Amy Manley

Subcutaneous Methylnaltrexone for Treatment of Opioid-Induced Constipation in Patients With Chronic, Nonmalignant Pain: A Randomized Controlled Study

UNLABELLED Methylnaltrexone is effective for opioid-induced constipation (OIC) in advanced illness patients. This 4-week, double-blind, randomized, placebo-controlled study investigated the effect of subcutaneous methylnaltrexone on OIC in patients receiving opioids for chronic, nonmalignant pain. Patients (N = 460) received subcutaneous methylnaltrexone 12 mg once daily (QD) or every other day (alternating with placebo) compared with placebo. Assessments included bowel movement count, time of bowel movement, straining, sense of complete evacuation, Bristol Stool Form Scales, and quality of life. Within 4 hours of first dose, 34.2% of patients in both methylnaltrexone groups had rescue-free bowel movements (RFBMs) versus 9.9% on placebo (P < .001). The estimated number needed to treat was about 4. On average, 28.9% of methylnaltrexone QD and 30.2% of methylnaltrexone alternate-day dosing resulted in RFBMs within 4 hours versus 9.4% QD and 9.3% alternate-day placebo injections (both P < .001). Both methylnaltrexone groups had significantly shorter time to first RFBM (P < .001) and greater increase in number of weekly RFBMs (P < .05) versus placebo. Adverse events included abdominal pain, diarrhea, nausea, and hyperhidrosis. Bristol Stool Form Scale scores (P = .002) and sensation of complete evacuation (P < .04) were significantly superior with methylnaltrexone QD; both methylnaltrexone groups reported no or mild straining during RFBMs in the first 2 weeks (P < .02). At 4 weeks, a significantly greater improvement in patient-reported, constipation-specific quality of life was seen in the alternate-day dosing (P < .05) and QD (P < .001) groups. PERSPECTIVE We present data demonstrating that subcutaneous methylnaltrexone 12 mg given once daily (QD) or every other day provides significant relief of OIC and was generally well tolerated in patients with chronic, nonmalignant pain. These results expand on prior effectiveness observed for the treatment of OIC in advanced illness patients to a broader population.

Effect of subcutaneous methylnaltrexone on patient-reported constipation symptoms.

BACKGROUND Methylnaltrexone, a selective peripheral acting mu-opioid receptor antagonist, alleviates the constipating effects of opioids without affecting centrally mediated analgesia. OBJECTIVES To assess the effect of subcutaneous (SC) methylnaltrexone injection on patient-reported constipation symptoms and pain scores. METHODS A total of 469 subjects on opioids for chronic non-malignant pain with opioid-induced constipation were randomized to methylnaltrexone SC with once daily (QD) or every other day (QOD) dosing or placebo for 4 weeks. Constipation symptoms and pain were assessed using the patient assessment of constipation-symptoms (PAC-SYM) questionnaire and a 11-point scale, respectively, at baseline, Day 14 and Day 28. Change from baseline in PAC-SYM and pain scores were compared between methylnaltrexone and placebo arms at Day 28 using analysis of covariance, with treatment group as factor and baseline score as covariate. RESULTS A majority of patients were women (60%), average age was 49 years old, and back pain (60%) was the primary pain condition. At Day 28, the methylnaltrexone SC QD group showed a significant improvement over placebo for rectal symptoms (-0.56 vs. -0.30; P < 0.05), stool symptoms (-0.76 vs. -0.43; P < 0.001) and global scores (-0.62 vs. -0.37; P < 0.001). Improvement in stool symptoms (-0.69 vs.-0.43; P < 0.05) and the global scores (-0.52 vs. -0.37; P < 0.05) were significantly greater than placebo in the methylnaltrexone QOD group. Differences in change from baseline in abdominal symptoms and pain scores between the methylnaltrexone SC QD or QOD dosing arms and placebo were not significant. CONCLUSION The results of our study indicate significant improvement in constipation symptoms with methylnaltrexone QD or QOD dosing compared to placebo without a significant effect on pain scores.

