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Drug Design, Development and Therapy 2011A formulation of crush-resistant extended-release opioids may deter abuse. The purpose of this study was to evaluate the bioequivalence of oxymorphone extended-release... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A formulation of crush-resistant extended-release opioids may deter abuse. The purpose of this study was to evaluate the bioequivalence of oxymorphone extended-release (Oxy-ER) and a crush-resistant formulation of oxymorphone extended-release (Oxy-CRF).
METHODS
In three open-label, randomized studies, healthy adults at a clinical research center received two single oral doses of Oxy-ER and two single doses of Oxy-CRF, each separated by a ≥7-day washout. Doses were administered under fasted conditions (study 1, 5 mg doses; study 2, 40 mg doses) or after a high-fat breakfast (study 3, 40 mg doses). Subjects administered 40 mg doses also received naltrexone. The primary endpoint was systemic oxymorphone exposure; the bioequivalence criterion was met if the 90% confidence intervals of the geometric mean ratio (Oxy-CRF/Oxy-ER) for oxymorphone area under the curve from time 0 to the last measured concentration (AUC(0-t)), AUC from time 0 to infinity (AUC(0-inf)), and maximum plasma concentration (C(max)) were within 0.8-1.25. Safety was assessed by monitoring adverse events.
RESULTS
In studies 1, 2, and 3, the safety population comprised 30, 37, and 36 subjects and the pharmacokinetics population comprised 27, 30, and 29 subjects, respectively. Oxy-ER and Oxy-CRF produced similar mean ± standard deviation oxymorphone AUC(0-t) (study 1, 5.05 ± 1.55 versus 5.29 ± 1.52 ng · h/mL; study 2, 31.51 ± 10.95 versus 31.23 ± 10.33 ng · h/mL; study 3, 50.16 ± 14.91 versus 49.01 ± 14.03 ng · h/mL) and C(max) (0.38 ± 0.11 versus 0.37 ± 0.12 ng/mL; 2.37 ± 1.20 versus 2.41 ± 0.94 ng/mL; 5.87 ± 1.99 versus 5.63 ± 2.26 ng/mL) under all conditions. The 90% confidence intervals for plasma oxymorphone AUC(0-t), AUC(0-inf), and C(max) fulfilled the bioequivalence criterion. Adverse event rates were similar with Oxy-ER and Oxy-CRF (study 1, 25% versus 23%; study 2, 9% versus 16%; study 3, 20% each group).
CONCLUSION
Oxy-CRF and Oxy-ER (5 mg and 40 mg) are bioequivalent under fasted and fed conditions, suggesting that Oxy-CRF will have clinical efficacy and safety equivalent to Oxy-ER.
Topics: Adolescent; Adult; Analgesics, Opioid; Area Under Curve; Biotransformation; Chemistry, Pharmaceutical; Cross-Over Studies; Delayed-Action Preparations; Demography; Female; Hardness; Humans; Hydroxylation; Male; Middle Aged; Oxymorphone; Safety; Solubility; Therapeutic Equivalency; Young Adult
PubMed: 22162639
DOI: 10.2147/DDDT.S24372 -
Journal of Pharmaceutical Sciences Sep 2013The aim of this study was to characterize the blood-brain barrier (BBB) transport and pharmacokinetics-pharmacodynamics (PKPD) relationship of oxymorphone and to further...
The aim of this study was to characterize the blood-brain barrier (BBB) transport and pharmacokinetics-pharmacodynamics (PKPD) relationship of oxymorphone and to further elucidate its possible contribution to oxycodone analgesia. The BBB transport of oxymorphone was studied using microdialysis in male Sprague-Dawley rats. Samples from microdialysis blood and brain probes, brain tissue, and plasma were analyzed by liquid chromatography with tandem mass spectrometry. The effect was measured as tail-flick latency. The study consisted of a PKPD experiment with combined microdialysis and antinociceptive measurements (n = 8), and another antinociceptive effect experiment (n = 9) using a 10 times lower dose. The combined data were analyzed with an integrated PKPD model in nonlinear mixed effect modeling utilizing a specific method (M3) for handling missing PD observations. The concentration of unbound oxymorphone was higher in brain than in blood, with a ratio of 1.9 (RSE, 9.7%), indicating active uptake at the BBB. The integrated PKPD model described the oxymorphone BBB transport and PKPD relationship successfully, with an EC50 in the brain of 63 ng/mL, and the M3 method was able to address the issue of censored observations. Oxymorphone has active uptake transport at the BBB in rats, with moderate uptake clearance to the brain. Its contribution to analgesia after oxycodone administration is not significant.
