Iv Formulation Research Articles

Valoración de la transición de vedolizumab intravenoso a subcutáneo en pacientes con enfermedad inflamatoria intestinal

AimsThe aim of the study is to evaluate the clinical and biochemical response of inflammatory bowel disease patients treated with vedolizumab, 16 weeks after transitioning from intravenous (iv) to subcutaneous (sc). MethodsAn observational, prospective, single-center cohort study was performed. Patients with inflammatory bowel disease and maintenance treatment with vedolizumab, stable for at least 4 months, were offered to switch to sc formulation. At the same time of treatment administration a blood test was performed, with vedolizumab levels and fecal calprotectin. ResultsForty-three patients were included, 12 of them (27.9%) chose to transition to sc formulation. All included patients remained in remission during follow-up. At week 16 no significant differences were found in terms of calprotectin levels in patients on iv treatment (mean 146.6±SD 45.9) vs. sc (159.26±53.9) (p=0.9). Vedolizumab serum levels at week 16 were higher in the sc group (22,364.3±5141.6) vs. iv (11,425.9±1514.2) (p=0.009). At week 16, 9 (75%) of the patients in the sc group were highly satisfied with the medication and 11 (91.7%) considered it easy to administer. Four patients (12.9%) in the iv group and 2 (16.6%) in the sc group presented mild adverse effects. The 2 cases (100%) of the sc group the adverse event was local inflammation at the injection site. ConclusionIn our experience, vedolizumab sc is a convenient alternative to iv administration. Vedolizumab serum levels in patients who transitioned to sc were higher than iv formulation.

P797 Assessment of pharmacokinetics and clinical response in patients transitioning from intravenous to subcutaneous vedolizumab

Abstract Background Vedolizumab is a humanized monoclonal antibody directed against α4β7 integrin used in inflammatory bowel disease (IBS) patients1. The usual dosage of Vedolizumab is 300 mg intravenously (iv). Recently the subcutaneous (sc) formulation (108 mg every 2 weeks) has been approved, which provides more independence for the patient, avoiding visits to the hospital and possible inconveniences associated with it2. Methods The aim of the study is to evaluate the clinical and biochemical response of IBS patients treated with vedolizumab, 16 weeks after transitioning from iv to sc. An observational, prospective, single-center cohort study was performed. Patients with IBS and maintenance treatment with vedolizumab, stable for at least 4 months, were offered to switch to sc formulation. At the same time of treatment administration a blood test was performed, with vedolizumab levels and fecal calprotectin. Clinical index as Harvey-Bradshaw Index (HBI)/Simple Clinical Colitis Activity Index (SCCAI) and questionaries (IBDQ-9 and TSQM) were performed on each visit. Results 43 patients were included, 12 of them (27.9%) chose to transition to sc formulation. Baseline characteristics of both groups are shown in Table 1. 34 (79.1%) patients were prescribed vedolizumab due to previous biologic failure, 7 (16.3%) in first line due to comorbidities and 2 (4.7%) because of adverse effects in prior treatment. All included patients remained in remission during follow-up. At week 16 (w16), no significant differences were found in calprotectin levels in patients on iv treatment (mean 146.6 ± SD 45.9) vs sc (159.26 ± 53.9) (p 0.9). Vedolizumab serum levels at w16 were higher in the sc group (22364.3 ± 5141.6) vs. iv (11425.9 ± 1514.2), with statistically significant differences (p 0.009). At w16, 9 (75%) of the patients in the SC group were highly satisfied with the medication and 11 (91.7%) considered it easy to administer. 1 patient (8.3%) in the sc group returned to iv treatment. 4 patients (12.9%) in iv and 2 (16.6%) in sc treatment presented mild adverse effects. The 2 cases (100%) of the sc group the adverse event was local inflammation at the injection site. Conclusion In our experience, vedolizumab sc is a safe and convenient alternative to iv administration. Vedolizumab serum levels in patients who transitioned to sc were higher than iv formulation. 1. Smith, Michael A et al. "Vedolizumab: an α4β7 integrin inhibitor for inflammatory bowel diseases." The Annals of pharmacotherapy vol. 48,12 (2014): 1629-35. 2. Vermeire, Séverine et al. "Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn's Disease: Results From the VISIBLE 2 Randomised Trial." Journal of Crohn's & colitis vol. 16,1 (2022): 27-38.

