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(187) A randomized pharmacokinetic study of AD 923 (Fentanyl Sublingual Spray) vs. Actiq (OTFC) and Fentanyl Citrate injection in healthy human volunteers
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Antidepressants (184) Is the improvement in vitality independent of the improvements in sleep interference and pain in patients with diabetic peripheral neuropathic pain? Responses to treatment with duloxetine D Fishbain, J Hall, R Risser, J Gonzales; Eli Lilly and Company, Indianapolis, IN A major issue in pain literature has been whether there is an etiological association between pain, sleep, and vitality. Data from duloxetine clinical trials in patients with diabetic peripheral neuropathic pain (DPNP) were used to investigate associations between pain, sleep and vitality. Data were pooled from 3 double-blind, randomized, placebo-controlled, 12-week trials in which major mood disorders were excluded. Study 1 (N⫽457) compared duloxetine 20mg once daily (QD), 60mg QD, 60mg twice daily (BID), and placebo; Studies 2 (N⫽334) and 3 (N⫽348) compared duloxetine 60mg QD and 60mg BID with placebo. A subset of patients (n⫽804) with complete data across the 4 assessments was constructed by dropping patients 1) reporting maximum vitality at baseline, 2) experiencing treatment-emergent somnolence, asthenia or fatigue or 3) taking sedating concomitant medications or duloxetine 20 mg/day. Efficacy measures included daily and night pain severity collected via patient diaries, Brief Pain Inventory (BPI) sleep interference, and SF-36 vitality domain. For duloxetine, mean improvements from baseline to endpoint in daily and night pain severity, BPI sleep interference, and vitality were significantly superior to placebo (ⱕ.002). Correlations between changes to endpoint in daily pain, night pain, and sleep interference with vitality changes were -.33, -.31, and -.28, respectively (p⬍.001). The direct effect of treatment on change in vitality was statistically significant (66%, p⫽.024) when assessed in an indirect manner through change in sleep interference alone but not when jointly assessed with average pain (32%, p⫽.283) or night pain (48%, p⫽.097). Results suggest weak to moderate associations between changes in average pain, night pain, and sleep interference with changes in vitality. Improvement in vitality was independent of improvements in sleep interference alone but the treatment effect on vitality was mediated by sleep interference when jointly modeled with improvement in average or night pain. This research received funding from Eli Lilly and Company.
(185) A comparison of strategies for switching patients from amitriptyline to duloxetine for the management of diabetic peripheral neuropathic pain M Robinson, V Whitmyer, R Risser, S Malcolm, J Ahl; Eli Lilly and Company, Indianapolis, IN Duloxetine is effective in the management of diabetic peripheral neuropathic pain (DPNP), and may have a better safety and tolerability profile than frequently prescribed tricyclic antidipressants, like amitriptyline. Strategies for switching medications attempt to balance the risk of discontinuation-emergent/treatment-emergent adverse events (AE) with onset of efficacy. This was a multicenter, randomized, doubleblind, parallel, 8-week trial in patients with DPNP treated with a stable dose of amitriptyline 25-100 mg/day to compare strategies for switching to duloxetine 60 mg/day. Patients were randomized into 3 groups: discontinue then titrate (DTT) (n⫽26), direct switch (DS) (n⫽26), or tapertitrate (TT) (n⫽26). The primary objective was to compare adverse event burden, measured by a “common adverse events” (CAE) total score from the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale, between DS and TT regimens during the initial 4-week switch period; DTT served as a control since their continued amitriptyline use was masked during this period. Randomized patients had diabetes (type II, 91%) for 13.3 years and neuropathic pain for 5.6 years. Inadequate pain efficacy was most commonly reported by patients (83%) and physicians (74%) as the reason for wanting to switch. Baseline CAE total score was 3.13⫾4.3, corresponding to having one severe AE, 3 mild AEs, or 1 mild and 1 moderate AE. Baseline 24-hour weekly average pain score was 4.3⫾2.3 (moderate). After switching to duloxetine, CAE total scores were not significantly changed, pain was not worsened, and differences between switch groups on these measures were not significant. These results suggest that switching from amytriptyline to duloxetine may not be associated with an increase in CAE or transient worsening in pain. Interpretation of these results is limited by the small sample size due to early termination of the trial because of enrollment difficulties. Supported by funding from Eli Lilly and Company.
