Spectral signal processing approaches for selective quantification of the recently FDA approved brand-new combination of Vaborbactam and Meropenem; for conformity assessment of bulk and batch release.

Vaborbactam (VBR) and Meropenem (MRP) is a recently approved combination for treatment of complicated urinary tract infection (cUTI). Three different signal processing approaches utilizing UV spectral data has been applied for quality assessment of Vabromere® injection. First, the simplest signal processing method, dual wavelength (DW) was developed, where VBR and MRP were determined at (234.0 & 291.0 nm) and (219.5 & 245.5 nm), respectively. The second one utilized signal processing through derivatization, where, each drug was determined without any interference. This was achieved at 250.0 & 318.0 nm for VBR and MRP, respectively. The third approach is the recently developed algorithm, pure component contribution (PCCA), which efficiently extracts the pure spectrum of each drug and therefore determination is achieved at their λmax with maximum sensitivity and lowest error. The applied methods were found to be linear in the concentration range of 5.00-100.00 µg/mL and 5.00-150.00 µg/mL, for VBR and MRP, respectively. Minimum solvent consumption and diminished preparation or extraction steps are achieved associated with accurate quantitation of VBR and MRP in bulk powders and injection. The developed methods were successfully compared to a reported HPLC method, where no significant difference was found regarding both accuracy and precision.

Biological assessment of self-assembled polymeric micelles for pulmonary administration of insulin.

Pulmonary delivery of drugs for both local and systemic action has gained new attention over the last decades. In this work, different amphiphilic polymers (Soluplus®, Pluronic® F68, Pluronic® F108 and Pluronic® F127) were used to produce lyophilized formulations for inhalation of insulin. Development of stimuli-responsive, namely glucose-sensitive, formulations was also attempted with the addition of phenylboronic acid (PBA). Despite influencing the in vitro release of insulin from micelles, PBA did not confer glucose-sensitive properties to formulations. Lyophilized powders with aerodynamic diameter (<6 µm) compatible with good deposition in the lungs did not present significant in vitro toxicity for respiratory cell lines. Additionally, some formulations, in particular Pluronic® F127-based formulations, enhanced the permeation of insulin through pulmonary epithelial models and underwent minimal internalization by macrophages in vitro. Overall, formulations based on polymeric micelles presenting promising characteristics were developed for the delivery of insulin by inhalation. FROM THE CLINICAL EDITOR: The ability to deliver other systemic drugs via inhalation has received renewed interests in the clinical setting. This is especially true for drugs which usually require injections for delivery, like insulin. In this article, the authors investigated their previously developed amphiphilic polymers for inhalation of insulin in an in vitro model. The results should provide basis for future in vivo studies.

The European medicines agency review of pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use.

On August 5, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pomalidomide in combination with dexamethasone for the treatment of adult patients with relapsed and refractory multiple myeloma (MM) who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. Pomalidomide is an immunomodulating agent. The recommended starting dose of pomalidomide is 4 mg once daily taken on days 1-21 of repeated 28-day cycles. The main evidence of efficacy for pomalidomide in MM was based on a phase III multicenter, randomized, open-label study (CC-4047-MM-003) in which pomalidomide plus low-dose dexamethasone therapy (POM+LoDEX) was compared with high-dose dexamethasone alone (HiDEX) in previously treated adult patients with relapsed and refractory multiple myeloma who had received at least two prior treatment regimens, including both lenalidomide and bortezomib, and had demonstrated disease progression on the last therapy. For the intent-to-treat population, median progression-free survival based on International Myeloma Working Group criteria was 15.7 weeks (95% confidence interval [CI]: 13.0-20.1) in the POM+LoDEX group versus 8.0 weeks (95% CI: 7.0-9.0) in the HiDEX group (log-rank p value <.001). Overall survival (secondary endpoint) was also different in the two treatment groups (hazard ratio 0.53 [95% CI: 0.37-0.74]). The most commonly reported adverse reactions to pomalidomide in clinical studies were anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%), fatigue (28.3%), pyrexia (21%), peripheral edema (13%), and infections including pneumonia (10.7%). Peripheral neuropathy adverse reactions were reported in 12.3% of patients, and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3% of patients. Pomalidomide is expected to be teratogenic. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

Risks and burden of viral respiratory tract infections in patients with multiple myeloma in the era of immunomodulatory drugs and bortezomib: experience at an Australian Cancer Hospital.

