5.6-fold), peak plasma concentration 1.7-fold and elimination half-life 2.0-fold (p < 0.001) when compared to placebo. The AUC₀₋[infinity] ratio of noroxycodone to oxycodone was decreased by 92% (p < 0.001), and that of oxymorphone increased by 108% (p < 0.01). Pharmacodynamic effects of oxycodone were modestly increased by voriconazole. Conclusions Voriconazole inhibits the CYP3A-mediated N-demethylation of oxycodone, drastically increasing exposure to oral oxycodone. Clinically, lower doses of oxycodone may be needed during voriconazole treatment to avoid opioid-related adverse effects especially after repeated dosing.

Aim: To further characterize the pharmacokinetics of Xtampza® ER. Subjects & methods: This was an open-label, randomized, active-controlled, five-treatment, five-period, naltrexone-blocked, cross-over study. Healthy subjects received five equivalent oxycodone doses: Xtampza ER (intact or crushed), OxyContin® (intact or crushed) or immediate-release (IR) oxycodone (crushed). Blood samples were collected to assess oxycodone concentrations. Results: Crushed and intact Xtampza ER resulted in lower peak plasma concentrations compared with crushed oxycodone IR; crushed and intact Xtampza ER were bioequivalent. Crushed OxyContin exhibited a rapid increase in plasma oxycodone and was bioequivalent to crushed oxycodone IR. Conclusion: This second pharmacokinetic study demonstrated that Xtampza ER maintains its ER properties after crushing, unlike OxyContin, which failed to retain its ER properties after crushing. ANZCTR registration number: ACTRN12614000613606

Background Dexketoprofen has been shown to provide efficient analgesia and an opioid-sparing effect after orthopedic surgery. In this dose-finding study, we evaluated the analgesic efficacy and opioid-sparing effect of dexketoprofen administered intravenously (i.v.) after laparoscopic cholecystectomy (LCC). Methods Twenty-four patients undergoing LCC were randomized to receive dexketoprofen 10 or 50 mg i.v. 15 min before the end of the surgery. Subjects were provided with 0.2 mg/kg of oxycodone at anesthesia induction. In the recovery room, pain was assessed with an 11-point numerical rating scale (NRS; score of 0 = no pain, score of 10 = most severe pain) every 10 min. When the NRS score was ≥3/10 at rest or ≥5/10 at wound compression, a plasma sample was taken for analysis of oxycodone [to determine the minimum effective concentration (MEC)], its metabolites, and dexketoprofen. After that, subjects were titrated with oxycodone 2 or 3 mg i.v. every 10 min until the NRS score was <3/10 at rest and <5/10 at wound compression. At this point, a second plasma sample was taken for analysis of oxycodone [minimum effective analgesic concentration (MEAC)], its metabolites, and dexketoprofen. Results At the onset of pain, the plasma oxycodone concentrations (MEC) were similar in the two groups: median 60 ng/mL (range 37–73) in the 10 mg group and median 52 ng/mL (range 24–79) in the 50 mg group. At the time of pain relief, the MEACs were 98 ng/mL (range 59–150) in the 10 mg group and 80 ng/mL (range 45–128) in the 50 mg group. The total doses of oxycodone needed to achieve pain relief were similar: 0.11 mg/kg (range 0–0.33) in the 10 mg group and 0.08 mg/kg (range 0–0.24) in the 50 mg group. Eleven subjects developed mild desaturation or a decreased respiratory rate after oxycodone titration. Conclusion In the present double-blinded, randomized clinical trial, the need for a rescue opioid analgesic, oxycodone, was similar with the two dose levels of dexketoprofen—10 and 50 mg i.v.—after LCC.

Abstract Objective. To correlate abuse-related pharmacodynamic measures and pharmacokinetic measures after administering immediate-release/extended-release and immediate-release oxycodone/acetaminophen fixed-dose combination analgesics Design. Randomized, double-blind, active- and placebo-controlled, 7-way crossover study Setting. Contract research organization Subjects. Nondependent recreational users of prescription opioids. Methods. Participants received single doses of intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 15/650 mg, intact immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen 30/1,300 mg, and placebo. Measures of pharmacodynamics (pupillometry, drug liking, drug high, good drug effects) and pharmacokinetics were assessed predose and up to 24 hours postdose, and correlations between pharmacokinetic parameters and pharmacodynamic data were explored. Results. Of 61 participants, 55 completed all 7 treatments. Intact immediate-release/extended-release oxycodone/acetaminophen produced 50% lower oxycodone peak plasma concentration (Cmax) than immediate-release oxycodone/acetaminophen. Median oxycodone time to Cmax (tmax) was significantly longer (P<0.001) for intact immediate-release/extended-release oxycodone/acetaminophen than immediate-release oxycodone/acetaminophen. The pharmacokinetics of crushed immediate-release/extended-release and immediate-release oxycodone/acetaminophen (30/1,300 mg) followed a similar pattern. Crushing did not shorten the median oxycodone tmax for immediate-release/extended-release oxycodone/acetaminophen (30/1,300 mg). Strong correlations were observed between oxycodone Cmax and area under the curve from time 0 to time x peak effects and area under the subjective effect curve from time 0 to time x for all subjective effects (R2=0.711–0.997). Conclusion. Immediate-release/extended-release oxycodone/acetaminophen produced lower oxycodone Cmax and longer tmax than immediate-release oxycodone/acetaminophen. Lower oxycodone concentrations, particularly at earlier time points, were strongly correlated with lesser positive subjective drug effects.