Modern Intravenous Iron Therapy: A Review on Safety and Practical Aspects

Introduction: Intravenous iron formulations have been approved in Europe and North America for the treatment of iron deficiency if oral iron is not tolerated or not efficacious. Recently-developed intravenous iron formulations exhibit specific physicochemical and immunological properties, with distinct bioavailability, efficacy and safety profiles. Area of Interest: intravenous iron formulations safety and tolerability were reviewed in the framework of a Swiss expert meeting. This work focused on the specificity of each compound with emphasis on the practical aspects of its use. Expert Opinion: Adverse reactions in response to iv formulations can be categorized into two main types: hypophosphataemia and hypersensitivity. Hypophosphatemia follows administration of ferric carboxymaltose at a higher rate in comparison to other formulations, but is mostly mild, transient and asymptomatic. However, the decrease in serum phosphate following repeated administration of iron preparations can affect bone health, particularly in patients at risk for osteomalacia. Severe hypersensitivity reactions are the most lifethreatening adverse reactions to intravenous iron supplementation. Iron (III)- isomaltoside 1000 seems to induce severe hypersensitivity more often (RR 5.6 - 16.2) than ferric carboxymaltose. Further studies are needed to address issues of long-term safety in high dose and prolonged administration of intravenous iron preparations in case of chronic diseases.

Development of neuroactive steroids for the treatment of postpartum depression.

Postpartum depression (PPD) is a common major depressive episode surrounding childbirth, with estimated rates ranging from 5.5% to 23.5% of all live births across Europe and the USA based on the presence of key symptoms. PPD has been associated with significant impairments in both maternal functioning and mother‐infant attachment, and these impairments can have lasting effects on the emotional and cognitive development of children. Although the precise pathophysiology of PPD is unknown, preclinical findings suggest that large fluctuations in neurosteroid hormone levels can induce physiological plasticity in the expression of functional GABAA receptors during pregnancy and the postpartum period, and that deficits in this plasticity may underpin a biological mechanism that contributes to the manifestation of depressive symptoms. Here, we review the controlled clinical trials to date that have assessed the efficacy of pharmacological treatments for PPD, including oestradiol, selective serotonin reuptake inhibitors, brexanolone (an iv formulation of allopregnanolone) and an investigational neuroactive steroid and GABAA positive allosteric modulator, zuranolone. Coupled with the GABAergic deficits implicated in major depressive disorder, these findings highlight not only the potential role of GABAA receptor plasticity in the pathophysiology of PPD, but also the novel therapeutic approach of using positive allosteric modulators targeting GABAergic transmission to treat women affected by PPD.

A review of waste paper recycling networks focusing on quantitative methods and sustainability

A discussion is currently under way in the literature on the sustainable benefits of recycling material, particularly paper, which has high global consumption and polluting capacity. Optimized planning of waste paper recycling networks stimulates sustainable processing efficiency, motivating the investigation of quantitative methods to guide decision-making. The objective of this article is to review papers that present quantitative models for planning waste paper recycling networks considering optimization of the echelons of this process, to analyze the evolution of research, find research opportunities and contribute to future research. The article presents an analysis of five categories of the selected studies: I—evolution of publications; II—echelons considered in different waste paper recycling systems; III—the sustainability pillars considered in the objectives of the formulated model; IV—formulations and techniques used; and V—uncertainty analysis. The proposal for waste paper recycling networks involves summary of the echelons considered in selected articles, to help future analysis. Research suggestions involving sustainability objectives, especially considering social issues, using different solution techniques and considering uncertainty were identified. This study, by reviewing the articles and identifying possibilities for future research, contributes to the development of research using quantitative methods for the efficient management of waste paper recycling networks or similar arrangements.

