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(241) Bioavailability of oxymorphone extended-release tablets following consumption of alcohol or food
P36 (240) A pharmacokinetic profile of intranasal hydromorphone in emergency room trauma patients P Lacouture, A Rudy, F Hefti, T Clinch, D Wermeling; Intranasal Therapeutics, Inc., Lexington, KY Intranasal hydromorphone HCl is under development for the management of moderate to severe trauma pain. An element of this investigation was to assess plasma concentrations at near peak times, at the end of a typical dosing interval and across a range of doses being evaluated for relative clinical efficacy and tolerability. Intranasal administration of hydromorphone with a sprayer configured to deliver 2, 4, 6, 8 or 10mg of hydromorphone in 100L of solution was studied in patients with pain ⬎5 on a 0-10 scale and were evaluated as candidates for opioid treatment. Blood was obtained at baseline and a single dose of intranasal hydromorphone administered. Samples were collected at 30, 60 and 180 minutes following dosing then assayed using LC/MS/MS for plasma hydromorphone concentrations. Patients (n⫽113) were dosed with 2mg (n⫽14), 4mg (n⫽19), 6mg (n⫽33), 8mg (n⫽28) or 10mg (n⫽19) of intranasal hydromorphone. Analysis of plasma hydromorphone demonstrated a dose-related increase at most timepoints. The maximum measured concentration was observed at 30 minutes (mean 2.22ng/mL with 2mg, 4.26ng/mL with 4mg, 5.04ng/mL with 6mg, 6.21ng/mL with 8mg and 7.14ng/mL with 10mg). Concentrations observed following 2mg intranasal doses were similar to those seen for 2mg doses in healthy volunteers. Therapeutic concentrations of hydromorphone in acute pain approximate 4ng/mL. With this intranasal administration at the 30 minute timepoint, 2mg was at or above this concentration in 7% of patients, in 42% of patients with 4mg, in 63% of patients with 6mg, in 81% of patients with 8mg and in 95% of patients with 10mg indicating potential for rapid pain relief. We conclude that for trauma patients presenting to the ER, intranasal administration of this product resulted in rapid absorption of hydromorphone into the plasma. These plasma hydromorphone concentrations are consistent with analgesic concentrations reported in the literature. Supported by Intranasal Therapeutics, Inc.
(241) Bioavailability of oxymorphone extended-release tablets following consumption of alcohol or food W Fiske, I Benedek, H Ahdieh; Endo Pharmaceuticals Inc., Chadds Ford, PA Two studies assessed the in vivo bioavailability of oral oxymorphone extended-release (ER) tablets under fed and fasted conditions (study 1) or following alcohol consumption (study 2). Both studies used a 4-period crossover design wherein healthy volunteers were randomized to receive a single oral dose of oxymorphone ER (40 mg) under fasting conditions and after a high-fat meal [immediate-release tablets (4x10 mg) were administered in 2 periods], or with each of 4 aqueous solutions containing 0%, 4%, 20%, or 40% ethanol. In both studies, subjects received naltrexone (50 mg) to minimize significant opioid-related adverse events, and each treatment was separated by a 7-day washout period. Serial blood samples for determination of oxymorphone pharmacokinetics were obtained through 72 (study 1) or 48 (study 2) hours postdose. Neither food nor ethanol was associated with significant alterations in area under the curve or most other pharmacokinetic parameters, with the exception of maximum concentration (Cmax). In study 1, Cmax was increased by 51% (geometric mean ratio for Cmax ⫽ 1.51; 90% CI, 1.34 –1.70) in fed subjects compared with fasted subjects. In study 2, concentration-related increases in Cmax were also observed when oxymorphone was administered with ethanol 4%, 20%, or 40% (7%, 31%, or 70%, respectively) relative to administration with water. Alterations in Cmax appear to be unrelated to direct effects of alcohol on the ER tablet because the rate of oxymorphone release in vitro was unaffected by alcohol concentrations up to 40%. In these studies, increases in the Cmax of oxymorphone ER administered after a high-fat meal or with alcohol were similar in magnitude and unrelated to ER matrix degradation, suggesting that Cmax may be increased through a similar mechanism (eg, gastric emptying, increased splanchnic blood flow). The clinical impact of these Cmax elevations is unknown. This research was funded by Endo Pharmaceuticals Inc.
