Once-weekly Dosing Research Articles

Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma

AbstractProteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m2. Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.

A reversible albumin-binding growth hormone derivative is well tolerated and possesses a potential once-weekly treatment profile.

Human growth hormone (hGH) replacement therapy currently requires daily sc injections for years/lifetime, which may be both inconvenient and distressing for patients. NNC0195-0092 is a novel hGH derivative intended for once-weekly treatment of GH deficiency. A noncovalent albumin binding moiety is attached to the hGH backbone. Clearance is reduced as a consequence of a reversible binding to circulating serum albumin, which prolongs the pharmacodynamic (PD) effect. To evaluate safety, local tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose (SD) and multiple doses (MD) of NNC0195-0092. Randomized, single-center, placebo-controlled, double-blind, SD/MD, dose-escalation trial of 105 healthy male subjects. NNC0195-0092 sc administration: Five cohorts of eight subjects received one dose of NNC0195-0092 (0.01-0.32 mg/kg) (n = 6) or placebo (n = 2). Sixteen subjects (equal numbers of Japanese and non-Asian) received once-weekly doses of NNC0195-0092 (0.02-0.24 mg/kg; n=12) or placebo (n=4) for 4 weeks. Blood samples were drawn for assessment of safety, PK, IGF-1, and IGF binding protein 3 profiles and anti-drug antibodies. SD and MD of NNC0195-0092 were well tolerated at all dose levels. No safety concerns or local tolerability issues were identified. A dose-dependent IGF-1 response was observed. IGF-1 profiles suggest that NNC0195-0092 may be suitable for once-weekly dosing, with a clinically relevant dose ≤0.08 mg/kg/week. No differences in PK and PD were observed between Japanese and non-Asian subjects. SD and MD of NNC0195-0092 administered to healthy Japanese and non-Asian male subjects were well tolerated at all doses. The present trial suggests that NNC0195-0092 has the potential for an efficacious, well-tolerated, once-weekly GH treatment.

Once-Weekly Dalbavancin versus Daily Conventional Therapy for Skin Infection

BackgroundDalbavancin, a lipoglycopeptide antibiotic agent that is active against gram-positive pathogens, has a long plasma half-life, allowing for once-weekly dosing. DISCOVER 1 and DISCOVER 2 were identically designed noninferiority trials of dalbavancin for the treatment of acute bacterial skin and skin-structure infection.MethodsWe randomly assigned patients to receive dalbavancin intravenously on days 1 and 8 or vancomycin intravenously for at least 3 days with the option to switch to oral linezolid to complete 10 to 14 days of therapy. The primary end point, early clinical response, required the cessation of spread of infection-related erythema and the absence of fever at 48 to 72 hours. Secondary end points at the end of therapy included clinical status and investigator's assessment of outcome.ResultsAnalysis of the primary end point showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. In the pooled analysis, 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin–linezolid group had an early clinical response indicating treatment success (weighted difference, −0.1 percentage point; 95% confidence interval, −4.5 to 4.2). The outcomes were similar in the analyses by study and the pooled analyses of clinical status at the end of therapy and the investigator's assessment of outcome. For patients infected with Staphylococcus aureus, including methicillin-resistant S. aureus, clinical success was seen in 90.6% of the patients treated with dalbavancin and 93.8% of those treated with vancomycin–linezolid. Adverse events and study days with an adverse event were less frequent in the dalbavancin group than in the vancomycin–linezolid group. The most common treatment-related adverse events in either group were nausea, diarrhea, and pruritus.ConclusionsOnce-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection. (Funded by Durata Therapeutics; DISCOVER 1 and DISCOVER 2 ClinicalTrials.gov numbers, NCT01339091 and NCT01431339.)

SAT0254 Safety and Tolerability of the Anti-C5ar Humanised Monoclonal Antibody NNC0151-0000 in Patients with Rheumatoid Arthritis: A Phase 2, Randomised, Double-Blind, Placebo-Controlled, Multiple-Dose Trial

BackgroundThe 1st generation compound NNC0151-0000 is a humanised monoclonal antibody that blocks the complement factor 5a receptor (C5aR). C5aR is mainly expressed on leukocytes and is thought to play an...

