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NSAIDs and acetaminophen
Abstracts (825) Comparison of analgesic efficacy of Rofecoxib 50 mg between patients with moderate pain and severe acute pain P. Desjardins, S. Bird, R. Petruschke, D. Chang; Merck & Co., Inc., West Point, PA Rofecoxib 50 mg is effective in the treatment of acute pain. A recently completed study compared patient responses to rofecoxib (ROF) and multidose oxycodone/acetaminophen (OXY/ACET) using a validated postoperative dental pain model. We further compared the response to ROF treatment between patients with moderate pain and severe pain in this double-blind, randomized control trial. Patients experiencing moderate or severe pain after surgical extraction of at least 2 third molars were randomized to a single dose of ROF 50mg (N⫽118), OXY/ACET 10/650mg followed by 5/325mg q6hrs PRN (N⫽122), or placebo (N⫽30) for 24hrs. Key endpoints were overall analgesic efficacy over 6hrs (TOPAR6) and 24hrs (SPID24). To compare responses to ROF between patients with moderate and severe pain, TOPAR6, SPID24, patient global responders, onset (time to confirmed perceptible pain relief), and duration (time to rescue medication within) were analyzed for consistency of treatment effect by baseline pain intensity subgroups. ROF demonstrated comparable overall efficacy to OXY/ACET on TOPAR6 and SPID24. ROF patients with moderate and severe pain achieved numerically similar responses on TOPAR6 and SPID24, which were comparable to moderate and severe pain subgroup responses with OXY/ACET. Patient global response was also numerically similar between ROF patients with moderate and severe pain at 6hrs (82.4% vs 78.7%) and at 24hrs (84.5% vs 78.7%) with similar treatment effects among the moderate and severe subgroups compared to OXY/ACET. ROF patients in the moderate and severe subgroups achieved pain relief in a similar timeframe (38 vs 39 minutes); the proportion of patients achieving onset was also similar (84.5% vs 80.9%). The duration of analgesia for ROF was ⬎24hrs for both subgroups. Rofecoxib 50 mg has similar analgesic efficacy in patients with severe acute postoperative dental pain and moderate pain, based on overall analgesic effect, onset, and duration.
(826) Response to treatment relative to baseline pain severity with Etoricoxib and Indomethacin for acute gouty arthritis D. Daikh, B. Rubin, H. Schumacher, J. Ng, Q. Yu, R. Petruschke, J. Boice, Z. Ozturk, K. Malmstrom, G. Geba; Merck & Co., Inc., West Point, PA Two similarly designed studies in acute gout demonstrated the comparable efficacy of etoricoxib and indomethacin. Combined analysis of the studies was performed to evaluate efficacy of etoricoxib and indomethacin in subgroups of patients according to severity of pain. Patients in two 8-day studies were randomly assigned to double-blind treatment with etoricoxib 120 mg once daily or indomethacin 50 mg three times daily. Subgroup analysis was performed of response to treatment relative to patients’ baseline level of pain (moderate or severe/extreme). Primary endpoint was mean change from baseline in Patient Assessment of Pain averaged over Days 2 to 5 using a 0- to 4- point Likert scale. Secondary endpoints included Patient and Investigator Global Assessment of Response to Therapy and Study Joint Tenderness. An ANCOVA model was utilized to evaluate treatment-by-subgroup interaction. This model was also used to construct the 95% confidence interval (CI) for within-treatment least-square means and least-square mean difference between treatments. 339 patients were randomized to etoricoxib (n⫽178) or indomethacin (n⫽161). Baseline characteristics were similar across treatment groups within the two studies. Difference in patient pain scores between etoricoxib and indomethacin was -0.16 (95% CI: -0.49, 0.17) for patients with moderate pain and 0.06 (95% CI -0.14, 0.26) for patients with severe/extreme pain. Differences were within pre-specified comparability bounds of ⫾0.5 on the Likert scale. Test for treatment by subgroup interaction was not significant. There was a greater reduction from baseline pain in those with severe/extreme versus moderate pain. Treatments were comparable for secondary endpoints in the subgroups.This subgroup analysis showed that treatment with etoricoxib 120 mg once daily and indomethacin 50 mg three times daily provided comparable and effective pain relief in the setting of acute pain when comparing patients with moderate pain and even those with severe/extreme pain.
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D14 - Opioids: Clinical Pharmacology (827) Dose-dependent increment in QTc interval duration in men, but not women, treated with chronic oral methadone in addition to other drugs known to prolong the QTc Y. Yap, P. Homel, R. Sekine, Y. Suzuki, D. Lussier, J. Lapin, P. Schweitzer, S. Yancovitz, R. Portenoy, R. Cruciani; Beth Israel Medical Center, New York, NY Methadone is commonly used for the treatment of pain and opioid addiction. Due to safety concerns based on reports of life-threatening arrhythmias, we looked at the effect of chronic oral methadone on the duration of the QTc interval. Patients receiving oral methadone for treatment of pain or opioid addiction had a 12-lead electrocardiogram done and the QTc interval was calculated. Normally distributed data are presented as mean ⫾ SD (minimum, maximum) while skewed data are presented as median (minimum, maximum). Gender (M: 66, F: 40), age (M: 45.6⫹9.5 (18,66)), F: 45⫾9.8 (23,67), methadone dose (M: 140 (20,800), F: 197 (20, 1440)), duration of treatment in months (M: 12 (1,444), F: 13.5 (1,384)), treated with other medications known to cause QTc prolongation (M:24, F: 18), and QTc duration (M: 433⫾22 (396,494), F: 435⫾ 27.2 (499,539)). 95% confidence limits for QTc were 424, 438 in males and 428, 441 in females. There was a strong correlation between the dose of methadone and QTc duration in males receiving other drugs known to prolong the QTc, (r⫽0.51, p⫽0.01, n⫽24), and weak in patients receiving only methadone (r⫽0.12, p⬍0.45, n⫽42). In women, the correlation was weak despite being on medications that could prolong the QTc (r⫽-0.16, p⬍0.47, n⫽22 and r⫽-0.34, p⬍0.17, n⫽18 in methadone alone). Of the 106 patients four patients presented a QTc duration above 496 msec and considered to be at high risk of torsade de pointes. QTc normalization was observed in one patient after reducing the methadone dose while the others remained constant. There was a dose dependent prolongation of the QTc in a significant number of men treated with methadone and other medications known to prolong the QTc, including increased risk for torsade de pointes.
