Oxymorphone Concentrations Research Articles

Sex, estrous cycle, and hormone regulation of CYP2D in the brain alters oxycodone metabolism and analgesia

Opioids, and numerous centrally active drugs, are metabolized by cytochrome P450 2D (CYP2D). There are sex and estrous cycle differences in brain oxycodone analgesia. Here we investigated the mechanism examining the selective role of CYP2D in the brain on sex, estrous cycle, and hormonal regulation. Propranolol, CYP2D-specific mechanism-based inhibitor, or vehicle was delivered into cerebral ventricles 24 h before administering oxycodone (or oxymorphone, negative control) orally to male and female (in estrus and diestrus) rats. Ovariectomized and sham-operated females received no treatment, estradiol, progesterone or vehicle. Analgesia was measured using tail-flick latency, and brain drug and metabolite concentrations were measured by microdialysis. Data were analyzed by two-way or mixed ANOVA. Following propranolol (versus vehicle) inhibition and oral oxycodone, there were greater increases in brain oxycodone concentrations and analgesia, and greater decreases in brain oxymorphone/oxycodone ratios (an in vivo phenotype of CYP2D in brain) in males and females in estrus, compared to females in diestrus; with no impact on plasma drug concentrations. There was no impact of propranolol pre-treatment, sex, or cycle after oral oxymorphone (non-CYP2D substrate) on brain oxymorphone concentrations or analgesia. There was no impact of propranolol pre-treatment following ovariectomy on brain oxycodone concentrations or analgesia, which was restored in ovariectomized females following estradiol, but not progesterone, treatment. Sex, cycle, and estradiol regulation of CYP2D in brain in turn altered brain oxycodone concentration and response, which may contribute to the large inter-individual variation in response to the numerous centrally acting CYP2D substrate drugs, including opioids.

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−1) and quantification (morphine 7.2 and oxymorphone 5.2 ng mL−1) 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.

Effects of Bariatric Surgery Observed in Postmortem Toxicology Casework.

Bariatric surgery has been on the rise and patients often have multiple indications for pre- and post-operative pharmacotherapy. Procedures target the stomach and/or small intestine and affect weight loss through restriction, malabsorption, or a combination of the two. The absorption and/or metabolism of drugs via the gastrointestinal tract could be altered by different mechanisms. Several cases at the North Carolina Office of the Chief Medical Examiner's Toxicology Laboratory (NCOCME) have raised questions about the potential impact of these procedures on the disposition of drugs in the body and how that altered disposition may affect cause and manner of death. Overmedication and postmortem redistribution are not enough to explain the phenomena seen in some NCOCME bariatric surgery-related casework. Case examples include a 46-year-old female with a history of Roux-en-Y gastric bypass (RYGB) who suffered a witnessed collapse. Toxicological findings included elevated concentrations of oxymorphone at 0.49mg/L in vena cava blood. A 67-year-old female, who died from vomiting and bacterial gastritis one day after placement of two intragastric weight-loss balloons, had elevated concentrations of duloxetine at 1.4mg/L in the iliac vein blood and 9.3mg/kg in the liver. Her medication was strictly controlled by her sister and gastric contents were without intact tablets or residue at autopsy.

(439) A transdermal oxymorphone patch delivers therapeutic plasma concentrations of oxymorphone: an open label Phase I clinical trial

The transdermal delivery of opioids offers significant advantages for the management of chronic pain. Transdermal delivery avoids first pass effects, allows sustained drug administration for improved analgesia with reduced breakthrough pain, reduces peak-related side effects and improves patient compliance through reduced dosing frequency. Oxymorphone was selected for clinical development because of its high potency and low oral bioavailability; characteristics ideal for transdermal delivery. We have previously demonstrated in humans that oxymorphone could be delivered from a transdermal matrix patch when formulated with a transdermal penetration enhancer called TPM.

