Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?

E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewisx) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewisx that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials.

Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain.

BACKGROUND: Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 µg of sufentanil are described. METHODS: Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used. RESULTS: Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-µg dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 ± 0.85 h) and 12 doses (2.5 ± 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment. CONCLUSIONS: The time course of a single 30-µg dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting.

Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children.

BACKGROUND/AIMS: MOD-4023 is a long-acting human growth hormone (hGH) in clinical trials for the treatment of growth hormone deficiency (GHD). A key goal is maintenance of serum concentrations of insulin-like growth factor (IGF) 1 within normal range throughout GH dosing. The study aimed to develop a pharmacokinetic model for MOD-4023 and a pharmacodynamic model for the effect of MOD-4023 on IGF-1 to allow estimation of peak and mean IGF-1 and to identify the optimal IGF-1 sampling day. METHODS: MOD-4023 (0.25, 0.48, or 0.66 mg/kg) was administered weekly for 12 months to 41 GH-naive GHD children (age 3-11 years). The control group (n = 11, age 4-9 years) received daily recombinant human growth hormone (r-hGH; 34 µg/kg). Sparse samples (4/subject) were obtained to determine serum concentrations of MOD-4023 or r-hGH and IGF-1. RESULTS: A 2-compartment pharmacokinetic model with first-order absorption fit MOD-4023 data well; a 1-compartment model was appropriate for r-hGH. For both, weight-normalized systemic parameters were preferred over allometric scaling. For MOD-4023, an indirect model fit IGF-1 SDS data well; baseline IGF-1 increased over time. At steady state, samples obtained 4 days following dose administration predicted mean IGF-1 SDS during the dosing interval well. CONCLUSION: The IGF-1 profile is consistent with the weekly dosing interval. Sampling 4 days following dose administration allows estimation of mean IGF-1 SDS during the dosing interval in GHD patients.

A Randomized Trial Comparing the Pharmacokinetics, Safety, and Tolerability of DFN-02, an Intranasal Sumatriptan Spray Containing a Permeation Enhancer, With Intranasal and Subcutaneous Sumatriptan in Healthy Adults.