Abstracts (186) Safety and tolerability of Duloxetine in the treatment of patients with Fibromyalgia: Analysis of 5 studies E Choy, P Mease, D Kajdasz, M Wohlreich, D Walker, A Chappell; King’s College London, London, UK Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has been shown to effectively treat patients with fibromyalgia. The objective of this integrative analysis is to evaluate the safety and tolerability of duloxetine during up to 60 weeks of treatment. Patients (N⫽1236) from 4 placebo-controlled studies employing doses of 20, 60, and 120mg/day of duloxetine, and one long-term study (N⫽350) employing doses of 60 and 120mg/day, were used in these analyses. Safety and tolerability were assessed via reasons for discontinuation, treatment-emergent adverse events (TEAEs), discontinuation-emergent adverse events, and changes in vital signs, weight, and laboratory analytes. In the placebocontrolled studies, overall exposure was 264 patient-years for duloxetine and 154 for placebo. The patients were primarily female (95%) and Caucasian (80.4%), with a mean age of 50.1 years. In the long-term study, patients were similar in demography and duloxetine exposure was 285 patient-years. Discontinuations due to adverse events were higher in the duloxetine group (duloxetine, 19.5%; placebo, 11.8%, P⬍.001), whereas discontinuations due to lack of efficacy were higher in the placebo group (duloxetine, 7.0%; placebo, 13.5%, P⬍.001). The most common TEAE was nausea (duloxetine, 29.3%; placebo, 11.4%, P⬍.001). Nausea was reported as mild to moderate and tended to resolve over time. Clinically small, but statistically significant differences (P⬍.01) in mean changes in pulse (bpm, 1.22, -.42), systolic (mmHg, 0.91, -1.58) and diastolic (mmHg, 1.04, -1.17) blood pressure, and weight (kg, -.43, 0.28) occurred, respectively, in the duloxetine group compared with the placebo group. In the long-term uncontrolled study, mean changes in vitals during up to 60 weeks of treatment with duloxetine were: -0.1 and -0.2 mmHg for supine systolic and diastolic blood pressure, 0.7 kg for weight (P⫽.005), and 1.9 bpm for pulse (P⬍.001) The safety and tolerability profile of duloxetine in these fibromyalgia studies was similar to that observed with duloxetine in other indications.
Cancer Pain–Opioids (187) A randomized pharmacokinetic study of AD 923 (Fentanyl Sublingual Spray) vs. Actiq (OTFC) and Fentanyl Citrate injection in healthy human volunteers R Tansley, S Connolly, R Bannister, S Snape, B Ruparelia, I Walker, A Raza; MDS Pharma Services, Neptune, NJ AD 923 is a sub-lingual fentanyl product being developed for the treatment of cancer breakthrough pain. This was a randomized, single-dose, 3-period, 3-treatment, crossover study. A total of 25 healthy subjects (8 females and 17 males), 18 – 45 years of age, with a BMI between 18 and 30 kg/m2 were enrolled (23 completed). Each subject received single doses of 200g AD 923, 200g Actiq (OTFC) and 100g intravenous fentanyl during 3 treatment periods separated by 4 to 7 days. Plasma fentanyl concentrations were determined at frequent intervals until 48 hours post-dose. AD 923 had a significantly shorter median Tmax compared with Actiq (40 vs. 120 minutes) indicating a faster onset of exposure of fentanyl after the AD 923 dose. AD 923 had a significantly higher absolute bioavailability compared to Actiq (77.7% vs. 50.9%). Mean Cmax (347 vs. 196 pg/mL) and AUC(0-⬁)(2165 vs. 1389 pg*hr/mL) were higher for AD 923 compared with Actiq. Mean plasma fentanyl half-lives ranged between 5.8-7.4 hours in the 3 groups. Neither race nor gender had a statistically significant effect on Cmax or AUC. All products were well tolerated with no SAEs reported. 32 treatment-emergent AEs (TEAEs) were reported by 12 (out of 25) subjects. Of the 32 TEAEs, 31 were mild in severity and 1 was moderate. AEs were reported most commonly following fentanyl injection (38%), followed by AD 923 (25%), and Actiq (21%). Dizziness, nausea, and pruritus were the most commonly reported TEAEs. No subject withdrew due to an AE. No clinically significant treatment-related trends were observed regarding laboratory, vital sign, ECG, or physical examination. In conclusion, AD 923 provides an attractive pharmacokinetic profile for the potential treatment of cancer breakthrough pain which warrants further investigation. All products were well tolerated in this population.
