Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of naloxegol at peripheral and central nervous system receptors in healthy male subjects: A single ascending-dose study.

This randomized, double-blind, placebo-controlled, ascending-dose, crossover study evaluated single oral doses of naloxegol (NKTR-118; 8, 15, 30, 60, 125, 250, 500, and 1000 mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol-matching placebo administered with morphine and lactulose in a 2-period crossover design. Periods were separated by a 5- to 7-day washout. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine-induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose-ordered antagonism of morphine's peripheral gastrointestinal effects. Forty-four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000 mg, indicating negligible antagonism of morphine's CNS effects at doses ≤ 125 mg. Rapid absorption, linear pharmacokinetics up to 1000 mg, and low to moderate between-subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000 mg.

Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol.

Opioid-induced constipation (OIC) is the most common and often a treatment-limiting adverse event (AE) of opioid therapy for chronic pain. Naloxegol (previously NKTR-118), a PEGylated derivative of naloxone that has minimal penetration of the central nervous system, has received regulatory approval as an oral therapy for OIC. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed to assess safety, tolerability, and pharmacokinetics of multiple doses of naloxegol in healthy volunteers. Four cohorts, each with 4 male and 4 female volunteers, were randomized 3:1 to a twice-daily naloxegol solution (25, 60, 125, and 250 mg) or matching placebo solution. Doses were given every 12 hours for 7 days, with a single final dose on the morning of day 8. All 32 subjects completed the study. The incidence of most AEs was similar in the naloxegol and placebo groups; no AE led to study discontinuation. Naloxegol was rapidly absorbed. Plasma naloxegol pharmacokinetics showed dose proportionality, negligible accumulation at steady state, and no sex differences. Naloxegol in doses up to 250 mg every 12 hours was generally safe and well tolerated in this healthy volunteer population.

A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors.

PURPOSE: This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol. EXPERIMENTAL DESIGN: Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w × 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 + 3 design. RESULTS: Seventy-six patients were entered onto 3 dosing schedules (58-245 mg/m(2)). The MTD was 115 mg/m(2) for the w × 3q4w schedule and 145 mg/m(2) for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer. CONCLUSION: Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m(2) q14d or q21d.

Randomized, double-blind, placebo-controlled study of the abuse potential of different formulations of oral oxycodone.

OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and abuse potential of different formulations of oxycodone. DESIGN: The participants completed an 8-day, placebo-controlled trial with four phases: naloxone challenge, double-blind drug discrimination, double-blind abuse liability, and discontinuation. SUBJECTS: Nineteen healthy, male, recreational drug abusers participated in this study. INTERVENTIONS: The participants were administered different doses and formulations of oxycodone (40 mg immediate release [IR], 40 mg controlled release [CR], crushed 40 mg CR, and 80 mg CR) to evaluate pharmacokinetic parameters and ratings of drug liking and high. OUTCOME MEASURES: Pharmacokinetic parameters were determined over a 12-hour dosing interval. The primary pharmacodynamic endpoints were two questions from the Drug Effects Questionnaire ("Do you like the drug?" and "How high are you now?"). RESULTS: Maximal plasma concentrations and area under the curve determinations were similar for 40 mg IR, crushed 40 mg CR, and 80 mg CR, which were all greater than 40 mg CR. For drug liking and high, the maximal effect and area under the effect curve were similar for the three formulations, which were all greater than 40 mg CR. The dose required to produce comparable reports of drug liking and high was approximately twofold greater for the CR vs IR formulation. When the 40 mg CR tablet was crushed, the pharmacokinetic and pharmacodynamic profile was similar to the 40 mg IR formulation. Adverse events were consistent with opioid administration. CONCLUSIONS: Intact, orally administered oxycodone CR produced less drug liking and high than IR oxycodone, and required approximately twofold greater doses to produce subjective effects comparable to IR oxycodone.

An enhanced bunionectomy model as a potential tool for early decision-making in the development of new analgesics.