Abstracts (242) Marked and sustained reduction of opioid requirements after administration of intravenous naloxone for respiratory depression S Maingi, N Moryl, C Inturrisi; Memorial Sloan Kettering Cancer Center, New York, NY Naloxone is a mu-opioid antagonist used to reverse opioid-induced sedation and respiratory depression. When administered at the low subtherapeutic doses concurrently with opioids, it has been observed to improve opioid analgesia in chronic but not acute pain. We present a case of a 33 year-old man with widely metastatic stage IV diffuse large B-cell lymphoma and a long history of intermittent exposure to hydromorphone. He required up to 18 mg intravenous boluses of hydromorphone during prior pain exacerbations. On this occasion, he had excruciating abdominal pain due to bowel prolapsed through his ileostomy. He was started on intravenous hydromorphone that was rapidly titrated to 19 mg/hr. At this dose, he experienced some improvement in analgesia and no sedation. He was changed to methadone over the next 2 days, and good analgesia was achieved 36 hours later at a dose of 8 mg/hr of intravenous methadone. Twelve hours later, the patient developed sedation and respiratory depression and was electively intubated for 12 hours. During that time naloxone 1.2 mg was administered intravenously in divided doses. Upon extubation the patient’s opioid requirements markedly dropped to 1.3 mg/hr hydromorphone (a 15-fold decrease). This effect was sustained for over 6 weeks. This case report demonstrates a marked (15-fold) and sustained decrease in opioid requirements after an episode of opioid-induced sedation and respiratory depression which were reversed by naloxone administration. Possible explanations of this unusual response are: 1) decreased opioid tolerance by naloxone; 2) resolution of hydromorphone-induced hyperalgesia while on methadone; 3) resolution of an acute pain crisis that incidentally coincided with the administration of a large dose of naloxone. However, none of these explanations adequately explains this patient’s profound and sustained reduction in opioid requirements.
(243) Comparative phase I PK study of aerosolized free and liposome-encapsulated fentanyl (AeroLEF) demonstrates rapid and extended plasma fentanyl concentrations following inhalation O Hung, D Pliura; Biovail Contract Research, Toronto, ON AeroLEF is a proprietary combination of free and liposome-encapsulated fentanyl for inhalation via breath-actuated nebulizers. We report the pharmacokinetics, safety, and tolerability of 1500g AeroLEF vs. 200g bolus IV fentanyl; values are mean (⫾ SD). Healthy, opiate-naı¨ve volunteers inhaled microdoses of AeroLEF (ⱕ 5g/breath; total emitted fentanyl dose ⱕ 1000g) over 7-15 min. Within 4 min of initiating AeroLEF inhalation, subjects attained plasma fentanyl concentrations (Cp) of 0.734 ng.mL-1. Maximum Cp was similar with AeroLEF and IV fentanyl (2.53 vs. 2.80 ng.mL-1). Cmax (mean of 15 min) occurred shortly after completion of AeroLEFTM inhalation (mean of 12 min), indicating rapid absorption from the lung. Cp values in the effective range persisted for several hours with AeroLEF (at 4 hr, Cp was 0.525 ⫾ 0.180 ng.mL-1) but not with IV administration (at 1 hr, Cp was 0.559 ⫾ 0.209 ng.mL-1). Similar inter-subject variability in exposure was observed in both treatment arms: coefficient in variation of AUC was 24% with IV administration vs. 29% with AeroLEF. Subjects were monitored continuously for adverse respiratory events. No severe adverse events were observed. Mild hypoxia was observed in both treatment groups. Mild bradycardia was observed in one subject receiving IV fentanyl. Spirometry measurements (FVC, FEV1 and FEF25%-75%) before and after AeroLEF indicated no significant changes in lung function. In summary, AeroLEF achieves rapid and persistent fentanyl concentrations in the therapeutic range and appears to be well tolerated. Industry support provided by YM BioSciences Inc.
(241) Bioavailability of oxymorphone extended-release tablets following consumption of alcohol or food W Fiske, I Benedek, H Ahdieh; Endo Pharmaceuticals Inc., Chadds Ford, PA Two studies assessed the in vivo bioavailability of oral oxymorphone extended-release (ER) tablets under fed and fasted conditions (study 1) or following alcohol consumption (study 2). Both studies used a 4-period crossover design wherein healthy volunteers were randomized to receive a single oral dose of oxymorphone ER (40 mg) under fasting conditions and after a high-fat meal [immediate-release tablets (4x10 mg) were administered in 2 periods], or with each of 4 aqueous solutions containing 0%, 4%, 20%, or 40% ethanol. In both studies, subjects received naltrexone (50 mg) to minimize significant opioid-related adverse events, and each treatment was separated by a 7-day washout period. Serial blood samples for determination of oxymorphone pharmacokinetics were obtained through 72 (study 1) or 48 (study 2) hours postdose. Neither food nor ethanol was associated with significant alterations in area under the curve or most other pharmacokinetic parameters, with the exception of maximum concentration (Cmax). In study 1, Cmax was increased by 51% (geometric mean ratio for Cmax ⫽ 1.51; 90% CI, 1.34 –1.70) in fed subjects compared with fasted subjects. In study 2, concentration-related increases in Cmax were also observed when oxymorphone was administered with ethanol 4%, 20%, or 40% (7%, 31%, or 70%, respectively) relative to administration with water. Alterations in Cmax appear to be unrelated to direct effects of alcohol on the ER tablet because the rate of oxymorphone release in vitro was unaffected by alcohol concentrations up to 40%. In these studies, increases in the Cmax of oxymorphone ER administered after a high-fat meal or with alcohol were similar in magnitude and unrelated to ER matrix degradation, suggesting that Cmax may be increased through a similar mechanism (eg, gastric emptying, increased splanchnic blood flow). The clinical impact of these Cmax elevations is unknown. This research was funded by Endo Pharmaceuticals Inc.