OBJECTIVE/BACKGROUND: Intranasal sumatriptan (Imitrex® ) may be an alternative for patients who refuse injections and cannot tolerate oral agents, but due to low bioavailability and slow absorption, the clinical utility of the currently marketed formulation is limited, highlighting an unmet need for an effective non-oral migraine medication with a rapid onset of action. To overcome the slow absorption profile associated with intranasal administration, we evaluated the impact of 1-O-n-Dodecyl-ß-D-Maltopyranoside (DDM, Intravail A-3™), a permeation enhancer, on sumatriptan's pharmacokinetic profile by comparing the pharmacokinetic characteristics of two commercial sumatriptan products, 4 mg subcutaneous and 6 mg subcutaneous in healthy adults, with DFN-02 - a novel intranasal agent comprised of sumatriptan 10 mg plus 0.20% DDM. We also determined the pharmacokinetic characteristics of DDM and evaluated its safety and tolerability. METHODS: We conducted two studies: a randomized, three-way crossover study comparing monodose and multidose devices for delivery of single doses of DFN-02 with commercially available intranasal sumatriptan 20 mg in 18 healthy, fasted adults, and an open-label, randomized, single-dose, three-way crossover bioavailability study comparing DFN-02 with 4 mg and 6 mg subcutaneous sumatriptan in 78 healthy, fasted adults. In the study comparing DFN-02 with IN sumatriptan, subjects received a single dose of DFN-02 (sumatriptan 10 mg plus DDM 0.20%) via monodose and multidose delivery systems with at least 5 days between treatments. In the comparison with SC sumatriptan, subjects received a single dose of each treatment with at least 3 days between treatments. In both studies, blood was sampled for pharmacokinetic evaluation of sumatriptan and DDM through 24 hours post-dose; safety and tolerability were monitored throughout. RESULTS: In the comparison with commercially available intranasal sumatriptan 20 mg, DFN-02 had a more rapid absorption profile; tmax was 15 minutes for DFN-02 monodose, 10.2 minutes for DFN-02 multidose, and 2.0 hours for commercially available intranasal sumatriptan 20 mg. Compared with 4 and 6 mg subcutaneous sumatriptan, DFN-02's median tmax (10 minutes) was significantly earlier (15 minutes; P < .0001). Mean sumatriptan exposure metrics were similar for DFN-02 and 4 mg sumatriptan: AUC0-2 : 35.12 and 44.82 ng*hour/mL, respectively; AUC0-∞ : 60.70 and 69.21 ng*hour/mL, respectively; Cmax : 51.79 and 49.07 ng/mL, respectively. With 6 mg subcutaneous sumatriptan, these exposure metrics were about 50% larger (AUC0-2 : 67.17 ng*hour/mL; AUC0-∞ : 103.78 ng*hour/mL; Cmax : 72.75 ng/mL). Inter-subject variability of AUC0-2 , AUC0-∞ , and Cmax was 42-58% for DFN-02, 15-22% for 4 mg subcutaneous sumatriptan, and 15-25% for 6 mg subcutaneous sumatriptan. DDM exposure was low (mean Cmax : 1.63 ng/mL), tmax was 30 minutes, and it was undetectable by 4 hours. There were no serious adverse events, discontinuations due to adverse events, or remarkable findings for vital signs, physical examinations (including nasal and injection site examinations), or clinical laboratory assessments. The overall incidence of adverse events was comparable across treatments, and all treatment-related events were mild in severity. Adverse events occurring in ≥10% of subjects were dysgeusia (19%), headache (18%), nausea (15%), paresthesia (15%), and dizziness (12%). CONCLUSIONS: In healthy subjects, DFN-02, an intranasal spray containing 10 mg sumatriptan plus DDM, had a more rapid absorption profile than commercially available intranasal sumatriptan 20 mg, and systemic exposure from a single-dose administration of DFN-02 was similar to 4 mg SC sumatriptan and two-thirds that of 6 mg SC sumatriptan. With DFN-02, plasma sumatriptan peaked 5 minutes earlier than with both subcutaneous formulations. Systemic exposure to sumatriptan was similar with DFN-02 and 4 mg subcutaneous sumatriptan; both yielded lower systemic exposure than 6 mg subcutaneous sumatriptan. Systemic exposure to DFN-02's excipient DDM was short-lived. DFN-02's safety and tolerability appear to be comparable to subcutaneous sumatriptan. Addition of a permeation enhancer improved the absorption profile compared with commercially available intranasal sumatriptan 20 mg.

The effect of weight, body mass index, age, sex, and race on plasma concentrations of subcutaneous sumatriptan: a pooled analysis.

OBJECTIVE/BACKGROUND: Factors such as body size (weight and body mass index [BMI]), age, sex, and race might influence the clinical response to sumatriptan. We evaluated the impact of these covariates on the plasma concentration (Cp) profile of sumatriptan administered subcutaneously. METHODS: We conducted three pharmacokinetic studies of subcutaneous sumatriptan in 98 healthy adults. Sumatriptan was administered subcutaneously (236 administrations) as either DFN-11 3 mg, a novel 0.5 mL autoinjector being developed by Dr. Reddy's Laboratories; Imitrex(®) (Sumatriptan) injection 3 mg or 6 mg (6 mg/0.5 mL); or Imitrex STATdose 4 mg or 6 mg (0.5 mL). Blood was sampled for 12 hours to determine sumatriptan Cp. Maximum Cp (Cmax), area under the curve during the first 2 hours (AUC0-2), and total area under the curve (AUC0-∞) were determined using noncompartmental methods. Post hoc analyses were conducted to determine the relationship between these exposure metrics and each of body weight, BMI, age, sex, and race (categorized as white, black, or others). RESULTS: Both weight and BMI correlated negatively with each exposure metric for each treatment group. Across all treatment groups, AUC0-2 for subjects with BMI less than or equal to median value was 1.03-1.12 times the value for subjects with BMI more than median value. For subjects with BMI less than or equal to median value receiving DFN-11, median AUC0-2 was slightly less than that for subjects with BMI more than median value receiving Imitrex 4 mg and larger than that for subjects with BMI more than median value receiving Imitrex 3 mg. Results were similar for the other exposure metrics and for weight. Exposure was higher in women than in men, which can be attributed in part to differences in weight. There was no relationship between exposure and age. For DFN-11, AUC0-2 and AUC0-∞ were lower in nonwhites compared with whites; the ratio of median values was 0.84 and 0.89, respectively. A similar, nonstatistically significant, trend was observed in the other products (ratio of median values ranging from 0.84 to 0.89). CONCLUSION: Weight and BMI appear to be important covariates for sumatriptan exposure: subjects with lower values for either metric of body size have higher systemic exposure compared with subjects with higher values. Additional studies are required to determine if doses of subcutaneous sumatriptan may be adjusted based on BMI for comparable efficacy and a potentially improved tolerability profile.

Tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials.

BACKGROUND: Most totally blind people have non-24-hour sleep-wake disorder (non-24), a rare circadian rhythm disorder caused by an inability of light to reset their circadian pacemaker. In two consecutive placebo-controlled trials (SET and RESET), we assessed safety and efficacy (in terms of circadian entrainment and maintenance) of once-daily tasimelteon, a novel dual-melatonin receptor agonist. METHODS: We undertook the placebo-controlled, randomised, double-masked trials in 27 US and six German clinical research centres and sleep centres. We screened totally blind adults (18-75 years of age), who were eligible for the randomisation phase of SET if they had a non-24-hour circadian period (τ) of 24·25 h or longer (95% CI greater than 24·0 and up to 24·9 h), as calculated from measurements of urinary 6-sulphatoxymelatonin rhythms. For SET, we used block randomisation to assign patients (1:1) to receive tasimelteon (20 mg) or placebo every 24 h at a fixed clock time 1 h before target bedtime for 26 weeks. Patients who entered the open-label group receiving tasimelteon in SET or who did not meet the SET inclusion criteria but did meet the RESET inclusion criteria were screened for RESET. A subset of the patients who entered the open-label group before the RESET study and who had eligible τ values were screened for RESET after completing the open-label treatment. In RESET, we withdrew tasimelteon in a randomised manner (1:1) in patients who responded (ie, entrained) after a tasimelteon run-in period. Entrainment was defined as having τ of 24·1 h or less and a 95% CI that included 24·0 h. In SET, the primary endpoint was the proportion of entrained patients, assessed in the intention-to-treat population. The planned step-down primary endpoint assessed the proportion of patients who had a clinical response (entrainment at month 1 or month 7 plus clinical improvement, measured by the Non-24 Clinical Response Scale). In RESET, the primary endpoint was the proportion of non-entrained patients, assessed in the intention-to-treat population. Safety assessments included adverse events and clinical laboratory measures, assessed in all treated patients. These trials are registered with ClinicalTrials.gov, numbers NCT01163032 and NCT01430754. FINDINGS: Between Aug 25, 2010, and July 5, 2012, we screened 391 totally blind patients for SET, of whom 84 (22%) were assigned to receive tasimelteon (n=42) or placebo (n=42). Two patients in the tasimelteon group and four in the placebo group discontinued the study before τ was measured, due to adverse events, withdrawal of consent, and a protocol deviation. Circadian entrainment occurred in eight (20%) of 40 patients in the tasimelteon group compared with one (3%) of 38 patients in the placebo group at month 1 (difference 17%, 95% CI 3·2-31·6; p=0·0171). Nine (24%) of 38 patients showed a clinical response, compared with none of 34 in the placebo group (difference 24%, 95% CI 8·4-39·0; p=0·0028). Between Sept 15, 2011, and Oct 4, 2012, we screened 58 patients for eligibility in RESET, 48 (83%) of whom had τ assessed and entered the open-label tasimelteon run-in phase. 24 (50%) patients entrained, and 20 (34%) were enrolled in the randomisation phase. Two (20%) of ten patients who were withdrawn to placebo remained entrained compared with nine (90%) of ten who continued to receive tasimelteon (difference 70%, 95% CI 26·4-100·0; p=0·0026). No deaths were reported in either study, and discontinuation rates due to adverse events were comparable between the tasimelteon (3 [6%] of 52 patients) and placebo (2 [4%] of 52 patients) treatment courses. The most common side-effects associated with tasimelteon in SET were headache (7 [17%] of 42 patients given tasimelteon vs 3 [7%] of 42 patients given placebo), elevated liver enzymes (4 [10%] vs 2 [5%]), nightmares or abnormal dreams (4 [10%] vs none), upper respiratory tract infection (3 [7%] vs none], and urinary tract infections (3 [7%] vs 1 [2%]). INTERPRETATION: Once-daily tasimelteon can entrain totally blind people with non-24; however, continued tasimelteon treatment is necessary to maintain these improvements. FUNDING: Vanda Pharmaceuticals.