Topics: Analgesics, Opioid; Animals; Biological Transport, Active; Blood-Brain Barrier; Brain; Male; Models, Biological; Oxycodone; Oxymorphone; Rats; Rats, Sprague-Dawley
PubMed: 23463542
DOI: 10.1002/jps.23492 -
Drug Testing and Analysis May 2018
Topics: Doping in Sports; Drug Stability; Gas Chromatography-Mass Spectrometry; Humans; Naltrexone; Narcotic Antagonists; Narcotics; Oxymorphone; Quaternary Ammonium Compounds; Substance Abuse Detection
PubMed: 29314653
DOI: 10.1002/dta.2353 -
Toxicological Sciences : An Official... Feb 2007Oxymorphone is a potent opioid analgesic. Oral administration of oxymorphone to rats at doses >or= 20 mg/kg and mice at 500 mg/kg produced an increase in micronucleated...
Oxymorphone is a potent opioid analgesic. Oral administration of oxymorphone to rats at doses >or= 20 mg/kg and mice at 500 mg/kg produced an increase in micronucleated polychromatic erythrocytes (MPCEs). Oxymorphone does not produce chromosome aberrations in vitro, suggesting that the increased MPCEs in vivo may involve indirect mechanisms. Opioids are known to affect thermoregulatory mechanisms. Changes in body temperature can increase the incidence of MPCEs in rodents. Studies were conducted to examine the relationship between increased MPCEs in rats given oxymorphone and changes in body temperature. Single oral doses of oxymorphone associated with increased MPCEs (20 and 40 mg/kg) also produced a marked, rapid increase in body temperature. When animals were pretreated with sodium salicylate, peak body temperature was lower and returned to baseline more quickly than when oxymorphone was given alone. MPCEs were evaluated in rats after administration of oxymorphone (40 mg/kg) alone or following pretreatment with an oral dose of sodium salicylate. Oxymorphone alone produced a statistically significant increase in the incidence of MPCEs (3.6 per 1000 polychromatic erythrocytes vs. 0.4 in controls). The number of MPCEs in animals pretreated with sodium salicylate was similar to controls. Sodium salicylate alone had no effect on the number of MPCEs. Systemic oxymorphone exposure was not affected by sodium salicylate pretreatment; maximum plasma concentration (C(max)) and area-under-the-curve values were similar after administration of oxymorphone alone or following pretreatment with sodium salicylate. These results indicate that the increased incidence of MPCEs following oxymorphone administration is directly related to increased body temperature.
Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Body Temperature; Bone Marrow; Dose-Response Relationship, Drug; Fever; Mice; Mice, Inbred ICR; Micronuclei, Chromosome-Defective; Micronucleus Tests; Oxymorphone; Rats; Rats, Inbred Strains; Sodium Salicylate
PubMed: 17077185
DOI: 10.1093/toxsci/kfl148 -
Clinical Pharmacy Aug 1989
Topics: Cesarean Section; Female; Humans; Hydromorphone; Morphine; Oxymorphone; Pain, Postoperative; Self Administration
PubMed: 2475287
DOI: No ID Found -
The Journal of Pain Jan 2012Adverse events may occur with an extended-release (ER) opioid if tampering or coadministration with ethanol causes excessive exposure (dose dumping) to the opioid. The... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Adverse events may occur with an extended-release (ER) opioid if tampering or coadministration with ethanol causes excessive exposure (dose dumping) to the opioid. The effects of ethanol on the in vitro dissolution and in vivo pharmacokinetics of oxymorphone ER and oxymorphone crush-resistant formulation (CRF) were evaluated. In vitro dissolution rates were measured for oxymorphone ER 40-mg and oxymorphone CRF 40-mg tablets in aqueous solutions of 0 to 40% ethanol. In 2 in vivo, open-label, randomized, crossover studies, fasted healthy volunteers received single oral doses of oxymorphone ER 40 mg or oxymorphone CRF 40 mg with 240 mL of 0 to 40% ethanol. Naltrexone was used to minimize opioid effects. In the in vitro analyses, dissolution rates of oxymorphone ER and CRF were unaffected in aqueous solutions of ≤40% ethanol. Coadministration of oxymorphone ER or oxymorphone CRF with ethanol 20 and 40% increased oxymorphone peak plasma concentrations (C(max)) by 14 to 80% and reduced time to C(max). For both formulations, oxymorphone area under the curve and terminal half-life were largely unaffected, but C(max) increased with ethanol dose. Neither oxymorphone formulation exhibited dose dumping in terms of overall exposure when coingested with ethanol.
PERSPECTIVE
Administering oxymorphone ER or oxymorphone CRF with 240 mL of ≤40% ethanol increased oxymorphone C(max) without dose dumping in terms of area under the curve. These results provide reassurance about the integrity of oxymorphone ER formulations with ethanol. Nonetheless, alcohol and opioids should never be combined because of the risk of respiratory depression.
Topics: Adult; Area Under Curve; Biological Availability; Central Nervous System Depressants; Chemistry, Pharmaceutical; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Ethanol; Female; Humans; Male; Middle Aged; Narcotics; Oxymorphone; Time Factors; Young Adult
PubMed: 22208805
DOI: 10.1016/j.jpain.2011.10.011 -
Journal of Palliative Medicine Jan 2010
Topics: Analgesics, Opioid; Clinical Trials as Topic; Humans; Oxymorphone; Pain
PubMed: 20050794
DOI: 10.1089/jpm.2010.9893 -
Neuroscience Letters Mar 2017Oxymorphone, one of oxycodone's metabolic products, is a potent opioid receptor agonist which is thought to contribute to the analgesic effect of its parent compound and...