Amphotericin B loaded ethyl cellulose nanoparticles with magnified oral bioavailability for safe and effective treatment of fungal infection

Amphotericin B is a gold standard drug used in various fungal and parasitic infection treatment. Most of the marketed formulations are administered intravenously, but show dose-dependent adverse effects i.e., nephrotoxicity and hemolysis. Oral route eliminates the toxic concern but exhibits poor bioavailability. Therefore, ethylcellulose nanoparticles (EC-NPs) have been used for magnified oral delivery of AmB, where EC provides gastrointestinal stability. These nanoparticles were synthesized by high-pressure emulsification solvent evaporation (HPESE) method and evaluated for in vitro and in vivo studies. This method yields small, monodisperse AmB-EC-NPs along with smooth surface morphology and improved encapsulation efficiency. The developed formulation showed a sustained release pattern following Higuchi diffusion kinetics along with gastric and storage stability. Aggregation study revealed that AmB was present in its monomeric form inside the biocompatible EC matrix. The antifungal result demonstrated that the MIC of AmB-EC-NPs was reduced ∼1/3rd than AmB and Fungizone® at 24 h whereas it was observed ∼1/8th at 48 h. in vivo pharmacokinetic analysis demonstrated 1.3-fold higher AUC than Fungizone® even at a 4.5-time lesser dose via the oral route and a ∼15-fold rise in the bioavailability in contrast to the native AmB. The hemolytic study revealed that the developed formulation exhibited 8-fold lesser hemolysis than Fungizone®. Furthermore, the biosafety profile of AmB-EC-NPs was ensured by the significantly lesser level of blood urea nitrogen and plasma creatinine along with the normal pattern of renal tubules in comparison to AmB and Fungizone®. In conclusion, the results stipulated that the AmB-EC-NPs could be effective, viable and a better alternative to currently existing iv formulations, for magnified oral delivery of AmB in the treatment of fungal infection without associated adverse effects.

Update on the subcutaneous administration of rituximab in Canadian cancer centres.

Results of studies comparing subcutaneous (sc) with intravenous (iv) rituximab indicate that the two formulations are comparable in efficacy, but most patients and health care professionals prefer the sc route, commonly because of shorter chair time and reduced risk of infusion-related reactions. Recent Canadian data, including those from the scuba study reported here, support the results of earlier international studies showing a reduction in preparation and administration time with the sc formulation, lower cost of administration, and reduced drug wastage because of the fixed sc dosing. Given the significant time and cost savings of the sc formulation, that formulation is generally preferred over the iv formulation for the treatment of follicular lymphoma, diffuse large B cell lymphoma, and chronic lymphocytic leukemia.

Intravenous Iron Promotes Low-Grade Inflammation in Anemic Patients By Triggering Macrophage Activation