INTRODUCTION: Infections are a leading cause of morbidity and mortality in patients with multiple myeloma. The epidemiology, risk factors and outcomes of viral respiratory tract infections (vRTI) are not well described in patients with multiple myeloma managed with novel agents, the current standard of care. METHODS: Patients with myeloma from 2009 to 2012 who tested positive on respiratory virus multiplex polymerase chain reaction had clinical, radiological and microbiological records reviewed. The Fourth European Conference on Infections in Leukaemia (ECIL-4) definitions of RTI were applied. Univariate and multivariate regression analysis of risk factors was performed using vRTI as the evaluable outcome. RESULTS: Of 330 patients, 75 (22.7%) tested positive for a total of 100 vRTI episodes. All patients received thalidomide, lenalidomide or bortezomib in combination with myeloma therapies (median of three treatment regimens). vRTI occurred most commonly in patients with progressive disease, and receipt of more than three lines of myeloma therapy was associated with an increased risk of vRTI (p < 0.01). Amongst key respiratory pathogens, influenza was associated with the highest hospital admission rate (66.7%), ICU admission rate (41.6%) and mortality (33.3%) whilst RSV was associated with prolonged hospital stay. CONCLUSION: Patients with multiple myeloma and advanced disease managed with multiple lines of therapy are at risk for vRTI, and targeted interventions for prevention/treatment are required.

Whole-body diffusion-weighted MR imaging for assessment of treatment response in myeloma.

PURPOSE: To determine the feasibility of whole-body diffusion-weighted (DW) magnetic resonance (MR) imaging for assessment of treatment response in myeloma. MATERIALS AND METHODS: This prospective single-institution study was HIPAA-compliant with local research ethics committee approval. Written informed consent was obtained from each subject. Eight healthy volunteers (cohort 1a) and seven myeloma patients (cohort 1b) were imaged twice to assess repeatability of quantitative apparent diffusion coefficient (ADC) estimates. Thirty-four additional myeloma patients (cohort 2) underwent whole-body DW imaging before treatment; 26 completed a posttreatment imaging. Whole-body DW data were compared before and after treatment by using qualitative (ie, observer scores) and quantitative (ie, whole-body segmentation of marrow ADC) methods. Serum paraproteins and/or light chains or bone marrow biopsy defined response. RESULTS: Whole-body DW imaging scores were significantly different between observers (P < .001), but change in scores between observers after treatment was not (P = .49). Sensitivity and specificity for detecting response according to observer scores were 86% (18 of 21 patients) and 80% (4 of 5 patients) for both observers. ADC measurement was repeatable: mean coefficient of variation was 3.8% in healthy volunteers and 2.8% in myeloma patients. Pretreatment ADC in cohort 2 was significantly different from that in cohort 1a (P = .03), but not from that in cohort 1b (P = .2). Mean ADC increased in 95% (19 of 20) of responding patients and decreased in all (five of five) nonresponders (P = .002). A 3.3% increase in ADC helped identify response with 90% sensitivity and 100% specificity; an 8% increase (greater than repeatability of cohort 1b) resulted in 70% sensitivity and 100% specificity. There was a significant negative correlation between change in ADC and change in laboratory markers of response (r = -0.614; P = .001). CONCLUSION: Preliminary work demonstrates whole-body DW imaging is a repeatable, quantifiable technique for assessment of treatment response in myeloma.

Comparative cost-effectiveness models for the treatment of multiple myeloma.

OBJECTIVES: To compare cost effectiveness models for the first-line treatment of multiple myeloma, and explore the differences between the models' structure, parameters, assumptions and results. METHODS: Three cost effectiveness models for the treatment of multiple myeloma, were compared that had been developed to inform resource allocation in the UK for the chemotherapy regimens bortezomib, melphalan and prednisolone (BMP); and melphalan, prednisolone and thalidomide (MPT) versus melphalan and prednisolone (MP). The models used alternative approaches and assumptions to estimate the overall survival and progression-free survival for each of the interventions. Through the use of sensitivity analyses, the most influential parameters and assumptions of each of the models were identified. RESULTS: The models developed by the manufacturers gave conflicting results, with each manufacturer favouring their drug. The differences between the model results were determined by two parameters: the hazard ratio for overall survival for MPT vs. MP and the cost of bortezomib. CONCLUSIONS: Using models developed for assessing treatments for multiple myeloma we demonstrated that it was feasible to compare models, which then aided decision makers in making reimbursement decisions.

Peripheral blood stem cell mobilization in multiple myeloma patients treat in the novel therapy-era with plerixafor and G-CSF has superior efficacy but significantly higher costs compared to mobilization with low-dose cyclophosphamide and G-CSF.

Studies comparing the efficacy and cost of peripheral blood stem and progenitor cells mobilization with low-dose cyclophosphamide (LD-CY) and granulocyte-colony stimulating factor (G-CSF) against plerixafor and G-CSF, in multiple myeloma (MM) patients treated in the novel therapy-era are not available. Herein, we report mobilization outcomes of 107 patients who underwent transplantation within 1-year of starting induction chemotherapy with novel agents. Patients undergoing mobilization with LD-CY (1.5 gm/m(2)) and G-CSF (n = 74) were compared against patients receiving plerixafor and G-CSF (n = 33). Compared to plerixafor, LD-CY was associated with a significantly lower median peak peripheral blood CD34+ cell count (68/µL vs. 36/µL, P = 0.048), and lower CD34+ cell yield on day 1 of collection (6.9 × 10(6)/kg vs. 2.4 × 10(6)/kg, P = 0.001). Six patients (8.1%) in the LD-CY group experienced mobilization failure, compared to none in the plerixafor group. The total CD34+ cell yield was significantly higher in the plerixafor group (median 11.6 × 10(6)/kg vs. 7 × 10(6)/kg; P-value = 0.001). Mobilization with LD-CY was associated with increased (albeit statistically non-significant) episodes of febrile neutropenia (5.4% vs. 0%; P = 0.24), higher use of intravenous antibiotics (6.7% vs. 3%; P = 0.45), and need for hospitalizations (9.4% vs. 3%; P = 0.24). The average total cost of mobilization in the plerixafor group was significantly higher compared to the LD-CY group ($28,980 vs. $19,626.5 P-value < 0.0001). In conclusion, in MM plerixafor-based mobilization has superior efficacy, but significantly higher mobilization costs compared to LD-CY mobilization. Our data caution against the use of LD-CY in MM patients for mobilization, especially after induction with lenalidomide-containing regimens.