Abstracts (242) Marked and sustained reduction of opioid requirements after administration of intravenous naloxone for respiratory depression S Maingi, N Moryl, C Inturrisi; Memorial Sloan Kettering Cancer Center, New York, NY Naloxone is a mu-opioid antagonist used to reverse opioid-induced sedation and respiratory depression. When administered at the low subtherapeutic doses concurrently with opioids, it has been observed to improve opioid analgesia in chronic but not acute pain. We present a case of a 33 year-old man with widely metastatic stage IV diffuse large B-cell lymphoma and a long history of intermittent exposure to hydromorphone. He required up to 18 mg intravenous boluses of hydromorphone during prior pain exacerbations. On this occasion, he had excruciating abdominal pain due to bowel prolapsed through his ileostomy. He was started on intravenous hydromorphone that was rapidly titrated to 19 mg/hr. At this dose, he experienced some improvement in analgesia and no sedation. He was changed to methadone over the next 2 days, and good analgesia was achieved 36 hours later at a dose of 8 mg/hr of intravenous methadone. Twelve hours later, the patient developed sedation and respiratory depression and was electively intubated for 12 hours. During that time naloxone 1.2 mg was administered intravenously in divided doses. Upon extubation the patient’s opioid requirements markedly dropped to 1.3 mg/hr hydromorphone (a 15-fold decrease). This effect was sustained for over 6 weeks. This case report demonstrates a marked (15-fold) and sustained decrease in opioid requirements after an episode of opioid-induced sedation and respiratory depression which were reversed by naloxone administration. Possible explanations of this unusual response are: 1) decreased opioid tolerance by naloxone; 2) resolution of hydromorphone-induced hyperalgesia while on methadone; 3) resolution of an acute pain crisis that incidentally coincided with the administration of a large dose of naloxone. However, none of these explanations adequately explains this patient’s profound and sustained reduction in opioid requirements.
(243) Comparative phase I PK study of aerosolized free and liposome-encapsulated fentanyl (AeroLEF) demonstrates rapid and extended plasma fentanyl concentrations following inhalation O Hung, D Pliura; Biovail Contract Research, Toronto, ON AeroLEF is a proprietary combination of free and liposome-encapsulated fentanyl for inhalation via breath-actuated nebulizers. We report the pharmacokinetics, safety, and tolerability of 1500g AeroLEF vs. 200g bolus IV fentanyl; values are mean (⫾ SD). Healthy, opiate-naı¨ve volunteers inhaled microdoses of AeroLEF (ⱕ 5g/breath; total emitted fentanyl dose ⱕ 1000g) over 7-15 min. Within 4 min of initiating AeroLEF inhalation, subjects attained plasma fentanyl concentrations (Cp) of 0.734 ng.mL-1. Maximum Cp was similar with AeroLEF and IV fentanyl (2.53 vs. 2.80 ng.mL-1). Cmax (mean of 15 min) occurred shortly after completion of AeroLEFTM inhalation (mean of 12 min), indicating rapid absorption from the lung. Cp values in the effective range persisted for several hours with AeroLEF (at 4 hr, Cp was 0.525 ⫾ 0.180 ng.mL-1) but not with IV administration (at 1 hr, Cp was 0.559 ⫾ 0.209 ng.mL-1). Similar inter-subject variability in exposure was observed in both treatment arms: coefficient in variation of AUC was 24% with IV administration vs. 29% with AeroLEF. Subjects were monitored continuously for adverse respiratory events. No severe adverse events were observed. Mild hypoxia was observed in both treatment groups. Mild bradycardia was observed in one subject receiving IV fentanyl. Spirometry measurements (FVC, FEV1 and FEF25%-75%) before and after AeroLEF indicated no significant changes in lung function. In summary, AeroLEF achieves rapid and persistent fentanyl concentrations in the therapeutic range and appears to be well tolerated. Industry support provided by YM BioSciences Inc.