(828) Population pharmacokinetic (PPK) modeling of oxycodone (OC) and its active metabolite, oxymorphone (OM) following administration of CR-oxycodone (OxyContin姞) A. El-Tahtawy, P. Nardy, V. Vashi, S. Harris; Purdue Pharma L.P., Stamford, CT 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.
(826) Response to treatment relative to baseline pain severity with Etoricoxib and Indomethacin for acute gouty arthritis D. Daikh, B. Rubin, H. Schumacher, J. Ng, Q. Yu, R. Petruschke, J. Boice, Z. Ozturk, K. Malmstrom, G. Geba; Merck & Co., Inc., West Point, PA Two similarly designed studies in acute gout demonstrated the comparable efficacy of etoricoxib and indomethacin. Combined analysis of the studies was performed to evaluate efficacy of etoricoxib and indomethacin in subgroups of patients according to severity of pain. Patients in two 8-day studies were randomly assigned to double-blind treatment with etoricoxib 120 mg once daily or indomethacin 50 mg three times daily. Subgroup analysis was performed of response to treatment relative to patients’ baseline level of pain (moderate or severe/extreme). Primary endpoint was mean change from baseline in Patient Assessment of Pain averaged over Days 2 to 5 using a 0- to 4- point Likert scale. Secondary endpoints included Patient and Investigator Global Assessment of Response to Therapy and Study Joint Tenderness. An ANCOVA model was utilized to evaluate treatment-by-subgroup interaction. This model was also used to construct the 95% confidence interval (CI) for within-treatment least-square means and least-square mean difference between treatments. 339 patients were randomized to etoricoxib (n⫽178) or indomethacin (n⫽161). Baseline characteristics were similar across treatment groups within the two studies. Difference in patient pain scores between etoricoxib and indomethacin was -0.16 (95% CI: -0.49, 0.17) for patients with moderate pain and 0.06 (95% CI -0.14, 0.26) for patients with severe/extreme pain. Differences were within pre-specified comparability bounds of ⫾0.5 on the Likert scale. Test for treatment by subgroup interaction was not significant. There was a greater reduction from baseline pain in those with severe/extreme versus moderate pain. Treatments were comparable for secondary endpoints in the subgroups.This subgroup analysis showed that treatment with etoricoxib 120 mg once daily and indomethacin 50 mg three times daily provided comparable and effective pain relief in the setting of acute pain when comparing patients with moderate pain and even those with severe/extreme pain.
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D14 - Opioids: Clinical Pharmacology (827) Dose-dependent increment in QTc interval duration in men, but not women, treated with chronic oral methadone in addition to other drugs known to prolong the QTc Y. Yap, P. Homel, R. Sekine, Y. Suzuki, D. Lussier, J. Lapin, P. Schweitzer, S. Yancovitz, R. Portenoy, R. Cruciani; Beth Israel Medical Center, New York, NY Methadone is commonly used for the treatment of pain and opioid addiction. Due to safety concerns based on reports of life-threatening arrhythmias, we looked at the effect of chronic oral methadone on the duration of the QTc interval. Patients receiving oral methadone for treatment of pain or opioid addiction had a 12-lead electrocardiogram done and the QTc interval was calculated. Normally distributed data are presented as mean ⫾ SD (minimum, maximum) while skewed data are presented as median (minimum, maximum). Gender (M: 66, F: 40), age (M: 45.6⫹9.5 (18,66)), F: 45⫾9.8 (23,67), methadone dose (M: 140 (20,800), F: 197 (20, 1440)), duration of treatment in months (M: 12 (1,444), F: 13.5 (1,384)), treated with other medications known to cause QTc prolongation (M:24, F: 18), and QTc duration (M: 433⫾22 (396,494), F: 435⫾ 27.2 (499,539)). 95% confidence limits for QTc were 424, 438 in males and 428, 441 in females. There was a strong correlation between the dose of methadone and QTc duration in males receiving other drugs known to prolong the QTc, (r⫽0.51, p⫽0.01, n⫽24), and weak in patients receiving only methadone (r⫽0.12, p⬍0.45, n⫽42). In women, the correlation was weak despite being on medications that could prolong the QTc (r⫽-0.16, p⬍0.47, n⫽22 and r⫽-0.34, p⬍0.17, n⫽18 in methadone alone). Of the 106 patients four patients presented a QTc duration above 496 msec and considered to be at high risk of torsade de pointes. QTc normalization was observed in one patient after reducing the methadone dose while the others remained constant. There was a dose dependent prolongation of the QTc in a significant number of men treated with methadone and other medications known to prolong the QTc, including increased risk for torsade de pointes.
(828) Population pharmacokinetic (PPK) modeling of oxycodone (OC) and its active metabolite, oxymorphone (OM) following administration of CR-oxycodone (OxyContin姞) A. El-Tahtawy, P. Nardy, V. Vashi, S. Harris; Purdue Pharma L.P., Stamford, CT 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.