Oxymorphone, one of oxycodone's metabolic products, is a potent opioid receptor agonist which is thought to contribute to the analgesic effect of its parent compound and may have high potential abuse liability. Nonetheless, the in vivo pharmacological binding profile of this drug is still unclear. This study uses mice lacking mu (MOP), kappa (KOP) or delta (DOP) opioid receptors as well as mice lacking all three opioid receptors to provide full characterisation of oxymorphone binding sites in the brain. Saturation binding studies using [H]oxymorphone revealed high affinity binding sites in mouse brain displaying Kd of 1.7nM and Bmax of 147fmol/mg. Furthermore, we performed quantitative autoradiography binding studies using [H]oxymorphone in mouse brain. The distribution of [H]oxymorphone binding sites was found to be similar to the selective MOP agonist [H]DAMGO in the mouse brain. [H]Oxymorphone binding was completely abolished across the majority of the brain regions in mice lacking MOP as well as in mice lacking all three opioid receptors. DOP and KOP knockout mice retained [H]oxymorphone binding sites suggesting oxymorphone may not target DOP or KOP. These results confirm that the MOP, and not the DOP or the KOP is the main high affinity binding target for oxymorphone.
Topics: Animals; Autoradiography; Binding Sites; Brain; Mice, Knockout; Oxymorphone; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu
PubMed: 28192197
DOI: 10.1016/j.neulet.2017.02.002 -
Journal of Chromatography. B,... Sep 2020In this work, a microwave-enhanced air-assisted liquid-liquid microextraction method combined with gas chromatography-mass spectrometry has been developed for morphine...
Determination of morphine and oxymorphone in exhaled breath condensate samples: Application of microwave enhanced three-component deep eutectic solvent-based air-assisted liquid-liquid microextraction and derivatization prior to gas chromatography-mass spectrometry.
In this work, a microwave-enhanced air-assisted liquid-liquid microextraction method combined with gas chromatography-mass spectrometry has been developed for morphine and oxymorphone assessment in EBC samples. For this purpose, choline chloride-menthol-phenylacetic acid deep eutectic solvent (as an extraction solvent), butyl chloroformate (as a derivatization agent), and picoline (as a catalyst) are used. After performing predetermined extraction cycles in the microextraction method, the obtained cloudy solution is exposed to microwave irradiations to enhance extraction and derivatization efficiencies. The method provided low limits of detection (morphine 2.1 and oxymorphone 1.5 ng mL) and quantification (morphine 7.2 and oxymorphone 5.2 ng mL) in the EBC samples. The method had proper repeatability, accuracy, and stability expressed as relative standard deviations less than 5.1, 9, and 9%, respectively. The developed method was successfully used to determine morphine and oxymorphone concentrations in the EBC samples of addict patients.
Topics: Breath Tests; Gas Chromatography-Mass Spectrometry; Humans; Limit of Detection; Linear Models; Liquid Phase Microextraction; Microwaves; Morphine; Oxymorphone; Reproducibility of Results; Solvents
PubMed: 32745969
DOI: 10.1016/j.jchromb.2020.122256 -
Journal of the American Association For... Mar 2011Oxymorphone is a pure μ-opioid receptor agonist that is commonly used in nonhuman primate medicine and surgery to minimize pain ranging in intensity from moderate to...
Oxymorphone is a pure μ-opioid receptor agonist that is commonly used in nonhuman primate medicine and surgery to minimize pain ranging in intensity from moderate to severe. We compared pharmacokinetic profiles and physiologic and behavioral responses to oxymorphone between titi monkeys (Callicebus spp.) and rhesus macaques (Macaca mulatta). Titi monkeys (n = 4) and rhesus macaques (n = 4) were injected intravenously with either a bolus of 0.075 mg/kg oxymorphone or placebo on multiple occasions, with a minimal washout period of 14 d between trials. Blood collection was limited to no more than 3 samples per trial, with samples collected at multiple time points until 10 h after injection. Collection periods, animal order, and testing day were randomized. In addition, macaques underwent a single serial collection at all time points to validate study design. A 2-compartment model best described the disposition of oxymorphone in both species. Clearance was faster in macaques than titi monkeys, in which terminal half-life was longer. Statistically significant physiologic differences were found between species and between treatments within species. Apart from these effects, oxymorphone did not significantly change physiologic parameters over time. After oxymorphone treatment, macaques demonstrated behaviors reflecting pruritis, whereas titi monkeys exhibited sedation. Despite its mild side effects, we recommend the consideration of oxymorphone for pain management protocols in both Old and New World nonhuman primates.
Topics: Analgesics, Opioid; Animals; Behavior, Animal; Injections, Intravenous; Macaca mulatta; Male; Motor Activity; Oxymorphone; Pain; Pitheciidae; Pruritus; Species Specificity
PubMed: 21439215
DOI: No ID Found