Bortezomib cumulative dose, efficacy, and tolerability with three different bortezomib-melphalan-prednisone regimens in previously untreated myeloma patients ineligible for high-dose therapy.

Substantial efficacy has been demonstrated with bortezomib-melphalan-prednisone in phase III studies in transplant-ineligible myeloma patients using various twice-weekly and once-weekly bortezomib dosing schedules. In VISTA, the regimen comprised four 6-week twice-weekly cycles, plus five 6-week once-weekly cycles. In the GIMEMA MM-03-05 study, the bortezomib-melphalan-prednisone regimen was either per VISTA ('GIMEMA twice-weekly'), or comprised nine 5-week once-weekly cycles ('GIMEMA once-weekly'). In the GEM2005MAS65 study, the regimen comprised one 6-week twice-weekly cycle, plus five 5-week once-weekly cycles. We evaluated the cumulative bortezomib dose administered during bortezomib-melphalan-prednisone, as well as efficacy and tolerability, using patient-level study data. Over all bortezomib-melphalan-prednisone cycles (nine in VISTA/GIMEMA; six in GEM2005MAS65), the median cumulative bortezomib dose administered was 38.5, 42.1, 40.3, and 32.9 mg/m(2) in VISTA, GIMEMA twice-weekly, GIMEMA once-weekly, and GEM2005MAS65, respectively, and the respective proportions of planned bortezomib dose actually delivered were 57.0%, 62.3%, 86.1%, and 90.4%. Response rates following bortezomib-melphalan-prednisone were 74-87% and appeared generally similar between studies. Three-year survival rates were 67.9-75.7% across studies. Grade 3/4 peripheral neuropathy rates were 13% in VISTA and 14% in GIMEMA twice-weekly, but were lower at 2% in GIMEMA once-weekly and 7% in GEM2005MAS65. Discontinuations and bortezomib dose reductions due to peripheral neuropathy were reduced in GIMEMA once-weekly versus VISTA and GIMEMA twice-weekly. Exclusive or predominant use of once-weekly bortezomib dosing in GIMEMA once-weekly and GEM2005MAS65 resulted in high efficacy, comparable with that demonstrated in VISTA, and similar cumulative bortezomib dose with reduced toxicity. Trials are registered with ClinicalTrials.gov: VISTA (Identifier:00111319), GIMEMA MM-03-05 (Identifier:01063179), and GEM2005MAS65 (Identifier:00443235).

Omarigliptin (MK-3102): A Novel Long-Acting DPP-4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes

In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.

Infant With a Papular Eruption Localized to the Back

A 9-week-old girl had a rash on her back that had been present for 7 weeks. The rashwasasymptomatic andstartedas redbumps that then evolved into pustules and blisters. On further questioning, it was discovered that thepatient’s fatherworked in a nursing home that had experienced a recent outbreak of scabies. Shortly after the onsetof theoutbreak, thepatient andall familymemberswere treated with 2 once-weekly doses of permethrin, 5%, cream. All other family members had significant improvement with the treatment; however, our patient’s lesions continued to worsen during the subsequent 2 weeks. On physical examination, the patient had numerous erythematousmacules, papules, andpustules onher back.Manyof the lesions had superimposed hemorrhagic crust and surrounding scale. In addition, several grouped papules were noted, including some in a linear array (Figure 1A andB). The rest of her cutaneous examination results were unremarkable except for a few fading pink papules noted on her left abdomen (Figure 1C). A B C

Rifapentine Pharmacokinetics and Tolerability in Children and Adults Treated Once Weekly With Rifapentine and Isoniazid for Latent Tuberculosis Infection.

In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults. Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME). There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed. A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults.