Antidepressants (184) Is the improvement in vitality independent of the improvements in sleep interference and pain in patients with diabetic peripheral neuropathic pain? Responses to treatment with duloxetine D Fishbain, J Hall, R Risser, J Gonzales; Eli Lilly and Company, Indianapolis, IN A major issue in pain literature has been whether there is an etiological association between pain, sleep, and vitality. Data from duloxetine clinical trials in patients with diabetic peripheral neuropathic pain (DPNP) were used to investigate associations between pain, sleep and vitality. Data were pooled from 3 double-blind, randomized, placebo-controlled, 12-week trials in which major mood disorders were excluded. Study 1 (N⫽457) compared duloxetine 20mg once daily (QD), 60mg QD, 60mg twice daily (BID), and placebo; Studies 2 (N⫽334) and 3 (N⫽348) compared duloxetine 60mg QD and 60mg BID with placebo. A subset of patients (n⫽804) with complete data across the 4 assessments was constructed by dropping patients 1) reporting maximum vitality at baseline, 2) experiencing treatment-emergent somnolence, asthenia or fatigue or 3) taking sedating concomitant medications or duloxetine 20 mg/day. Efficacy measures included daily and night pain severity collected via patient diaries, Brief Pain Inventory (BPI) sleep interference, and SF-36 vitality domain. For duloxetine, mean improvements from baseline to endpoint in daily and night pain severity, BPI sleep interference, and vitality were significantly superior to placebo (ⱕ.002). Correlations between changes to endpoint in daily pain, night pain, and sleep interference with vitality changes were -.33, -.31, and -.28, respectively (p⬍.001). The direct effect of treatment on change in vitality was statistically significant (66%, p⫽.024) when assessed in an indirect manner through change in sleep interference alone but not when jointly assessed with average pain (32%, p⫽.283) or night pain (48%, p⫽.097). Results suggest weak to moderate associations between changes in average pain, night pain, and sleep interference with changes in vitality. Improvement in vitality was independent of improvements in sleep interference alone but the treatment effect on vitality was mediated by sleep interference when jointly modeled with improvement in average or night pain. This research received funding from Eli Lilly and Company.
(185) A comparison of strategies for switching patients from amitriptyline to duloxetine for the management of diabetic peripheral neuropathic pain M Robinson, V Whitmyer, R Risser, S Malcolm, J Ahl; Eli Lilly and Company, Indianapolis, IN Duloxetine is effective in the management of diabetic peripheral neuropathic pain (DPNP), and may have a better safety and tolerability profile than frequently prescribed tricyclic antidipressants, like amitriptyline. Strategies for switching medications attempt to balance the risk of discontinuation-emergent/treatment-emergent adverse events (AE) with onset of efficacy. This was a multicenter, randomized, doubleblind, parallel, 8-week trial in patients with DPNP treated with a stable dose of amitriptyline 25-100 mg/day to compare strategies for switching to duloxetine 60 mg/day. Patients were randomized into 3 groups: discontinue then titrate (DTT) (n⫽26), direct switch (DS) (n⫽26), or tapertitrate (TT) (n⫽26). The primary objective was to compare adverse event burden, measured by a “common adverse events” (CAE) total score from the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale, between DS and TT regimens during the initial 4-week switch period; DTT served as a control since their continued amitriptyline use was masked during this period. Randomized patients had diabetes (type II, 91%) for 13.3 years and neuropathic pain for 5.6 years. Inadequate pain efficacy was most commonly reported by patients (83%) and physicians (74%) as the reason for wanting to switch. Baseline CAE total score was 3.13⫾4.3, corresponding to having one severe AE, 3 mild AEs, or 1 mild and 1 moderate AE. Baseline 24-hour weekly average pain score was 4.3⫾2.3 (moderate). After switching to duloxetine, CAE total scores were not significantly changed, pain was not worsened, and differences between switch groups on these measures were not significant. These results suggest that switching from amytriptyline to duloxetine may not be associated with an increase in CAE or transient worsening in pain. Interpretation of these results is limited by the small sample size due to early termination of the trial because of enrollment difficulties. Supported by funding from Eli Lilly and Company.