Background and Objectives ALO-02 capsules, intended to deter abuse, contain pellets of extended-release oxycodone hydrochloride (HCl), an opioid agonist, surrounding sequestered naltrexone HCl, an opioid antagonist. The objective of this study was to determine the effects of administration of ALO-02 with 20 or 40 % ethanol on the pharmacokinetics of oxycodone. Methods This was an open-label, single-dose, randomized, three-way crossover study in 18 healthy fasting adults administered ALO-02 20/2.4 mg (oxycodone/naltrexone) with water, 20 % ethanol, or 40 % ethanol, each under naltrexone block. Results Median time to maximum concentration was 12 h postdose when ALO-02 was administered with water or 20 % ethanol and decreased to 8 h postdose with 40 % ethanol. Geometric mean area under the plasma concentration–time curve (AUC) from time zero extrapolated to infinity (AUC ∞ ) and maximum concentration ( C max ) values were similar for ALO-02 administered with water or 20 % ethanol, and increased by about 13 and 37 %, respectively, for ALO-02 administered with 40 % ethanol versus water. The 90 % confidence intervals (CIs) for AUC ∞ and C max ratios of ALO-02 with 20 % ethanol versus water were within 80–125 %; upper 90 % CIs were >125 % for ALO-02 with 40 % ethanol versus water. The most common adverse events were mild-to-moderate vomiting, nausea, headache, and somnolence. Incidence of adverse events increased for ALO-02 given with ethanol versus water. Conclusions Oxycodone exposures ( C max ) were unaffected when ALO-02 was administered with 20 % ethanol but C max increased by 37 % with 40 % ethanol versus water. ALO-02 administered with ethanol under naltrexone block was generally well tolerated.

The aim of present study was to design oxycodone once-a-day controlled-release (CR) tablets and to perform in vitro/in vivo characterizations. Release profiles to achieve desired plasma concentration versus time curves were established by using simulation software and reported pharmacokinetic parameters of the drug. Hydroxypropyl methylcellulose (HPMC) 100,000 mPa·s was used as a release modifier because the polymer was found to be resistant to changes in conditions of the release study, including rotation speed of paddle and ion strength. The burst release of the drug from the CR tablets could be suppressed by applying an additional HPMC layer as a physical barrier. Finally, the oxycodone once-a-day tablet was comprised of two layers, an inert HPMC layer and a CR layer containing drug and HPMC. Commercial products, either 10 mg bis in die (bid [twice a day]) or once-a-day CR tablets (20 mg) were administered to healthy volunteers, and calculated pharmacokinetic parameters indicated bioequivalence of the two different treatments. The findings of the present study emphasize the potential of oxycodone once-a-day CR tablets for improved patient compliance, safety, and efficacy, which could help researchers to develop new CR dosage forms of oxycodone.

Background Peripherally acting opioids, particularly peripheral κ-opioid agonists, may be effective for treating visceral pain by activating receptors expressed on afferent nerves within the gut. Objective The objective of this study was to investigate the pharmacokinetic/pharmacodynamic profile of a novel peripherally selective κ-opioid agonist, CR665 (JNJ-38488502), and compare it to that of oxycodone, a non-selective brain-penetrant opioid. Methods In a randomized, placebo-controlled, double-blind, three-way crossover study, healthy male volunteers were administered CR665 (0.36 mg/kg, intravenous), oxycodone (15 mg, oral) or placebo (intravenous and oral), followed by assessment of visceral pain tolerance thresholds (VPTT) measured as volume of water (mL) in the bag placed on an oesophageal probe. Plasma drug concentration data were used to generate pharmacokinetic models, which were then used to fit the VPTT data using NONMEM ® VI to generate population pharmacokinetic/pharmacodynamic models. Results CR665 kinetics were optimally fitted with a two-compartment model, while oxycodone kinetics were best described by a one-compartment model with transit compartment absorption feeding directly into the central compartment. For both drugs, the plasma concentration effects on VPTT were best fit by a direct linear model, i.e. without the concentration–analgesia delay characteristic of brain-penetrant opioids. The slope of oxycodone (0.089 mL per ng/mL) was steeper than that of CR665 (0.0035 mL per ng/mL) for the plasma drug concentration acting on the VPTT. Conclusion The results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.