Pharmacokinetics of ammonium sulfate gradient loaded liposome–encapsulated oxymorphone and hydromorphone in healthy dogs

ObjectiveTo evaluate the pharmacokinetics, in dogs, of liposome–encapsulated oxymorphone and hydromorphone made by the ammonium sulfate gradient loading technique (ASG). AnimalsFour healthy purpose–bred Beagles aged 9.5 ± 3.2 months and weighing 13.4 ± 2.3 kg. Study designRandomized cross–over design. MethodsEach dog was given either 4.0 mg kg−1 of ASG–oxymorphone or 8.0 mg kg−1 of ASG–hydromorphone SC on separate occasions with a 3–month washout period. Blood was collected at baseline and at serial time points up to 1032 hours (43 days) after injection for determination of serum opioid concentrations. Serum opioid concentrations were measured with HPLC–MS and pharmacokinetic parameters were calculated using commercial software and non–compartmental methods. ResultsSerum concentrations of oxymorphone remained above the limit of quantification for 21 days, while those for hydromorphone remained above the limit of quantification for 29 days. Cmax for ASG–oxymorphone was 7.5 ng mL−1; Cmax for ASG–hydromorphone was 5.7 ng mL−1. Conclusions and clinical relevanceOxymorphone and hydromorphone, when encapsulated into liposomes using the ammonium sulfate gradient loading technique, result in measureable serum concentrations for between 3 to 4 weeks. This formulation may have promise in the convenient use of opioids for clinical treatment of chronically painful conditions in dogs.

Validation of Blood and Liver Oxymorphone Analysis Using LC-MS-MS: Concentrations in 30 Fatal Overdoses

A sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the quantitation of oxymorphone (OM) in human whole blood and liver. Sample preparation was done by solid-phase extraction, using deuterated OM as the internal standard. Separation was achieved using a Waters Aquity UPLC HSS T3 column. Analysis utilized positive electrospray ionization and multiple reaction monitoring. As part of the validation, studies were conducted to determine potential interference, selectivity, ion suppression/enhancement and carryover. Calibration model, limit of detection (LOD), lower limit of quantitation (LLOQ), precision and accuracy were also established. The linear range of the method was 2-500 ng/mL in blood and 5-500 ng/g in the liver. The LOD and LLOQ were 2 ng/mL for blood and 5 ng/g for the liver. Blood and/or liver specimens from 30 cases were analyzed. OM concentrations ranged from 23 to 554 ng/mL ( , n = 26) in blood and 48 to 1740 ng/g ( , n = 30) in the liver.

Cancer Cachexia Raises the Plasma Concentration of Oxymorphone Through the Reduction of CYP3A But Not CYP2D6 in Oxycodone-Treated Patients

This study evaluated the plasma concentrations of oxycodone and its demethylates and opioid-induced adverse effects based on cachexia stage in cancer patients receiving oxycodone. Seventy patients receiving oxycodone for cancer pain were enrolled. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined at the titration dose. Opioid-induced adverse effects were monitored for 2 weeks after the titration. Plasma concentrations of oxycodone and oxymorphone but not noroxycodone in patients with a GPS of 2 were significantly higher than that with a GPS of 0. The metabolic ratios of noroxycodone but not oxymorphone to oxycodone in patients with a GPS of 1 and 2 were significantly lower than in those with a GPS of 0. A higher GPS was associated with a higher incidence of somnolence, while the GPS did not affect the incidence of vomiting. Plasma concentrations of oxycodone and oxymorphone were not associated with the incidence of adverse effects. In conclusion, cancer cachexia raised the plasma exposures of oxycodone and oxymorphone through the reduction of CYP3A but not CYP2D6. Although the cachexia elevated the incidence of somnolence, alterations in their pharmacokinetics were not associated with the incidence.

Is Oxycodone Efficacy Reflected in Serum Concentrations? A Multicenter, Cross-Sectional Study in 456 Adult Cancer Patients

ContextThe relationship between oxycodone and metabolite serum concentrations and clinical effects has not previously been investigated in cancer pain patients. ObjectivesThe aim of this study was to assess whether there is a relationship between oxycodone concentrations and pain intensity, cognitive functioning, nausea, or tiredness in cancer patients. Also, oxymorphone and noroxymorphone contributions to analgesia and the adverse effects of oxycodone were assessed. MethodsFour hundred fifty-six cancer patients receiving oxycodone for cancer pain were included. Pain was assessed using the Brief Pain Inventory. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-C30 was used to assess the symptoms of tiredness, nausea, constipation, and depression. Cognitive function was assessed using the Mini-Mental State Examination. Associations were examined by multiple linear or ordinal logistic regressions. Whether patients classified as being a “treatment success” or a “treatment failure” had different serum concentrations of oxycodone or metabolites was assessed using Mann-Whitney U-tests. ResultsSerum concentrations of oxycodone and metabolites were not associated with pain intensity, nausea, tiredness, or cognitive function, with the exception that increased pain intensity was associated with higher oxymorphone concentrations. Patients with poor pain control and side effects had higher serum concentrations of the oxycodone metabolites, noroxycodone and noroxymorphone, compared with those with good pain relief and without side effects. ConclusionThis study of patients receiving oxycodone for cancer pain confirms previous observations that there is most likely no association between serum concentrations of opioid analgesics and clinical effects.