Patients with iron deficiency anemia (IDA) who have intolerance or an unsatisfactory response to oral iron or present with chronic kidney disease often receive intravenous (iv) iron formulations to improve their anemic condition. Here we investigated whether iv iron induces inflammation in anemic patients and the underlying cellular and molecular mechanisms. We analyzed plasma samples of anemic patients before and 3 weeks after receiving a single-bolus treatment with the iv formulation iron-carboxymaltose and measured circulating inflammatory cytokines. To understand the inflammatory action of iron, we studied the effect of iron-carboxymaltose and non-transferrin bound-like iron (NTBI) source exposure both in an in vitro and in vivo model system. Anemic patients show an increase in circulating cytokine levels still 3 weeks after iron-carboxymaltose injection, compared to their steady-state condition. We found elevated IL-6, TNFα, CCL2 and INFγ. Importantly, patients with more pronounced increase in circulating inflammatory cytokines show higher serum ferritin as well as hepcidin levels, likely induced by inflammation. These observations suggest that iv iron exerts a pro-inflammatory action in anemic patients. Similarly, treatment of wild-type as well as iron-deficient mice with iron-carboxymaltose induces inflammation by triggering cytokine release in the circulation. Since iron formulations might first target macrophages to allow iron recycling, we analyzed the phenotype and production of cytokines induced by iron in these cells both in vitro and in vivo. Iron-carboxymaltose triggers a pro-inflammatory phenotypic switching of bone marrow-derived macrophages (BMDMs), hallmarked by increased expression of the M1 markers MHCII, CD86, iNOS and inflammatory cytokines (e.g. TNFα, IL-6, IL-1β) and reduced expression of the M2 markers CD206, Arg-1, Ym1 and IL-10. This effect is directly due to the presence of iron in the formulation, as exposure of BMDMs to NTBI-like iron (ferric-nitrilotriacetate) induces the same polarization shift, which is prevented by the iron carrier transferrin and the iron chelator deferoxamine. Consistently, inflammatory polarization of reticulo-endothelial (RES) macrophages of the liver and the spleen is observed in mice, either in steady-state and IDA condition, after treatment with NTBI-like iron sources (e.g. ferric-ammonium citrate, ferric-nitrate) as well as iron-carboxymaltose. RES macrophages from treated mice show iron deposition and increased expression of iron-related genes (ferroportin, ferritin, HO-1), together with high cytokine production. Transferrin significantly attenuates iron-mediated macrophage activation in mice, leading to an overall reduction of circulating inflammatory cytokines. These results indicate that iron-activated macrophages contribute to inflammatory cytokine release after administration of intravenous iron. We further confirmed that this process occurs with other iron formulations, including iron-sucrose and iron-dextran. Mechanistically, iron affects macrophage plasticity by triggering reactive oxygen species (ROS) production. Application of anti-oxidant molecules such as N-acetyl-cysteine prevents iron-mediated macrophage polarization both in BMDMs and mice. Collectively, these results indicate that iv iron exerts a clear inflammatory effect in anemic patients through the pro-inflammatory activation of macrophages. Our findings have potential implications for IDA patients who might develop a chronic low-grade inflammation in response to treatment with iv iron formulations. We suggest that inflammation in this context might have a further detrimental effect on the underlying anemia, through a multifactorial action resulting from (i) erythropoiesis suppression, due to the inhibitory action of inflammatory cytokines and (ii) hepcidin induction, which leads to further reduction in iron absorption. In addition, alteration in the inflammatory status might be responsible for commonly reported iv iron-related adverse events, including headache, dizziness, nausea, abdominal pain, constipation, diarrhea, rash and injection-site reactions. We propose that the co-administration of transferrin or anti-oxidants with iv iron in IDA patients is of benefit to counteract iron-induced inflammation, thus improving anemia more effectively and preventing adverse effects. Disclosures Vinchi: Vifor Pharma: Research Funding; Pharmanutra: Research Funding; Silence Therapeutics: Consultancy; Novartis: Research Funding. Muckenthaler:Novartis: Research Funding; Silence Therapeutics: Consultancy. Girelli:Vifor Pharma: Other: honoraria for lectures; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; La Jolla Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.

Administration of Subcutaneous Monoclonal Antibodies in Patients With Cancer.

Subcutaneous (SC) formulations for monoclonal antibodies (mAbs) must be evaluated for efficacy and safety in comparison with preexisting IV formulations to identify potential benefits and risks. This is a systematic review of clinical trials. MEDLINE®/PubMed, EMBASE, Cochrane Library, LILACS (Latin American and Caribbean Health Sciences Literature), and reference lists were searched for relevant studies. Data regarding efficacy and safety were registered in a form designed for this review. Risk of bias was assessed using the Jadad scale. SC administration of alemtuzumab, trastuzumab, and rituximab presented therapeutic efficacy with similar safety profiles compared to their respective IV formulations, except for the higher prevalence of local adverse events following SC administration. SC mAbs require slow administration (no less than five minutes), and the injection site should be changed at each cycle. Patient guidelines should include information about expected adverse effects, signs or symptoms of side effects requiring emergency care, and how to reduce potential discomfort caused by the injection.

Landiolol: pharmacology and its use for rate control in atrial fibrillation in an emergency setting.

This article provides new insight on landiolol, an ultra-short acting injectable betablocker, recently approved in Europe, with regard to its pharmacokinetic and pharmacodynamic profile, along with its first experience in Caucasian healthy volunteers and patients with atrial fibrillation. Landiolol as iv formulation exhibited in an emergency setting rapid rate reduction in patients with tachycardic atrial fibrillation without pronounced blood pressure drop both in caucasian and asian populations in similar manner.

Abstract P3-12-04: Is 6 hour monitoring for administration related reactions after first administration of subcutaneous trastuzumab necessary? A single institution audit