Abstracts (186) Safety and tolerability of Duloxetine in the treatment of patients with Fibromyalgia: Analysis of 5 studies E Choy, P Mease, D Kajdasz, M Wohlreich, D Walker, A Chappell; King’s College London, London, UK Duloxetine, a serotonin-norepinephrine reuptake inhibitor, has been shown to effectively treat patients with fibromyalgia. The objective of this integrative analysis is to evaluate the safety and tolerability of duloxetine during up to 60 weeks of treatment. Patients (N⫽1236) from 4 placebo-controlled studies employing doses of 20, 60, and 120mg/day of duloxetine, and one long-term study (N⫽350) employing doses of 60 and 120mg/day, were used in these analyses. Safety and tolerability were assessed via reasons for discontinuation, treatment-emergent adverse events (TEAEs), discontinuation-emergent adverse events, and changes in vital signs, weight, and laboratory analytes. In the placebocontrolled studies, overall exposure was 264 patient-years for duloxetine and 154 for placebo. The patients were primarily female (95%) and Caucasian (80.4%), with a mean age of 50.1 years. In the long-term study, patients were similar in demography and duloxetine exposure was 285 patient-years. Discontinuations due to adverse events were higher in the duloxetine group (duloxetine, 19.5%; placebo, 11.8%, P⬍.001), whereas discontinuations due to lack of efficacy were higher in the placebo group (duloxetine, 7.0%; placebo, 13.5%, P⬍.001). The most common TEAE was nausea (duloxetine, 29.3%; placebo, 11.4%, P⬍.001). Nausea was reported as mild to moderate and tended to resolve over time. Clinically small, but statistically significant differences (P⬍.01) in mean changes in pulse (bpm, 1.22, -.42), systolic (mmHg, 0.91, -1.58) and diastolic (mmHg, 1.04, -1.17) blood pressure, and weight (kg, -.43, 0.28) occurred, respectively, in the duloxetine group compared with the placebo group. In the long-term uncontrolled study, mean changes in vitals during up to 60 weeks of treatment with duloxetine were: -0.1 and -0.2 mmHg for supine systolic and diastolic blood pressure, 0.7 kg for weight (P⫽.005), and 1.9 bpm for pulse (P⬍.001) The safety and tolerability profile of duloxetine in these fibromyalgia studies was similar to that observed with duloxetine in other indications.
Cancer Pain–Opioids (187) A randomized pharmacokinetic study of AD 923 (Fentanyl Sublingual Spray) vs. Actiq (OTFC) and Fentanyl Citrate injection in healthy human volunteers R Tansley, S Connolly, R Bannister, S Snape, B Ruparelia, I Walker, A Raza; MDS Pharma Services, Neptune, NJ AD 923 is a sub-lingual fentanyl product being developed for the treatment of cancer breakthrough pain. This was a randomized, single-dose, 3-period, 3-treatment, crossover study. A total of 25 healthy subjects (8 females and 17 males), 18 – 45 years of age, with a BMI between 18 and 30 kg/m2 were enrolled (23 completed). Each subject received single doses of 200g AD 923, 200g Actiq (OTFC) and 100g intravenous fentanyl during 3 treatment periods separated by 4 to 7 days. Plasma fentanyl concentrations were determined at frequent intervals until 48 hours post-dose. AD 923 had a significantly shorter median Tmax compared with Actiq (40 vs. 120 minutes) indicating a faster onset of exposure of fentanyl after the AD 923 dose. AD 923 had a significantly higher absolute bioavailability compared to Actiq (77.7% vs. 50.9%). Mean Cmax (347 vs. 196 pg/mL) and AUC(0-⬁)(2165 vs. 1389 pg*hr/mL) were higher for AD 923 compared with Actiq. Mean plasma fentanyl half-lives ranged between 5.8-7.4 hours in the 3 groups. Neither race nor gender had a statistically significant effect on Cmax or AUC. All products were well tolerated with no SAEs reported. 32 treatment-emergent AEs (TEAEs) were reported by 12 (out of 25) subjects. Of the 32 TEAEs, 31 were mild in severity and 1 was moderate. AEs were reported most commonly following fentanyl injection (38%), followed by AD 923 (25%), and Actiq (21%). Dizziness, nausea, and pruritus were the most commonly reported TEAEs. No subject withdrew due to an AE. No clinically significant treatment-related trends were observed regarding laboratory, vital sign, ECG, or physical examination. In conclusion, AD 923 provides an attractive pharmacokinetic profile for the potential treatment of cancer breakthrough pain which warrants further investigation. All products were well tolerated in this population.