Effect of amantadine on oxymorphone‐induced thermal antinociception in cats

This study examined the effect of amantadine, an N-methyl-d-aspartate receptor antagonist, on the thermal antinociceptive effect of oxymorphone in cats. Six adult healthy cats were used. After baseline thermal threshold determinations, oxymorphone was administered intravenously to maintain plasma oxymorphone concentrations of 10, 20, 50, 100, 200, and 400 ng/mL. In addition, amantadine, or an equivalent volume of saline, was administered intravenously to maintain a plasma amantadine concentration of 1100 ng/mL. Thermal threshold and plasma oxymorphone and amantadine concentrations were determined at each target plasma oxymorphone concentration. Effect maximum models were fitted to the oxymorphone concentration-thermal threshold data, after transformation in % maximum response. Oxymorphone increased skin temperature, thermal threshold, and thermal excursion (i.e., the difference between thermal threshold and skin temperature) in a concentration-dependent manner. No significant difference was found between the amantadine and saline treatments. Mean ± SE oxymorphone EC(50) were 14.2 ± 1.2 and 24.2 ± 7.4 ng/mL in the amantadine and saline groups, respectively. These values were not significantly different. Large differences in oxymorphone EC(50) in the saline and amantadine treatment groups were observed in two cats. These results suggest that amantadine may decrease the antinociceptive dose of oxymorphone in some, but not all, cats.

Pharmacokinetics of oxymorphone in cats

This study reports the pharmacokinetics of oxymorphone in spayed female cats after intravenous administration. Six healthy adult domestic shorthair spayed female cats were used. Oxymorphone (0.1 mg/kg) was administered intravenously as a bolus. Blood samples were collected immediately prior to oxymorphone administration and at various times up to 480 min following administration. Plasma oxymorphone concentrations were determined by liquid chromatography-mass spectrometry, and plasma oxymorphone concentration-time data were fitted to compartmental models. A three-compartment model, with input in and elimination from the central compartment, best described the disposition of oxymorphone following intravenous administration. The apparent volume of distribution of the central compartment and apparent volume of distribution at steady state [mean ± SEM (range)] and the clearance and terminal half-life [harmonic mean ± jackknife pseudo-SD (range)] were 1.1 ± 0.2 (0.4-1.7) L/kg, 2.5 ± 0.4 (2.4-4.4) L/kg, 26 ± 7 (18-38) mL/min.kg, and 96 ± 49 (62-277) min, respectively. The disposition of oxymorphone in cats is characterized by a moderate volume of distribution and a short terminal half-life.

Oxymorphone-Involved Fatalities: A Report of Two Cases

There has been an increased awareness of illicit opiate abusers using the narcotic oxymorphone (Opana) by inhalation. Many laboratory screening techniques currently in use cannot detect oxymorphone in blood or urine. Consequently, biological specimens containing low to moderate concentrations of oxymorphone will likely go undetected. The circumstances, pathology findings, and toxicology results of two fatalities involving oxymorphone are presented. An opiate confirmation gas chromatography-mass spectrometry (GC-MS) procedure, described in detail was able to detected, confirm, and quantify oxymorphone in both subjects. The blood concentrations were 0.05 mg/L (50 microg/L) and 0.12 mg/L (120 microg/L).