Abstract Background: Subcutaneous (sc) trastuzumab has demonstrated non-inferiority to intravenous (iv) trastuzumab and is preferred by patients and providers. Serious administration related reactions (ARRs) such as hypotension, respiratory distress etc. were not reported in the pivotal HannaH study. However, the summary of product characteristics (SPC) advises that patients should be observed for ARRs for 6 hours post the first injection (and 2 hours post subsequent injections), similar to the iv formulation. Methods: We conducted an audit of patients commencing sc trastuzumab at our institution. Medical notes of each patient were reviewed to record adverse events reported on the day of first administration or at the subsequent visit. In addition all patients were interviewed by telephone and questioned regarding adverse events with first or subsequent injections. Results: 39 patients were identified, 32 had received prior iv trastuzumab. Patients received a mean of 12 injections. In total patients received 470 sc trastuzumab injections, associated with a recommended 1,096 hours of observation as per SPC. 3 injections (0.6%) were associated with ARRs within 24 hours, all on the first cycle. 2 patients (5%) experienced injection site reactions immediately post injection and 1 patient had injection site pain during the injection. 1 patient experienced pyrexia and dry cough 24 hours post injection and was hospitalized for respiratory tract infection. No patient experienced a reaction between 2 and 6 hours post first injection. There were no serious ARRs. Conclusions: ARRs related to sc trastuzumab are usually immediate, mild and self-limiting. Observing patients for 6 hours post first injection and 2 hours post subsequent injections represents an inefficient use of healthcare resources. Citation Format: Karmali S, Hughes N, Galiauskas R, Cook J, Murphy K, Bird BR, Murphy CG. Is 6 hour monitoring for administration related reactions after first administration of subcutaneous trastuzumab necessary? A single institution audit [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-12-04.

Development of New Strategies for Enzyme Replacement Therapy for Lysosomal Storage Disorders

Enzyme replacement therapy (ERT) is a well-established means of treating lysosomal storage disease (LSD). However, classical IV infusion based ERT method produces less than ideal results, especially, CNS defects and quality of life in patients. To improve these main problems of parental IV formulation for LSDs, we investigate modified ERT method and evaluated the efficacy in animal model.

In Vitro and In Vivo Assessment of Docetaxel Formulation Developed for Esophageal Stents.

Esophageal cancer (EC) mostly affects the elderly population and is frequently diagnosed at an advanced stage. Self-expanding metal stents (SEMS) are the most popular mode of palliation, but they are associated with reocclusion caused by tumor growth. To overcome this problem, docetaxel (DTX)-loaded polyurethane formulations were prepared for stent application. The films were evaluated against the cancer cell lines, OE-19 and OE-21, and normal esophageal cell line Het-1A. The DTX and the formulations were evaluated in vitro for the cytotoxicity and in vivo in nude mice. It was found that DTX and the formulations have a weak activity against the EC cell lines and an even weaker activity against Het-1A cell line. Preliminary in vivo studies showed skin toxicity in nude mice necessitating modification of the formulation. Reevaluation in a mouse xenograft model resulted in toxicity at high dose formulations while the low dose formulation exhibited modest advantage over commercial IV formulation; however, there was no significant difference between the commercial IV and blank formulation. DTX combination with an anti-cancer agent having complementary mode of action and non-overlapping toxicity could yield better outcome in future.

TIDILAP: Treatment of iron deficiency in lipoprotein apheresis patients – A prospective observational multi-center cohort study comparing efficacy, safety and tolerability of ferric gluconate with ferric carboxymaltose

ObjectivesIron deficiency (ID) and iron deficiency anemia (IDA) are common findings in patients undergoing lipoprotein apheresis (LA). Different intravenous (iv) formulations are used to treat ID in LA patients, however guidelines and data on ID/IDA management in LA patients are lacking.We therefore performed a prospective observational multi-center cohort study of ID/IDA in LA patients, comparing two approved i.v. iron formulations, ferric gluconate (FG) and ferric carboxymaltose (FCM). MethodsInclusion criteria were a) serum ferritin <100 μg/L or b) serum ferritin <300 μg/L and transferrin saturation <20%. Patients received either FG (62.5 mg weekly) or FCM (500 mg once in ID or up to 1000 mg if IDA was present) i.v. until iron deficiency was resolved. Efficacy and safety were determined by repeated laboratory and clinical assessment. Iron parameters pre and post apheresis were measured to better understand the pathogenesis of ID/IDA in LA patients. Results80% of LA patients treated at the three participating centers presented with ID/IDA; 129 patients were included in the study. Serum ferritin and transferrin levels were reduced following apheresis (by 18% (p < 0.0001) and by 13% (p < 0.0001) respectively). Both FG and FCM were effective and well tolerated in the treatment of ID/IDA in LA patients. FCM led to a quicker repletion of iron stores (p < 0.05), while improvement of ID/IDA symptoms was not different. Number and severity of adverse events did not differ between FG and FCM, no severe adverse events occurred. ConclusionsOur results suggest that FG and FCM are equally safe, well-tolerated and effective in treating ID/IDA in LA patients. These data form the basis for follow-up randomized controlled trials to establish clinical guidelines.