Efficacy of Subcutaneous Methylnaltrexone in the Treatment of Opioid‐Induced Constipation: A Responder Post Hoc Analysis

OBJECTIVE Methylnaltrexone, a selective peripherally acting mu-opioid receptor antagonist, effectively treats opioid-induced constipation (OIC) in patients with advanced illness and shows efficacy in patients with chronic nonmalignant pain. The objective was to identify patients who achieved maximal treatment effect based on response to initial four methylnaltrexone doses. DESIGN A post hoc analysis of a randomized, double-blind, placebo-controlled study evaluating patients with OIC and chronic nonmalignant pain who received 12 mg subcutaneous methylnaltrexone daily for 4 weeks was performed to determine if response to the first four methylnaltrexone doses predicted overall response during the study. Patients receiving ≥8 doses were included. OUTCOME MEASURES Patients having ≥3 rescue-free bowel movements (RFBMs)/week; change from baseline in RFBMs/week; percentage of doses with RFBMs within 4 hours after dosing. RESULTS Of 137 patients, 58 patients (42.3%) had RFBMs after ≥2 of four doses. Among those with response to ≥2 of four doses, 81% had ≥3 RFBMs/week vs. 43% for those with response to <2 of four (P < 0.0001). Those with RFBMs after ≥2 of first four doses averaged 4.8 RFBMs/week vs. 2.0 RFBMs/week for those with <2 of four (P < 0.0001). Percentage of subsequent injections resulting in RFBMs within 4 hours was 45.9 ± 27.6 for those with response to ≥2 of four doses vs. 17.1 ± 19.1 for those with response to <2 of four (P < 0.0001). Abdominal pain was the most frequently reported adverse event. CONCLUSION Early response to ≥2 of first four doses of methylnaltrexone identified patients who demonstrated a particularly robust effect of treatment over the duration of use.

Comparison of Omadacycline and Tigecycline Pharmacokinetics in the Plasma, Epithelial Lining Fluid, and Alveolar Cells of Healthy Adult Subjects

ABSTRACT The steady-state concentrations of omadacycline and tigecycline in the plasma, epithelial lining fluid (ELF), and alveolar cells (AC) of 58 healthy adult subjects were obtained. Subjects were administered either omadacycline at 100 mg intravenously (i.v.) every 12 h for two doses followed by 100 mg i.v. every 24 h for three doses or tigecycline at an initial dose of 100 mg i.v. followed by 50 mg i.v. every 12 h for six doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject following the start of the fifth dose of omadacycline at 0.5, 1, 2, 4, 8, 12, or 24 h and after the start of the seventh dose of tigecycline at 2, 4, 6, or 12 h. The value of the area under the concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0–24) (based on mean concentrations) in ELF and the ratio of the ELF to total plasma omadacycline concentration based on AUC0–24 values were 17.23 mg · h/liter and 1.47, respectively. The AUC0–24 value in AC was 302.46 mg · h/liter, and the ratio of the AC to total plasma omadacycline concentration was 25.8. In comparison, the values of the AUC from time zero to 12 h postdosing (AUC0–12) based on the mean concentrations of tigecycline in ELF and AC were 3.16 and 38.50 mg · h/liter, respectively. The ratio of the ELF and AC to total plasma concentrations of tigecycline based on AUC0–12 values were 1.71 and 20.8, respectively. The pharmacokinetic advantages of higher and sustained concentrations of omadacycline compared to those of tigecycline in plasma, ELF, and AC suggest that omadacycline is a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