BACKGROUND: bunionectomy has been used as a model of postoperative pain for opioids and nonsteroidal anti-inflammatory drugs/cyclooxygenase-2 inhibitors with a fast onset of analgesia. The present study was conducted to assess whether the utility of the model can be broadened in assessing the efficacy of analgesics with diverse mechanisms and pharmacokinetic profiles in drug development and to enhance the sensitivity of a bunionectomy model. METHODS: this was a single center, randomized, double-blind, placebo-controlled, three-arm, parallel group methodology study to evaluate the effects of pregabalin and naproxen sodium on postoperative pain following bunionectomy. Patients (n=100) were randomized 1:1:1 to three treatments (administered 1 hour before and at defined intervals after surgery): pregabalin 300 mg before surgery and 150 mg every 8 hours; naproxen sodium 550 mg before surgery and 550 mg every 12 hours; or placebo in a double-dummy fashion. Primary endpoints were patient-controlled analgesic (PCA) hydromorphone consumption and the time to first PCA hydromorphone use postsurgery over 24 hours. RESULTS: of the 100 patients randomized, 96 completed the study. Relative to placebo, pregabalin and naproxen sodium, respectively, reduced PCA hydromorphone consumption by 51% (P=0.005) and 65% (P<0.001) and increased the median time to first use of PCA hydromorphone by 1.5 hours (P=0.004) and 3.7 hours (P<0.001). Both drugs significantly (P<0.050) decreased use of oral opioid rescue medication over 24-48 hours postsurgery relative to placebo. Although there were no statistically significant differences between naproxen sodium and pregabalin in opioid consumption and global evaluation of medication, overall naproxen sodium appeared to be more effective at reducing pain. CONCLUSIONS: the model provided a sensitive method for evaluating efficacy of compounds with diverse mechanisms and pharmacokinetic profiles. The robustness of the enhanced pain model renders bunionectomy pain a valuable tool to assess novel analgesic compounds in small numbers of subjects early in drug development.

Safety and pharmacokinetics of NXN-188 after single and multiple doses in five phase I, randomized, double-blind, parallel studies in healthy adult volunteers.

BACKGROUND: NXN-188 is a dual-action oral therapeutic being developed for the treatment of acute migraine. The mechanism of action of NXN-188 involves inhibition of both the neuronal nitric oxide synthase enzyme isoform and affinity for serotonin (5-hydroxytryptamine1B/D) receptors. OBJECTIVES: The aims of the initial Phase I clinical studies were to compare the pharmacokinetic (PK) properties of NXN-188 administered as a single dose or multiple twice-daily doses to healthy adult volunteers and to determine the tolerability of NXN-188 in these individuals. METHODS: Healthy adult male and female subjects were enrolled in 5 Phase I, randomized, double-blind studies, all of which (except for a fed/fasted trial) were placebo controlled. In the 4 single-dose studies, which differed with respect to feeding status and the formulation used (capsules or solution), subjects received NXN-188 at doses of 2 to 800 mg (0.027-11.2 mg/kg). In the repeat-dose study, subjects received 50-mg (0.71 mg/kg) doses twice daily for 4 days. Serum samples were analyzed for NXN-188 using validated HPLC-MS/MS methods. Standard clinical laboratory analyses (chemistry, hematology, and urinalysis) and measurements of serum creatine kinase and myoglobin levels were conducted at screening, admission, discharge, and follow-up. Baseline and postexposure values were compared to assess tolerability. Electrocardiography and physical examination were conducted at screening and at discharge and follow-up if any negative change occurred from the previous findings. Vital signs (heart rate, blood pressure, respiration), including assessment for orthostatic changes, were measured at screening, check-in, and follow-up visits (1 hour before dosing, every 30 minutes for the first 4 hours, then every hour for the next 4 hours, then every 4 hours for the remainder of the 24-hour study). Adverse events were recorded, reviewed, and monitored throughout the study. RESULTS: Two hundred three subjects (102 women, 101 men) 18 to 50 years of age were enrolled in the 5 studies; 168 subjects received NXN-188 and 35 received placebo. Most (91%) of the subjects were white; weight ranged from 69.3 to 71.8 kg (body mass index, 24.5-25.8 kg/m(2)). The initial absorption phase of orally administered NXN-188 peaked at approximately 1 hour, followed by a second absorption phase with a T(max) of approximately 4 to 5 hours. Exposure (C(max) and AUC) increased in a slightly greater than dose-proportional manner across a dose range of 2 to 800 mg (0.027-11.2 mg/kg). Elimination was multiexponential, with an initial rapid plasma drug elimination (plasma concentrations decreased approximately 70%-90% from Cmax within 24 hours after dosing), followed by a prolonged clearance phase of very low NXN-188 concentrations ( approximately 1%-5% of Cmax) that persisted for several weeks. Clearance ranged from 70 to 130 L/h, and the NXN-188 halflife ranged from 11 to 178 hours. Neither food nor gender had any measurable effect on the PK properties of NXN-188. Overall, dizziness was reported more often in the NXN-188 groups than in the placebo groups (6.3% vs 2.9%, respectively). Frequently reported adverse events that occurred more often in the placebo groups than in the NXN-188 groups were somnolence (11.4% vs 6.3%, respectively), and headache (8.6% vs 6.9%). Incidences of orthostatic hypotension (6.3% vs 5.7%) and postural (orthostatic) tachycardia syndrome (6.3% vs 5.7%) were comparable in the NXN-188 and placebo groups, respectively. No serious adverse events were reported at any dose of NXN-188 up to the current maximum dose (800 mg or 11.2 mg/kg). CONCLUSION: NXN-188 exhibited linear pharmaco-kinetics over the dose range studied and appeared to be well tolerated in these healthy volunteers.