Human pharmacokinetics/pharmacodynamics of an interleukin-4 and interleukin-13 dual antagonist in asthma.

Pitrakinra, a 15-kDa recombinant human interleukin-4 mutein, targets allergic Th2 inflammation by competitively binding to interleukin-4 receptor alpha to interfere with interleukin-4 and interleukin-13 action. The authors characterized pitrakinra pharmacokinetics using data from 96 atopic patients, then compared pharmacokinetics with pharmacological response in asthma following subcutaneous versus inhalation dosing. A 1-compartment systemic model with site-specific absorption describes pitrakinra pharmacokinetics following subcutaneous, nebulization, and inhalation powder delivery. Typical CL/F and V/F, referenced to subcutaneous administration, are 15.5 L/h and 67.5 L, yielding a 3.0-hour half-life of plasma decline. Absorption into the blood (half-life

Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials.

BACKGROUND: Circadian rhythm sleep disorders are common causes of insomnia for millions of individuals. We did a phase II study to establish efficacy and physiological mechanism, and a phase III study to confirm efficacy of the melatonin agonist tasimelteon (VEC-162) for treatment of transient insomnia associated with shifted sleep and wake time. METHODS: We undertook phase II and phase III randomised, double-blind, placebo-controlled, parallel-group studies. In a phase II study, 39 healthy individuals from two US sites were randomly assigned to tasimelteon (10 [n=9], 20 [n=8], 50 [n=7], or 100 mg [n=7]) or placebo (n=8). We monitored individuals for 7 nights: 3 at baseline, 3 after a 5-h advance of sleep-wake schedule with treatment before sleep, and 1 after treatment; we measured plasma melatonin concentration for circadian phase assessment. In a phase III study, 411 healthy individuals from 19 US sites, who had transient insomnia induced in a sleep clinic by a 5-h advance of the sleep-wake schedule and a first-night effect in a sleep clinic, were given tasimelteon (20 [n=100], 50 [n=102], or 100 mg [n=106]) or placebo (n=103) 30 min before bedtime. Prespecified primary efficacy outcomes were polysomnographic sleep efficiency (phase II study), latency to persistent sleep (phase III study), and circadian phase shifting (phase II study). Analysis was by intention to treat. Safety was assessed in both studies. These trials are registered with ClinicalTrials.gov, numbers NCT00490945 and NCT00291187. FINDINGS: In the phase II study, tasimelteon reduced sleep latency and increased sleep efficiency compared with placebo. The shift in plasma melatonin rhythm to an earlier hour was dose dependent. In the phase III study, tasimelteon improved sleep latency, sleep efficiency, and wake after sleep onset (ie, sleep maintenance). The frequency of adverse events was similar between tasimelteon and placebo. INTERPRETATION: After an abrupt advance in sleep time, tasimelteon improved sleep initiation and maintenance concurrently with a shift in endogenous circadian rhythms. Tasimelteon may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders.

Relative analgesic potency of fentanyl and sufentanil during intermediate-term infusions in patients after long-term opioid treatment for chronic pain.