Dulaglutide for the treatment of type 2 diabetes

Dulaglutide is a novel glucagon-like peptide 1 (GLP-1) receptor agonist with a unique structure that supports once-weekly dosing in patients with type 2 diabetes (T2DM), most of whom have a big pill burden. It appears to be efficacious in reducing hemoglobin A1c (HbA1c) up to 1.59% and promotes modest weight loss up to 3 kg with a low incidence of hypoglycemia and mild to moderate gastrointestinal adverse events. Convenient weekly dosing could improve compliance and help attain sustained glycemic goals. Addressing obesity is an integral part of T2DM management and weight loss may contribute to better glycemic and cardiovascular benefits. Results of ongoing clinical trials on cardiovascular safety are important to determine the risk-to-benefit ratio. As with any drug, patient selection and ongoing monitoring will be important. If approved, dulaglutide will be one of the first weekly GLP-1 receptor agonist to be available in a ready-to-use pen device with an automatic injector.

Acquired haemophilia A in a patient with chronic hepatitis C virus infection receiving treatment with pegylated interferon plus ribarivin: role of rituximab.

Acquired haemophilia is an uncommon condition caused by the development of clotting factor inhibitors. To eliminate them, immunosuppressive therapy with corticosteroids and cytotoxic drugs is required. We describe a case of rituximab use in acquired haemophilia refractory to conventional therapy in a 63 year old male patient with chronic hepatitis C virus infection who was receiving treatment with pegylated-interferon-a-2a plus ribavirin. After 21 weeks of antiviral therapy, the patient was admitted to hospital with a large haematoma in the abdominal muscles. Factor VIII level was zero and inhibitor titer was 345 Bethesda units. Oral immunosuppressive therapy with methylprednisolone and cyclophosphamide was administered for 1 month, with limited improvement. Therefore, cyclophosphamide was replaced by a four once-weekly dose of intravenous rituximab. Two months later, factor VIII level was normal and inhibitor titer was undetectable. Rituximab may be useful for the treatment of acquired haemophilia resistant to standard therapy.

Tsunami of diabetes: Help is on the way

In his presidential address at the 73rd Scientifi c Sessions of the American Diabetes Association (ADA), John Anderson, MD, asked whether the United States is prepared for this “tsunami of diabetes.” Held in June, this year’s 73rd Scientifi c Sessions drew nearly 18,000 participants and included 2,500 abstracts, more than 2,000 research posters, and 92 symposia. The meeting was internationally attended. An estimated 60% of meeting attendees came to Chicago from countries outside of the United States. This year’s program included presentations on treatment strategies for type 1 diabetes, as well as information on the effi cacy of novel agents for diabetes and potential pathways for targeting better control of the disease. Key highlights from the meeting included a look back on important trials such as the Diabetes Control and Complications Trial (DCCT) and a glimpse into the future for the treatment of diabetes, including new drugs and formulations of antidiabetic agents.

Clinical effects of once-weekly exenatide for the treatment of type 2 diabetes mellitus

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, administration, dosage, place in therapy, and cost of extended-release exenatide are reviewed. Regular-release exenatide has a half-life of 2.4 hours and is administered twice daily. In order to allow for once-weekly administration, exenatide was encapsulated in poly(lactic-co-glycolic acid) microspheres, a biodegradable polymer. After subcutaneous injection, the microspheres slowly degrade, and the drug is released. A single injection of extended-release exenatide reaches maximum plasma concentration after 4-8 hours and remains at therapeutic levels for 8-16 hours, depending on the dosage. Based on the pharmacokinetics of a single dose, researchers determined that 0.8- and 2-mg once-weekly doses were likely to maintain therapeutic levels in the serum. Patients who used extended-release exenatide monotherapy had significantly lower glycosylated hemoglobin (HbA1c) levels and lost more weight than those receiving sitagliptin or pioglitazone (p < 0.05). In combination with metformin, extended-release exenatide reduced HbA1c levels more than did insulin glargine. This new formulation reduced HbA1c levels by 1.5-1.9%, fasting blood glucose concentrations by 31-42 mg/dL, and weight by 2.3-3.7 kg. The most common adverse events were injection-site reactions and transient nausea. Postmarketing reports have described acute pancreatitis and acute necrotizing or hemorrhagic pancreatitis in patients treated with exenatide. The published average wholesale price for a one-month supply of extended-release exenatide 2 mg is $388. Extended-release exenatide taken once weekly is an effective second-line therapy for patients with type 2 diabetes who have not achieved glycemic goals with metformin alone.