Effect of Food on the Bioavailability of Omadacycline in Healthy Participants

Omadacycline is a first‐in‐class aminomethylcycline antibiotic being evaluated in phase 3 studies as oral and intravenous monotherapy for bacterial infections. This was a phase 1, randomized, open‐label, 4‐period, crossover study that evaluated the effect of food consumption on the bioavailability of omadacycline. Healthy participant were randomized to 1 of 4 sequences, which included the following predose conditions in different orders (A) ≥6‐hour fast, (B) high‐fat, nondairy meal 4 hours before dosing, (C) high‐fat, nondairy meal 2 hours before dosing, and (D) high‐fat meal containing dairy 2 hours before dosing. Participants received a single 300‐mg oral dose of omadacycline during each treatment period; periods were separated by ≥5 days. Blood samples for pharmacokinetic (PK) analysis were collected over 24 hours after each dose, and safety assessments were performed during each treatment period. Least‐squares mean and 90% confidence intervals were compared for fed state vs fasted state. Thirty‐one participants were included in the PK analysis. Fasted AUC0‐∞, AUC0‐t, and AUC0‐24 were 10.2, 7.2, and 7.2 μg·h/mL, respectively, and Cmax was 0.6 μg/mL. Compared with a fasted dose, bioavailability was reduced by 15% to 17% by a nondairy meal 4 hours before dosing, 40% to 42% by a nondairy meal 2 hours before dosing, and 59% to 63% for a dairy meal 2 hours before dosing. Two participants experienced adverse events (mild nausea, mild somnolence). A 300‐mg oral dose of omadacycline administered within 2 to 4 hours after food had reduced bioavailability compared with the fasted state. Oral omadacycline should be administered in a fasted state.

Effect of Food on the Bioavailability of Omadacycline in Healthy Subjects

Omadacycline is a first‐in‐class aminomethylcycline antibiotic being evaluated in phase 3 studies as oral and intravenous monotherapy for bacterial infections. This was a phase 1, randomized, open‐label, 4‐period, crossover study that evaluated the effect of food consumption on the bioavailability of omadacycline. Healthy participant were randomized to 1 of 4 sequences, which included the following predose conditions in different orders (A) ≥6‐hour fast, (B) high‐fat, nondairy meal 4 hours before dosing, (C) high‐fat, nondairy meal 2 hours before dosing, and (D) high‐fat meal containing dairy 2 hours before dosing. Participants received a single 300‐mg oral dose of omadacycline during each treatment period; periods were separated by ≥5 days. Blood samples for pharmacokinetic (PK) analysis were collected over 24 hours after each dose, and safety assessments were performed during each treatment period. Least‐squares mean and 90% confidence intervals were compared for fed state vs fasted state. Thirty‐one participants were included in the PK analysis. Fasted AUC0‐∞, AUC0‐t, and AUC0‐24 were 10.2, 7.2, and 7.2 μg·h/mL, respectively, and Cmax was 0.6 μg/mL. Compared with a fasted dose, bioavailability was reduced by 15% to 17% by a nondairy meal 4 hours before dosing, 40% to 42% by a nondairy meal 2 hours before dosing, and 59% to 63% for a dairy meal 2 hours before dosing. Two participants experienced adverse events (mild nausea, mild somnolence). A 300‐mg oral dose of omadacycline administered within 2 to 4 hours after food had reduced bioavailability compared with the fasted state. Oral omadacycline should be administered in a fasted state.

Pharmacokinetics and Safety of Omadacycline in Subjects With Impaired Renal Function

ABSTRACT Many antibiotics require dose adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad spectrum of bacterial pathogens, including drug-resistant strains. Data from completed phase 3 studies of omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) showed intravenous (i.v.) to once-daily oral omadacycline to be clinically effective and well tolerated. To determine if the dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of i.v. omadacycline (100 mg) was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (n = 8) and in matched healthy subjects (n = 8). i.v. administration of omadacycline produced similar plasma concentration-time profiles in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar values of the PK parameters were observed when omadacycline was administered i.v. after or before dialysis. The mean area under the concentration-time curve from time zero extrapolated to infinity in plasma was 10.30 μg · h/ml when omadacycline was administered to ESRD subjects after dialysis, 10.20 μg · h/ml when omadacycline was administered to ESRD subjects before dialysis, and 9.76 μg · h/ml when omadacycline was administered to healthy subjects. The mean maximum observed concentration of omadacycline in plasma in ESRD subjects was 1.88 μg/ml when it was administered after dialysis and 2.33 μg/ml when it was administered before dialysis, and in healthy subjects it was 1.92 μg/ml. The 100-mg i.v. dose of omadacycline was generally safe and well tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis.