Pharmacokinetics of the antiepileptic drug levetiracetam in healthy Japanese and Caucasian volunteers following intravenous administration.

The intravenous (iv) formulation of levetiracetam has been available in clinical practice worldwide for several years, but not in Japan. Two open-label studies were conducted: Study A evaluated the bioequivalence of iv and oral tablet formulations in healthy Japanese volunteers; and Study B subsequently compared the pharmacokinetics of iv levetiracetam in healthy Japanese and Caucasian volunteers. Study A had a randomised, two-way crossover design; a single 1,500mg levetiracetam dose was administered as a 15-min iv infusion and as 3×500mg oral tablets to Japanese volunteers. In Study B, 1,500mg levetiracetam was administered as single and repeated 15-min iv infusions to Japanese and Caucasian volunteers. Overall, 26/27 volunteers completed Study A and 32/32 (16 Japanese; 16 Caucasian) completed Study B. In Study A, the point estimate and 90% confidence interval (CI) for the geometric least squares mean (LSM) ratio (iv vs oral) were fully included within the acceptance range for bioequivalence (0.85-1.25) for the area under plasma concentration-time curve from 0 to last quantifiable observation (AUClast 0.97 [0.95, 0.99]), but not for the maximum plasma concentration (C max 1.64 [1.47, 1.83]). In Study B, after a single iv infusion, the point estimates (90% CI) for the geometric LSM ratio (Japanese vs Caucasian) for body weight-normalised C max and AUClast were 1.21 (1.07, 1.36) and 0.97 (0.90, 1.04), respectively. Corresponding values after repeated iv infusions were C max,ss 1.01 (0.91, 1.12) and AUCτ,ss 0.89 (0.83, 0.96). Levetiracetam was well tolerated in both studies. Study A did not demonstrate the bioequivalence of single doses of levetiracetam 1,500mg administered as an iv infusion and as oral tablets in healthy Japanese adults. Study B, however, showed that pharmacokinetic profiles were generally similar between Japanese and Caucasian adults after single and repeated iv infusions of levetiracetam 1,500mg.

QTc Veränderungen bei intravenöser Akutsedierung mit Haloperidol, Prothipendyl und Lorazepam

Specific sedation of acute psychotic patients with iv Haloperidol has been repeatedly criticized due to its cardiac risk on the basis of QTc prolongation, cumulating in the fact that iv application is no longer recommended according to the producer. Since Haloperidol still provides the only iv formulation of a high potency neuroleptic medication, and iv application offers some crucial advantages over other forms of application, we wanted to objectify QTc prolongation of Haloperidol iv as well as QTc prolongation of Prothipendyl iv, a low potency neuroleptic medication for unspecific sedation. In our department all treatments with Haloperidol and Prothipendyl iv are ECG monitored and documented following an appointed guideline. Over 3 years all treatments according to this scheme and additionally treatments with Lorazepam iv have been analyzed regarding QTc prolongation. Non-parametric tests have been applied due to missing normal distribution of the data. 99 patients have been included in the survey. According to the iv medication applied patients have been divided into different subgroups. A significant QTc prolongation compared to the Lorazepam control group could be seen in the Haloperidol/Prothipendyl combination group as well as in the Prothipendyl monotherapy group, but not in the haloperidol monotherapy group. When patients were included, who additionally had received Lorazepam, results did not differ essentially with the exception that the Haloperidol/Prothipendyl combination had a significant greater prolongation than the Haloperidol group. Our data proves the well known fact that Haloperidol iv causes a pronounced QTc prolongation. However QTc prolongation by iv Prothipendyl is still more pronounced according to our data. Most potent in producing a QTc prolongation proved a combination of Prothipendyl and Haloperidol, a fact that most likely depicts a dose effect. Since we assume, that there will be continuing need for iv medication with Haloperidol and Prothipendyl in the future, due to lack of arguable alternatives, we recommend safety measures like ECG monitoring not only for Haloperidol, but too for unspecific sedation with iv Prothipendyl.