Longitudinal changes of MRI marker in Alzheimer's disease and frontotemporal dementia

ECGs, vital sign measurements, and laboratory parameters. PK parameters were derived from plasma concentrations versus time data in young and elderly female subjects. Results: Among 304 enrolled subjects, 60 were randomized and treated with BMS-241027 (n1⁄445) or placebo (n1⁄415). There were no deaths or discontinuations due to AEs and most AEs were mild. One patient experienced a Grade 3 hypersensitivity reaction w2.5 hours after the fourth and final dose of 0.002 mg/kg BMS-241027 (5-minute IV infusion), that responded to treatment without residual symptoms. Infusion time was lengthened to 60 minutes for remaining dose panels without additional hypersensitivity reactions. Overall, AEs occurred in 44 (73.3%) subjects: BMS-241027, 35 (77.8%); placebo, 9 (60%). The most common AEs were constipation (33.3%) and headache (30%) without cognitive or peripheral nervous system AEs. No clinically significant abnormalities were observed in ECG parameters, vital signs, or laboratory parameters. BMS-241027 exposure (Cmax and AUC) increased dose proportionately with negligible accumulation after once-weekly administration, without evidence of time-dependent PK.Elderly subjects at 0.02 mg/kg had 2-6 fold higher exposures than young subjects. Conclusions: BMS-241027 was well-tolerated at multiple once-weekly doses up to 0.06 mg/kg, and single doses up to 0.2 mg/kg; the MTD was not achieved. Overall, healthy female subjects given lower doses with prolonged infusion times showed better safety than subjects dosed in oncology trials. These data support future investigation of BMS-241027 in the treatment of AD and other tauopathies.

A randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability and pharmacokinetics of a microtubule stabilizer (BMS-241027) in healthy females

In Alzheimer's disease (AD), tau loss of function is hypothesized to cause microtubule (MT) destabilization and intraneuronal tau accumulation within neurofibrillary tangles. BMS-241027 is a brain-penetrant MT stabilizer which normalizes tau binding at low doses. BMS-241027 has been previously evaluated in solid tumor oncology trials with a high frequency of adverse events (AEs). Study CN167–002 assessed the safety and tolerability of multiple ascending doses of BMS-241027 in healthy female subjects at exposures >150 -fold lower than used in the oncology studies. BMS-241027 (0.002 mg/kg-0.2 mg/kg IV) was administered as multiple once-weekly doses up to 0.06 mg/kg for 4 weeks, and single doses up to 0.2 mg/kg. Safety assessments were based on AE reports, ECGs, vital sign measurements, and laboratory parameters. PK parameters were derived from plasma concentrations versus time data in young and elderly female subjects. Among 304 enrolled subjects, 60 were randomized and treated with BMS-241027 (n=45) or placebo (n=15). There were no deaths or discontinuations due to AEs and most AEs were mild. One patient experienced a Grade 3 hypersensitivity reaction ∼2.5 hours after the fourth and final dose of 0.002 mg/kg BMS-241027 (5-minute IV infusion), that responded to treatment without residual symptoms. Infusion time was lengthened to 60 minutes for remaining dose panels without additional hypersensitivity reactions. Overall, AEs occurred in 44 (73.3%) subjects: BMS-241027, 35 (77.8%); placebo, 9 (60%). The most common AEs were constipation (33.3%) and headache (30%) without cognitive or peripheral nervous system AEs. No clinically significant abnormalities were observed in ECG parameters, vital signs, or laboratory parameters. BMS-241027 exposure (Cmax and AUC) increased dose proportionately with negligible accumulation after once-weekly administration, without evidence of time-dependent PK. Elderly subjects at 0.02 mg/kg had 2–6 fold higher exposures than young subjects. BMS-241027 was well-tolerated at multiple once-weekly doses up to 0.06 mg/kg, and single doses up to 0.2 mg/kg; the MTD was not achieved. Overall, healthy female subjects given lower doses with prolonged infusion times showed better safety than subjects dosed in oncology trials. These data support future investigation of BMS-241027 in the treatment of AD and other tauopathies.