Sufentanil, a potent mu-opioid agonist, historically has not been been given systemically to treat chronic pain. An implantable, fixed-rate osmotic pump that delivers sufentanil subcutaneously is being developed for this purpose. In that transdermal fentanyl may be a useful intermediary to estimate the appropriate sufentanil dose before implant, accurate information is needed about the relative analgesic potency of sufentanil and fentanyl during continuous infusion. To determine this relative potency, we administered these drugs to opioid-treated chronic pain patients using a target-controlled infusion (TCI). Sixty-three patients with stable chronic pain and daily oral opioid requirements equivalent to 100-1000 mg of morphine received TCI of fentanyl and sufentanil, each for a minimum of 16 h. Drug administration was double-blind and the order of administration was randomly assigned. Target concentration was changed until the patient reported that analgesia was adequate (defined as a pain level equal to or better than baseline). Seven patients did not complete the infusion and protocol violations invalidated data for 15 patients. For the remaining 41 patients, target concentrations associated with adequate analgesia were achieved for both sufentanil and fentanyl. The median value for the equianalgesic concentration ratio (steady-state fentanyl infusion to steady-state sufentanil infusion) was 7.5; mean potency ratio was 7.44 (95% confidence interval 6.8-8.2). During titrated, intermediate-term infusions in patients previously treated with opioids for chronic pain, sufentanil is approximately 7.5 times as potent as fentanyl.

Pharmacokinetics of an implanted osmotic pump delivering sufentanil for the treatment of chronic pain.

BACKGROUND: A matchstick-sized implanted osmotic pump (Chronogesic) that delivers sufentanil subcutaneously for more than 90 days is being developed to treat chronic pain. This study evaluates pharmacokinetic characteristics related to the absorption of sufentanil using a prototype 60-day system. METHODS: Twelve opioid-naive volunteers were given naltrexone to prevent opioid effects. Sufentanil, 60 microg, was infused intravenously over 6 h, then 48 h later, the pump was implanted subcutaneously in the upper arm under local anesthesia. Pumps were removed 9 days later. In six volunteers, fever (1.6-3.3 degrees C) was induced with interleukin-2. Plasma was sampled and population pharmacokinetic modeling was performed to estimate in vivo release rate and absorption half-life. Bioavailability was calculated by comparing in vivo to in vitro release rates. The impact of perturbations in release rate on sufentanil plasma concentration (Cp) was simulated. RESULTS: Fever had no systematic effect on Cp. Release rate estimated in vivo was similar to that measured in vitro; bioavailability did not differ from 100%. Absorption half-life was 16.2 h. Simulation demonstrated that supplemental release of sufentanil from the implant (as might occur with local heating) increases Cp an average of 2.5-2.8% per hours supplemental dose. CONCLUSIONS: An implantable osmotic pump delivered sufentanil in vivo at the rate predicted from in vitro experiments. The rate at which sufentanil was absorbed from the subcutaneous space (half-life > 16 h) was markedly slower than reported with subcutaneous or intramuscular administration of large volumes of dilute opioids; this slow absorption dampens potential changes in Cp if release rate is perturbed.

Pharmacodynamic modeling of muscle relaxants: effect of design issues on results.

BACKGROUND: Pharmacodynamic studies of muscle relaxants use different dosing regimens (such as administration by bolus vs. infusion and doses that produce complete vs. incomplete paralysis). The authors used published data to evaluate the effect of modeling assumptions on pharmacodynamic estimates. METHODS: The authors used a pharmacokinetic-pharmacodynamic dataset in which patients received cisatracurium, 75 or 300 microg/kg (1.5 or 6 x ED95), to generate plasma concentration (Cp) and twitch depression (effect) curves. They then evaluated the impact of the following: assuming that Cp decreased monotonically versus increasing initially before decreasing monotonically; misrecording effect data by 6 s or less; and doses targeting incomplete versus complete paralysis. Parameters evaluated were the steady state Cp depressing twitch tension 50% (C50) and the rate constant for equilibration between plasma and effect site concentrations (k(e0)). RESULTS: With the large dose, increasing the time at which Cp peaked from 0.0 to 1.5 min decreased C50 and increased k(e0) markedly; with the small dose, changes in both were small. Misrecording the timing of effect had a larger impact with the large dose compared with the small dose. Doses smaller than ED50 or those producing prolonged, complete twitch depression yielded biased and variable estimates. CONCLUSION: The erroneous assumption that Cp decreases monotonically after bolus administration affects accuracy of pharmacodynamic estimates with doses producing rapid, complete twitch depression. Other errors (e.g., misrecording the time of drug administration) impact on pharmacodynamic estimates, particularly with large doses. The authors' findings suggest that investigators performing neuromuscular (and other) pharmacodynamic studies should carefully consider the impact of study design on their parameter estimates.