Phase 1 Study of ABT-348, A Dual Aurora/VEGF-Receptor Kinase Inhibitor, in Patients with Advanced Hematologic Malignancies.

AbstractAbstract 2617 Introduction:ABT-348 is a potent, novel, adenosine triphospate competitive inhibitor of Aurora A, B and C kinases. ABT-348 is also a potent inhibitor of all members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase (RTK) families. ABT-348 has demonstrated strong antitumor activity in a variety of preclinical cancer cell line models, in vitro and in vivo, including leukemias as monotherapy and in combination with the DNA methyltransferase inhibitor, azacitidine. Objectives:The primary objectives of this study are to determine the safety and pharmacokinetics (PK) of orally and IV administered ABT-348 as monotherapy or in combination with azacitidine in patients (pts) with advanced hematologic malignancies. Secondary objectives include determination of the maximum tolerated dose (MTD) and exploration of biomarkers associated with ABT-348 activity. Methods:This phase 1 dose-escalation study of ABT-348 utilizes a modified continual reassessment method in pts with advanced hematologic malignancies: acute myelogenous leukemia (AML), acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia and myelodysplasia (MDS). Adult pts with histological or cytological confirmed disease, ECOG status 0–2, adequate hematological, renal and hepatic function and without significant hypertension or proteinuria are eligible. This study has four arms consisting of ABT-348 administered on a 28-day (D) cycle. Pts receive ABT-348 monotherapy once daily (QD, Arm A) or twice daily (BID; Arm B) on Days (D) 1, 8, and 15 of a 28-day cycle under fasting conditions. In Arm C, ABT-348 is given on the same schedule as Arm A in combination with azacitidine (75 mg/m2) administered IV or SC on Days 1 – 7 of each 28-day cycle. In Arm D, pts receive ABT-348 monotherapy on the same schedule as Arm A, but via IV administration. Samples are collected for PK and biomarker analyses. Pts are treated until progressive disease (PD) or unacceptable toxicity. Adverse event (AE) severity is graded using NCI-CTCAE v4.0. Results:39 pts (median age, 66 y [45–86]) have enrolled (Arm A, n=32; Arm B, n=4; Arm C, n=3). Of these pts, 27 had AML, 11 had MDS and 1 had CML. Pts received a median of 4 prior therapies (range, 1 – 8). Best response to last prior therapy was: complete or partial response in 3 pts, stable disease in 11 pts, PD in 24, and not determined in 1. Dose escalation is shown in the table. The first dose-limiting toxicity (DLT) of grade 3 pancreatitis was observed at 640 mg in Arm A. Due to this DLT, along with a second case of grade 3 pancreatitis, further enrollment in Arm A was held and Arms B and C were opened. A DLT of grade 4 acute kidney injury was seen at 440 mg in Arm C. ABT-348-related AEs in greater than 2 pts were proteinuria (23%), nausea (21%), diarrhea (18%), hypertension (13%), vomiting (10%) and fatigue (8%). Grade 3/4 ABT-348-related AEs were hypertension (13%), pancreatitis (5%), acute kidney injury (3%) and diarrhea (3%). One patient in Arm A achieved a CRi (640 mg). Five of 32 pts in Arm A were treated for ≥4 cycles, including 2 of 7 pts at ABT-348 doses ≥ 640 mg. Based on preliminary PK analyses, Cmax and AUC of ABT-348 were approximately dose proportional in the dose range studied (10–690 mg); co-administration of azacitidine had no apparent effect on ABT-348 PK. Evidence of dual aurora/VEGF receptor kinase inhibition has been demonstrated by induction of polyploidy and PlGF, respectively. 33 pts have discontinued and 6 remain on study. Conclusions:ABT-348 has demonstrated on-target biomarker and clinical activity in pts with advanced hematologic magnancies, and was well tolerated at doses below 640 mg in Arm A. PK appears to be dose-proportional. Dose escalation is ongoing in Arms B and C (with azacitidine); an IV formulation of ABT-348 will also be evaluated.ArmDose (mg)NDLTsResponsesA103--201––401––802––1603––2405––3403––4404––5403––6406Grade 3 pancreatitisCRi6901––B320BID4––C4403Grade 4 acute kidney injury–CRi = Complete response with incomplete blood count recovery Disclosures:Off Label Use: Clofarabine in AML. Tibes:Abbott: Research Funding. Chiu:Abbott: Employment, Owns stocks Other. Xiong:Abbott: Employment, own Abbott stock Other. Qin:Abbott: Employment. Ansell:Abbott: Employment, own Abbott stock Other. Albert:Abbott: Employment, own Abbott stock Other. Tse:Abbott: Employment, own Abbott stock Other. Oliver:Abbott: Employment, own Abbott stock Other. Sajwani:Abbott: Employment, own Abbott stocks and participated in study design, data collection, analysis, interpretation and reviewing approving study documents related to ABT-348 programs. Other. McKee:Abbott: Employment, own Abbott stocks Other. Ricker:Abbott: Employment, own Abbott stocks Other.