SAT0112 Improvements in Patient-Reported Physical Function, Pain and Global Disease Activity in Patients with Rheumatoid Arthritis after Treatment with Nnc0109-0012 (Anti-IL-20 Mab) in a Phase 2A Trial

BackgroundNNC0109-0012 (anti-IL-20 mAb) is a novel human monoclonal IgG4 antibody which binds to IL-20 and neutralises its activity. The primary endpoint in this multicentre, randomised, double-blind, placebo-controlled, parallel group trial...

Exenatide Once Weekly: Opportunities in the Primary Care Setting

Type 2 diabetes mellitus is a pandemic, with millions of new diagnoses made each year. In the United States, > 90% of patients with type 2 diabetes mellitus are cared for by primary care physicians who bear the primary responsibility of diagnosing and treating this disease. Building an optimal treatment regimen for a patient from the many choices available depends on many factors, including the ability of a given therapy to safely and effectively lower blood glucose levels, and potential benefits on body weight, cardiovascular risk factors, and hypoglycemia risk. With these considerations at the forefront, this article provides an overview of exenatide once weekly (EQW), a recently available antidiabetes therapy in the glucagon-like peptide-1 receptor agonist class designed to provide continuous glycemic control with once-weekly dosing. We discuss the clinical trials that have demonstrated the ability of EQW to effectively lower blood glucose levels and body weight with a minimal risk of hypoglycemia. In addition, we examine other issues likely to be relevant in a primary care setting, including safety and tolerability profiles, pharmacology and dosing, ease of use, recommended place in treatment, and patient perceptions of EQW.

Albiglutide: clinical overview of a long-acting GLP-1 receptor agonist in the treatment of Type 2 diabetes

Glucagon-like peptide-1 receptor agonists have become an important therapeutic option for patients with Type 2 diabetes because of their ability to lower blood glucose and help patients lose weight. There are currently three glucagon-like peptide-1 receptor agonists on the market. In the near future, albiglutide will undergo review by the US FDA for possible approval. Results from Phase I/II trials have demonstrated that albiglutide is a safe and efficacious medication for treating Type 2 diabetes. It lowers hemoglobin A1c and decreases bodyweight. It appears to have fewer gastrointestinal side effects than liraglutide. The once-weekly (or possibly longer duration) dosing of albiglutide may improve adherence. Several Phase III trials are expected to be completed in 2013. These trials will shed further light on the safety and efficacy of albiglutide.

Abstract 3375: Phase 1 pharmacodyamic activity of multiple-dose PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors.