Concentration of Oxymorphone in Postmortem Fluids and Tissue

Oxymorphone, a semi-synthetic opioid analgesic, has been available as Numorphan since the 1950s in the form of injectable solutions and a suppository. Recently, in 2006, oxymorphone was approved by the Federal Drug Administration for use in the form of immediate and extended release tablets under the trade name Opana. Since the advent of Opana, the number of deaths involving oxymorphone has risen considerably in the State of North Carolina. To date, there are very few reported values for postmortem concentrations of oxymorphone in the literature to aid in the interpretation of these cases. We report 33 medical examiner cases involving oxymorphone and provide the distribution of oxymorphone in postmortem blood, liver, and urine samples. Oxymorphone was detected in blood by enzyme immunoassay and confirmed by gas chromatography- mass spectrometry utilizing a solid-phase extraction procedure. Calibration curves from 0.025 to 0.50 mg/L were established with a limit of quantitiation of 0.025 mg/L. The mean concentration for oxymorphone in postmortem central (n = 28) and peripheral (n = 23) blood samples was 0.15 mg/L. The median values for the central and peripheral samples were 0.10 mg/L (range: 0.011-0.59) and 0.075 mg/L (range: 0.017-0.82), respectively. Liver concentrations ranged from "none detected" to > 2.0 mg/kg, with mean and median values of 0.36 and 0.30 mg/kg, respectively. The majority of urine samples were > 0.50 mg/L.

SEX DIFFERENCES IN THE PHARMACOKINETICS, OXIDATIVE METABOLISM AND ORAL BIOAVAILABILITY OF OXYCODONE IN THE SPRAGUE‐DAWLEY RAT

1. The pharmacokinetics and oxidative metabolism of oxycodone were investigated following intravenous and oral administration in male and female Sprague-Dawley (SD) rats. 2. High-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-tandem mass spectrometry (MS-MS) was used to quantify plasma concentrations of oxycodone and its oxidative metabolites noroxycodone and oxymorphone following administration of single bolus intravenous (5 mg/kg) and oral (10 mg/kg) doses of oxycodone. 3. The mean (+/-SEM) clearance of intravenous oxycodone was significantly higher in male than female SD rats (4.9 +/- 0.3 vs 3.1 +/- 0.3 L/h per kg, respectively; P < 0.01). Mean areas under the plasma concentration versus time curves (AUC) for oxycodone were significantly higher in female than male SD rats following intravenous (approximately 1.6-fold; P < 0.01) and oral (approximately sevenfold; P < 0.005) administration. 4. The oral bioavailability of oxycodone was low (at 1.2 and 5.0%, respectively) in male and female SD rats, a finding consistent with high first-pass metabolism. Noroxycodone : oxycodone AUC ratios were significantly higher in male than female SD rats after intravenous (approximately 2.4-fold; P < 0.005) and oral (approximately 12-fold; P < 0.005) administration. 5. Circulating oxymorphone concentrations remained very low following both routes of administration. Noroxycodone : oxymorphone AUC ratios were greater in male than female SD rats after intravenous (approximately 13- and fivefold, respectively) and oral (approximately 90- and sixfold, respectively) administration. 6. Sex differences were apparent in the pharmacokinetics, oxidative metabolism and oral bioavailability of oxycodone. Systemic exposure to oxycodone was greater in female compared with male SD rats, whereas systemic exposure to metabolically derived noroxycodone was higher in male than female SD rats. 7. Oral administration of oxycodone to the SD rat is a poor model of the human for the study of the pharmacodynamic effects of oxycodone.

The Effect of Single-Dose Tramadol on Oxycodone Clearance

We have noticed increased prescribing of tramadol by emergency physicians for breakthrough pain in patients chronically taking oxycodone. Both oxycodone and tramadol undergo oxidative metabolism by CYP2D6 and CYP3A4, suggesting the possibility that tramadol may compete with oxycodone for metabolism. A randomized controlled trial in 10 human volunteers was performed to determine if single-dose tramadol therapy would impair oxycodone clearance. Subjects were randomized whether to enter the control or experimental arm of the study first, with each subject serving as his or her own control. In the control arm, each subject received 10 mg immediate-release oxycodone orally and had serial plasma oxycodone and oxymorphone concentrations measured over 8 h. The experimental arm was identical except that 100 mg tramadol was ingested 1.5 h before oxycodone. Clearance divided by fraction absorbed (CL/f) was calculated using the dose and the area under the 8-h time-plasma oxycodone concentration curve. Peak plasma oxycodone concentrations (C max) and time until peak oxycodone concentrations (T max) were secondary outcome parameters. Group size was chosen to produce a power of 0.8 to detect a 20% difference in CL/f between study arms. Values for CL/f, C max, and T max were compared between study arms using two-tailed, paired t-tests. No statistically significant difference between groups was demonstrated for any parameter. We failed to demonstrate that single doses of tramadol impaired oxycodone clearance.