Opioid formulations in development designed to curtail abuse: who is the target?

BACKGROUND: Opioids are increasingly prescribed for chronic cancer and noncancer pain, and misuse, abuse, and diversion have risen dramatically. Formulations are being developed with the intent to curtail abuse through physical barriers that resist alteration, inclusion of excipients that antagonize opioid effects when altered, and other technologies. OBJECTIVE: To examine various new drug formulations designed to curtail opioid abuse, their stages of development, their technologies, and the population targeted. METHODS: The discussion encompasses formulations currently undergoing clinical trials in North America. CONCLUSION: Emerging opioid formulations may prove useful to minimizing prescription opioid abuse, but the magnitude of their clinical utility and societal impact will be unknown until epidemiological studies can be conducted. Realistic expectations for what the new formulations can achieve are encouraged.

Oral tramadol for the treatment of pain of 7-30 days' duration in children.

IMPLICATIONS: This open-label, multicenter trial was designed to determine the safety profile and analgesic efficacy of tramadol for the treatment of painful conditions lasting 7-30 days in 7-16-yr-old children. We found that tramadol 1-2 mg/kg per os every 4-6 h (maximal dose = 8 mg x kg(-1). d(-1), not to exceed 400 mg/d) is a safe and effective analgesic in this patient population.

An evaluation of the efficacy and tolerability of oral tramadol hydrochloride tablets for the treatment of postsurgical pain in children.

UNLABELLED: In this double-blinded, randomized, multicenter study, we examined analgesic efficacy and tolerability of tramadol in postoperative pediatric patients. Eighty-one postsurgical ASA physical status I and II patients ages 7-16 yr received oral tramadol (approximately 1 or 2 mg/kg) for postoperative analgesia when they were ready to transition from morphine patient-controlled analgesia to oral analgesics. Rescue analgesia consisted of morphine patient-controlled analgesia or an oral equivalent dose of oxycodone. Patients rated their pain just before the administration of tramadol and at regular intervals for 8 h afterwards using the Wong-Baker Faces Pain Rating Scale. The 2-mg/kg group required approximately half as much rescue analgesia as the 1-mg/kg group (P = 0.006). Parents rated the larger dose more favorably. Adverse events were generally mild to moderate in severity (vomiting [10%], nausea [9%], pruritus [7%], rash [4%]) and similar between the two treatment groups. There were no significant changes in hemodynamic variables, respiratory rate, or SpO(2) percentages between the two treatment groups or in all patients compared with pretreatment values. IMPLICATIONS: Oral tramadol 1-2 mg/kg is well tolerated and effective in postoperative children ready to transition from morphine patient-controlled analgesia. The group receiving 2 mg/kg required less rescue analgesic compared with those receiving 1 mg/kg.