Safety and Pharmacokinetics of the Aminomethylcycline Antibiotic Omadacycline Administered to Healthy Subjects in Oral Multiple Dose Regimens

ABSTRACT Omadacycline, a first-in-class aminomethylcycline antibiotic, is related to tetracyclines but is structurally modified to circumvent mechanisms of resistance to tetracyclines. Omadacycline demonstrates potent activity against a broad range of pathogens, including drug-resistant strains, and is in late-stage development for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Previous studies support an intravenous-to-oral transition regimen with 300-mg once-daily oral dosing. This phase 1 study investigated the pharmacokinetics and safety/tolerability of multiple oral omadacycline doses higher than 300 mg. Using a 3-period crossover design, healthy adults were randomized to receive oral omadacycline at 300, 450, and 600 mg in variable sequence (n = 26) or placebo (n = 7) once daily for 5 consecutive days per period. In plasma, omadacycline maximum concentration and total exposure increased with increasing dose but were less than dose proportional. The kinetics of omadacycline plasma accumulation were similar between dose levels; exposure on day 5 was ∼50% higher than that on day 1. Omadacycline plasma concentrations on day 1 of 450-mg dosing were similar to those on day 5 of 300-mg dosing. All doses were generally well tolerated, but the 600-mg dose was associated with more gastrointestinal adverse events.

Poster 279: Subcutaneous Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Patients with Chronic Nonmalignant Pain

Disclosures: E. R. Blonsky, None. Objective: To determine if subcutaneous methylnaltrexone alleviates opioid-induced constipation (OIC) in patients with chronic nonmalignant pain. Design: Double-blind, randomized, placebo-controlled, phase 3 study. Setting: Outpatient pain centers and clinical research centers. Participants: 460 patients on stable doses of opioids with 3 rescue-free bowel movements (RFBMs)/week. Interventions: Patients were randomized to 1 of 2 regimens of methylnaltrexone bromide (12 mg QD [n 150] or 12 mg QOD [n 148]) or placebo (n 162) for 4 weeks. Routine laxatives were not permitted; “rescue” laxative use was standardized and allowed if needed. Main Outcome Measures: Co-primary endpoints were RFBM within 4 hours of first dose and RFBM within 4 hours after active doses. Results: Patients were mostly women (60.2%), mean age 48.8 years, median weight 84.0 kg. Most had back pain (59.1%). The median baseline opioid dose was 160 mg/d oral morphine equivalents. Methylnaltrexone demonstrated a 34.2% response rate within 4 hours after first dose vs 9.9% for placebo (P .001). Methylnaltrexone also maintained a consistent response rate of 28.9% and 30.2% for QD and QOD regimens, respectively, within 4 hours of dose vs 9.4% and 9.3% for placebo (P .001) for the 4-week period. Time to first bowel movement was significantly shorter for methylnaltrexone than placebo (P .001), with 46% in the methylnaltrexone group having an RFBM within 24 hours vs 25.3% for placebo. Methylnaltrexone patients showed improvements in straining, stool consistency, and completeness of evacuation compared with placebo. Methylnaltrexone treatment groups also had significantly less rescue laxative use (P .001 vs placebo). The most common AEs with frequency notably different from placebo were abdominal pain, dizziness, increased sweating, nausea, and diarrhea. Conclusions: The results of this study will help determine the safety and efficacy of subcutaneous methylnaltrexone in providing rapid and reliable laxation in patients with chronic nonmalignant pain and OIC.