Oxycodone’s Mechanism of Action and Potency Differences after Spinal and Systemic Routes of Administration

Thank you for the opportunity to comment on the letter by Smith et al. and to clarify some recurring misconceptions regarding the pharmacology of oxycodone.Oxycodone is a potent opioid, comparable to morphine, when given systemically. However, as Smith et al. also write, oxycodone has a significantly lower affinity for the μ-opioid receptor compared with morphine. This has been shown in several studies.1,2Indeed, the results of our own recent study3further support the findings that oxycodone has a significantly lower potency compared with morphine when administrated directly to the central nervous system in rats.4,5Smith et al. challenge our study and those by many others by arguing that the antinociceptive effect of oxycodone is mediated trough the κ-opioid receptor. The previous in vivo studies clearly demonstrate that oxycodone is a μ-opioid receptor agonist.1,2,6,7In these studies, the affinity of oxycodone for the κ-opioid receptor is remarkably lower than for the μ-opioid receptor.2,6To the best of our knowledge, not a single in vitro study (binding- or G-protein activation) showing κ-opioid receptor agonism of oxycodone has been published.Beardsley et al. 8studied the pharmacology of oxycodone in mice, rats, and rhesus monkeys. In an excellent article, they reported that oxycodone had potent antinociceptive effects in the mouse paraphenylquinone writhing, hot-plate, and tail-flick assays acting as a μ-opioid receptor agonist. The selective opioid receptor antagonists were studied in the mice tail-flick test. The antinociceptive effect of oxycodone (subcutaneous administration) was only blocked by the selective μ-opioid receptor antagonist β-funaltrexamine (intracerebroventricular administration). The selective κ- and δ-opioid receptor antagonists nor-binaltorphimine (administered subcutaneously 2 h before the agonist) and naltrindole (subcutaneous administration) were not able to block the antinociceptive effect of oxycodone.8Beardsley et al. wrote, “The results have shown that oxycodone is a robust antinociceptive agent, with an abuse liability profile consistent with full μ-opioid receptor agonists.”8Oxycodone completely suppressed signs of withdrawal in morphine-dependent rhesus monkeys. In the previous studies, the selective κ-opioid receptor agonists did not suppress signs of morphine withdrawal.9,10Beardsley et al. 8also demonstrated that even very high doses of oxycodone did not induce behavior (salivation or diuresis) indicative of κ-opioid like activity. Therefore, high-quality classic pharmacology experiments clearly show that oxycodone is a μ-opioid receptor agonist, not a κ-opioid receptor agonist.Smith et al. agree that oxymorphone is a potent μ-opioid receptor agonist.11In our recent study,3nor-binaltorphimine (administered 30 min before study drugs) was not able to antagonize the antinociceptive effect of oxymorphone or oxycodone. Should nor-binaltorphimine behave as a μ-opioid receptor antagonist when given 30 min before the study drugs, as suggested by Smith et al. , the antinociceptive effect of oxymorphone should have been significantly attenuated. The antinociceptive effect of oxymorphone, like that of oxycodone, was prevented only by naloxone, not by nor-binaltorphimine.In our recent study,3oxycodone showed weaker activation of the spinal μ-opioid receptors compared with morphine. The mechanisms behind this difference are interesting and will be studied further. In the brain, oxycodone activated the μ-opioid receptors, albeit to a lesser extent than morphine. The reason why oxycodone produces more potent antinociception compared with morphine after systemic administration remains to be clarified. Smith et al. argue that we are suggesting that the analgesic effects of systemic oxycodone are due to oxymorphone. This is not what we concluded. We suggested that the metabolites may have a role in oxycodone-induced analgesia. We agree that the circulating concentrations of oxymorphone after systemic administration of oxycodone are low, as we12–14and others15have shown. Because systemic oxycodone causes potent μ-opioid receptor agonist effects while being a weak μ-opioid receptor agonist with insignificant binding to other opioid receptors, pharmacokinetic explanations must be considered. One possibility is that the access of either oxycodone itself and/or some of its active metabolites to the central nervous system are more effective compared with that of morphine. There are a number of oxycodone metabolites produced in oxidative and reductive reactions that have not been studied in vivo . Oxymorphone, on the other hand, is an interesting spinal analgesic, and it has recently been launched as an oral analgesic, too.Oxycodone binds to the μ-opioid receptor and activates the μ-opioid receptor, whereas it does not bind to the κ-opioid receptor and does not activate the κ-opioid receptor. Importantly, in human beings, oxycodone behaves as a μ-opioid receptor agonist producing analgesia, euphoria, dependence, and other typical μ-opioid effects. Oxycodone does not cause psychotomimetic effects, dysphoria, diuresis, or other effects typical for a κ-opioid agonist. Several aspects of oxycodone pharmacology still need to be studied. However, it is obvious that oxycodone is a μ-opioid receptor agonist, not a κ-opioid receptor agonist.*University of Helsinki, Helsinki, Finland. kim.lemberg@helsinki.fi