Abstract Enzymatic degradation of hyaluronan (HA), a key component of the extracellular matrix (ECM), can enhance tumor perfusion, improve delivery of chemotherapeutics, and enhance the effects of anti-tumor agents. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational therapeutic agent under clinical development for the treatment of patients with solid tumors that may accumulate HA. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Twenty-six patients with advanced solid tumors were enrolled in a Phase 1 multi-center trial. Patients received weekly or twice weekly doses of IV PEGPH20 (0.5 - 5 μg/kg) for the first 4-week cycle, followed by once-weekly dosing for the subsequent 4-week cycles. Serial blood samples were drawn from each patient, and plasma concentrations were measured by an ultrasensitive hyaluronidase activity assay to assess PEGPH20 pharmacokinetics (PK). Plasma levels of HA catabolites were measured using a quantitative HPLC method to characterize PEGPH20 pharmacodynamics (PD). Other measures of PD activity were evaluated in selected patients, including DCE-MRI, DW-MRI, 18FDG-PET, textural analysis on CT, and histochemical staining of HA in tumor biopsies collected both before and after PEGPH20 treatment. Peak plasma PEGPH20 concentrations increased with dose, and plasma pharmacokinetics (PK) were well described by a linear PK model. Pre-treatment plasma HA levels were typically &amp;lt;1 μg/mL and increased in a dose-dependent fashion after PEGPH20 treatment. Increased plasma HA corresponded with decreased HA staining in patients with available tumor biopsies. DCE-MRI analysis indicated early (24-48 hr) and rapid increase in tumor perfusion compared to baseline in 4 patients with serial MRI assessments. Pharmacodynamic activity was also demonstrated when pre-treatment 18FDG-PET scans were compared with images collected at scheduled times after PEGPH20 dosing. Reduction in FDG uptake exceeding 25% was demonstrated in 3 of 4 patients after one cycle of treatment, consistent with a partial metabolic response. These data are consistent with the mechanism of action reported in preclinical models, and results support continued evaluation of PEGPH20 in combination with anti-tumor agents via modification of the ECM. Citation Format: Ping Jiang, Daniel C. Maneval, Ramesh K. Ramanathan, Jeffrey R. Infante, Mitesh Borad, Alberto Bessudo, Patricia LoRusso, Barry J. Sugarman, Deborah Carson, Marie A. Printz, Curtis B. Thompson, Paneer Selvam, Joy Zhu, Ronald Korn, H Michael Shepard, Gregory I. Frost. Phase 1 pharmacodyamic activity of multiple-dose PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3375. doi:10.1158/1538-7445.AM2013-3375

Comprehensive update of dalbavancin activity when tested against uncommonly isolated streptococci, Corynebacterium spp., Listeria monocytogenes, and Micrococcus spp. (1357 strains)

Dalbavancin is an investigational lipoglycopeptide having an extended serum elimination half-life allowing once-weekly dosing. Data from testing 1357 strains of uncommonly isolated species expand the dalbavancin spectrum details as follows (MIC50/90): β-haemolytic streptococcal serogroups C, F, and G (≤0.03/≤0.03 μg/mL), 7 viridans group of streptococci (≤0.03/≤0.03–0.06 μg/mL), 5 Corynebacterium spp. (0.06/0.12 μg/mL), Listeria monocytogenes (0.06/0.12 μg/mL), and Micrococcus spp. (≤0.03/≤0.03 μg/mL). Among all reported isolates, 99.8% of tested strains were inhibited at dalbavancin MIC values at ≤0.12 μg/mL. Dalbavancin remains very potent against rarer Gram-positive pathogens, using in vitro test experience with organisms cultured through 2011.

Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients.

Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in patients with cancer. Low molecular weight heparins are the preferred option for anticoagulation in cancer patients according to current clinical practice guidelines. Fondaparinux may also have a place in prevention of VTE in hospitalized cancer patients with additional risk factors and for initial treatment of VTE. Although low molecular weight heparins and fondaparinux are effective and safe, they require daily subcutaneous administration, which may be problematic for many patients, particularly if long-term treatment is needed. Studying anticoagulant therapy in oncology patients is challenging because this patient group has an increased risk of VTE and bleeding during anticoagulant therapy compared with the population without cancer. Risk factors for increased VTE and bleeding risk in these patients include concomitant treatments (surgery, chemotherapy, placement of central venous catheters, radiotherapy, hormonal therapy, angiogenesis inhibitors, antiplatelet drugs), supportive therapies (ie, steroids, blood transfusion, white blood cell growth factors, and erythropoiesis-stimulating agents), and tumor-related factors (local vessel damage and invasion, abnormalities in platelet function, and number). New anticoagulants in development for prophylaxis and treatment of VTE include parenteral compounds for once-daily administration (ie, semuloparin) or once-weekly dosing (ie, idraparinux and idrabiotaparinux), as well as orally active compounds (ie, dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban). In the present review, we discuss the pharmacology of the new anticoagulants, the results of clinical trials testing these new compounds in VTE, with special emphasis on studies that included cancer patients, and their potential advantages and drawbacks compared with existing therapies.