Critical appraisal of temozolomide formulations in the treatment of primary brain tumors: patient considerations

Critical appraisal of temozolomide formulations in the treatment of primary brain tumors: patient considerations Margarita Garc&iacute;a,1 Ana Clop&eacute;s,2 Jordi Bruna,3 Mar&iacute;a Mart&iacute;nez,4 Eduard Fort,2 Miguel Gil51Clinical Research Unit, Institut Catal&agrave; d&rsquo;Oncologia-IDIBeLL, L&rsquo;Hospitalet, Barcelona, Spain; 2Pharmacy Department, Institut Catal&agrave; d&rsquo;Oncologia-IDIBeLL, L&rsquo;Hospitalet, Barcelona, Spain; 3Neurology Department and Neuro-Oncology Unit, Hospital Universitario de Bellvitge-IDIBeLL, L&rsquo;Hospitalet, Barcelona, Spain; 4Oncology Department, Hospital del Mar, Barcelona, Spain; 5Oncology Department and Neuro-Oncology Unit, Institut Catal&agrave; d&rsquo;Oncologia-IDIBeLL, L&rsquo;Hospitalet, Barcelona, SpainAbstract: Chemotherapy is assuming an increasingly important role in the treatment of malignant gliomas, of which temozolomide (TMZ ) is a key part. TMZ belongs to a class of second-generation imidazotetrazinone prodrugs that exhibit linear pharmacokinetics and do not require hepatic metabolism for activation to the active metabolite. New intravenous (iv) TMZ formulations have recently been approved based on studies of bioequivalence between iv and oral TMZ. The efficacy of TMZ was initially evaluated in patients with recurrent disease but phase II and III trials in newly diagnosed gliomas are available. The results of a large phase III trial that compared RT alone vs RT concomitant with oral TMZ created a new standard of adjuvant treatment. Efficacy data for iv TMZ on which its approval was based are those extrapolated from clinical trials with oral TMZ. No comparative data are available on the differences in tolerability and patient satisfaction between oral and iv formulations of TMZ, or for quality of life. New oral formulations could encourage the adherence of patients to treatment. Although patients presumably would prefer oral treatment, iv formulations may be an alternative in noncompliant patients or patients for whom good adherence could not be expected.Keywords: temozolomide, brain tumors, new formulations, patient considerations, chemotherapy, glioblastoma&nbsp

Critical appraisal of temozolomide formulations in the treatment of primary brain tumors: patient considerations

Chemotherapy is assuming an increasingly important role in the treatment of malignant gliomas, of which temozolomide (TMZ) is a key part. TMZ belongs to a class of second-generation imidazotetrazinone prodrugs that exhibit linear pharmacokinetics and do not require hepatic metabolism for activation to the active metabolite. New intravenous (iv) TMZ formulations have recently been approved based on studies of bioequivalence between iv and oral TMZ. The efficacy of TMZ was initially evaluated in patients with recurrent disease but phase II and III trials in newly diagnosed gliomas are available. The results of a large phase III trial that compared RT alone vs RT concomitant with oral TMZ created a new standard of adjuvant treatment. Efficacy data for iv TMZ on which its approval was based are those extrapolated from clinical trials with oral TMZ. No comparative data are available on the differences in tolerability and patient satisfaction between oral and iv formulations of TMZ, or for quality of life. New oral formulations could encourage the adherence of patients to treatment. Although patients presumably would prefer oral treatment, iv formulations may be an alternative in noncompliant patients or patients for whom good adherence could not be expected.

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