Comparison of the Pharmacokinetics of Oxycodone and Noroxycodone in Male Dark Agouti and Sprague–Dawley Rats: Influence of Streptozotocin-Induced Diabetes

The aims of this study are to evaluate whether cytochrome P450 (CYP)2D1/2D2-deficient dark agouti (DA) rats and/or CYP2D1/2D2-replete Sprague-Dawley (SD) rats are suitable preclinical models of the human, with respect to mirroring the very low plasma concentrations of metabolically derived oxymorphone seen in humans following oxycodone administration, and to examine the effects of streptozotocin-induced diabetes on the pharmacokinetics of oxycodone and its metabolites, noroxycodone and oxymorphone, in both rodent strains. High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to quantify the serum concentrations of oxycodone, noroxycodone, and oxymorphone following subcutaneous administration of bolus doses of oxycodone (2 mg/kg) to groups of nondiabetic and diabetic rats. The mean (+/-SEM) areas under the serum concentration vs. time curves for oxycodone and noroxycodone were significantly higher in DA relative to SD rats (diabetic, p<0.05; nondiabetic, p<0.005). Serum concentrations of oxymorphone were very low (<6.9 nM). Both DA and SD rats are suitable rodent models to study oxycodone's pharmacology, as their systemic exposure to metabolically derived oxymorphone (potent micro-opioid agonist) is very low, mirroring that seen in humans following oxycodone administration. Systemic exposure to oxycodone and noroxycodone was consistently higher for DA than for SD rats showing that strain differences predominated over diabetes status.

Sedative effects and serum concentrations across time after subcutaneous administration of liposome-encapsulated or standard oxymorphone in healthy dogs

Our lab has developed a slow-release liposomal formulation of oxymorphone (LEOx). The purpose of this study was to compare sedative effects and serum concentrations of oxymorphone after administration of LEOx and standard oxymorphone (STDOx) to dogs. At baseline, 1 mL of blood was drawn from the cephalic vein and sedation score was recorded. Dogs were divided into four groups (n = 6): (i) LEOx 1.0 mg kg–1; (ii) LEOx 0.5 mg kg–1; (iii) STDOx 0.1 mg kg–1; (iv) STDOx 0.05 mg kg–1. Unloaded liposomal vehicle (0.5 mL) was used as a control (n = 2). All treatments were given subcutaneously between the scapulae. Sedation score and serum concentration of drug were recorded at 0.5, 1, 2, 4, 8, 12, 16, 24 hours and daily for 5 days. Serum concentrations were measured with ELISA. At all time points, drug was not detected and sedation score was 0 in the control group. Sedation score for group 1 was significantly higher (p < 0.05) at 1 hour than for groups 2,3, and 4. There was no difference in sedation score between treatment groups at any other time. Serum concentrations of drug were significantly higher (p < 0.05) for group 1 at all time points measured after baseline. In groups 2, 3, and 4, serum concentrations of drug fell below the limit of detection (1.5 ng mL–1) by 24 hours. Serum concentrations after 0.1 mg kg–1of STDOx were 11.1 ± 3.6 ng mL–1at 4 hours, which is the recommended time for redosing and presumably reflects the lower end of a therapeutic serum concentration. Serum concentrations were comparable after 1.0 mg kg–1 of LEOx (10.5 ± 2.4 ng mL–1) 48 hours after administration. These results suggest that liposomal oxymorphone may provide therapeutic serum concentrations of drug for 2 days after a single subcutaneous administration without undue sedation or other deleterious effects in healthy dogs. Further studies are warranted to assess analgesic efficacy and pharmacokinetics of lipsomal oxymorphone in dogs.

Serum concentrations across time after subcutaneous administration of liposome-encapsulated or standard oxymorphone in Rhesus macaques

Our lab has developed a slow-release liposomal formulation of oxymorphone (LEOx). The purpose of this study was to compare serum concentrations of oxymorphone after administration of LEOx and standard oxymorphone (STDOx) to healthy female rhesus macaques. At baseline, 1 mL of blood was drawn from the femoral vein with the animal in a restraint cage. Primates were divided into two groups: (i) LEOx 1.0 mg kg–1(n = 4); 2) STDOx 0.1 mg kg–1(n = 4). Unloaded liposomal vehicle (0.5 mL) was used as a control (n = 2). All treatments were given subcutaneously in a shaved area proximal to the right ileal wing. Femoral venous blood was drawn and serum concentrations of drug were measured at 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours. Serum concentrations were measured with ELISA. Serum concentrations were compared between groups and within groups across time with anova. Drug was not detected at any time point in the control group. While sedation was not objectively measured, no animal appeared overly sedate after either treatment. All animals willingly accepted treats and did not appear nauseated or somnolent. Serum concentrations of drug were not significantly different between the two treatment groups from 0 to 2 hours. From 4 hours through 72 hours, however, serum concentrations were significantly higher (p < 0.05) in the animals that received LEOx. By 12 hours, serum concentrations of drug fell below the limit of detection (1.5 ng mL–1) in animals that received STOx. In animals that received LEOx, serum concentrations at 72 hours were comparable to those measured at 4 hours in animals that received STOx. These results suggest that subcutaneous administration of liposomal oxymorphone yields extended serum levels of drug. These results also suggest that liposomal oxymorphone may provide therapeutic (i.e. analgesic) serum concentrations of drug for 2–3 days after a single subcutaneous administration. Further studies are warranted to assess analgesic efficacy and pharmacokinetics of lipsomal oxymorphone in primates.

Sedative effects and serum drug concentrations of oxymorphone and metabolites after subcutaneous administration of a liposome‐encapsulated formulation in dogs

Sedative effects and serum drug concentrations of oxymorphone and metabolites after subcutaneous administration of a liposome‐encapsulated formulation in dogs

Opioids: clinical pharmacology: Population pharmacokinetic (PPK) modeling of oxycodone (OC) and its active metabolite, oxymorphone (OM) following administration of CR-oxycodone (OxyContin®)

The purpose was to develop a PPK model that simultaneously predicts the plasma concentrations of OC and OM following OxyContin® (oxycodone HCL controlled-release) Tablets administration. Data were pooled from two Phase I studies in order to build the parent-metabolite model in NONMEM. In the first dose escalating study, OM was administered to healthy volunteers either as intravenous injection or oral solution. The second study provided OC and OM plasma levels after oral administration of OxyContin®. Oxymorphone undergoes significant first pass effects resulting in bioavailability of 5%, whereas oxycodone is less prone to first pass effects and its bioavailability is >50%. Significant intersubject variability was observed following OM administration. An 8-compartment model with 18 pharmacokinetic (PK) parameters was established where the rate of OM formation from oxycodone was estimated as mean (interindividual variability; %CV): 8.27(40%). The estimates of clearances for OM and OC were: 43.3(58) L/h and 94.7(44) L/h, respectively and estimates of volume of distribution for OM and OC were: 77.4(36) L and 541.0(37) L, respectively, were also estimated. External validation of the PPK model was performed by comparing the model-predicted values to the observed OC and OM plasma levels after oxycodone dosing. The model provides good estimates of the PPK parameters and their associated variabilities for both OC and OM. The model is useful in predicting both the parent and metabolite exposures following all dosing regimens of OxyContin®. The model quantified the very low bioavailability and the high inter-subject variability that was observed following oral oxymorphone administration.