Health care costs and resource utilization, including patient burden, associated with novel-agent-based treatment versus other therapies for multiple myeloma: findings using real-world claims data.

BACKGROUND: . Treatment of multiple myeloma has dramatically improved with the introduction of bortezomib (BOR), thalidomide (THAL), and lenalidomide (LEN). Studies assessing health care costs, particularly economic burden on patients, are limited. We conducted a claims-based, retrospective analysis of total health care costs as well as patient burden (patient out-of-pocket costs and number of ambulatory/hospital visits) associated with BOR/THAL/LEN treatment versus other therapies (OTHER). METHODS. Treatment episodes starting between January 1, 2005 and September 30, 2010 were identified from the claims database of a large U.S. health plan. Health care costs and utilization were measured during 1 year after initiation and analyzed per treatment episode. Multivariate analyses were used to adjust for patient characteristics, comorbidities, and line of treatment. RESULTS: A total of 4,836 treatment episodes were identified. Mean adjusted total costs were similar between BOR ($112,889) and OTHER ($111,820), but higher with THAL ($129,412) and LEN ($158,428). Mean adjusted patient out-of-pocket costs were also similar for BOR ($3,846) and OTHER ($3,900) but remained higher with THAL ($4,666) and LEN ($4,483). Mean adjusted rates of ambulatory visits were similar across therapies (BOR: 69.67; THAL: 66.31; LEN: 65.60; OTHER: 69.42). CONCLUSIONS: Adjusted analyses of real-world claims data show that total health care costs, as well as patient out-of-pocket costs, are higher with THAL/LEN treatment episodes than with BOR/OTHER therapies. Additionally, similar rates of ambulatory visits suggest that any perceived advantage in patient convenience of the orally administered drugs THAL/LEN is not supported by these data.

The cost-effectiveness of initial treatment of multiple myeloma in the U.S. with bortezomib plus melphalan and prednisone versus thalidomide plus melphalan and prednisone or lenalidomide plus melphalan and prednisone with continuous lenalidomide maintenance treatment.

The outlook for transplant-ineligible multiple myeloma patients has improved enormously over recent years with the incorporation of new agents into standard regimens. Novel regimens combine melphalan and prednisone (MP) with bortezomib (VMP), with thalidomide (MPT), and with lenalidomide with (MPR-R) and without (MPR) lenalidomide maintenance. The efficacy, safety, and cost-effectiveness of these regimens have not yet been compared; therefore, we conducted a pharmacoeconomic analysis using data from randomized controlled trials versus MP. Using a Markov model developed from a U.S. payer's perspective, we compared VMP with MPT and MPR-R over a lifetime horizon. MPT and MPR-R were chosen because, like VMP, they are superior to MP in response and outcomes. Data from the Velcade as Initial Standard Therapy in Multiple Myeloma (VISTA; VMP), Intergroupe Francophone du Myelome (IFM) 99-06 (MPT), and MM-015 (MPR-R) trials were used. The IFM 99-06 study was selected because of the superior activity in this study compared with other MPT studies. Using patient-level (VMP) and published (MPT, MPR-R) data, we estimated the health-state transition and adverse event probabilities for each regimen, related costs, and state-specific utility estimates. Costs (in 2010 U.S. dollars) and health outcomes were discounted at 3%. Discounted lifetime direct medical costs were lowest with VMP at $119,102. MPT cost $142,452 whereas MPR-R cost $248,358. Incremental cost-effectiveness ratio calculations projected that VMP would confer cost savings and better health outcomes relative to MPT and MPR-R. We conclude that VMP is highly likely to be cost-effective compared with MP, MPT, and MPR-R.

Real-world health care costs of relapsed/refractory multiple myeloma during the era of novel cancer agents.

WHAT IS KNOWN AND OBJECTIVE: High costs of novel agents increasingly put pressure on limited healthcare budgets. Demonstration of their real-world costs and cost-effectiveness is often required for reimbursement. However, few published economic evaluations of novel agents for multiple myeloma exist. Moreover, existing cost analyses were heavily based on conventionally treated patients. We investigated real-world health care costs of relapsed/refractory multiple myeloma in Dutch daily practice. METHODS: A retrospective medical chart review was conducted for 139 patients treated between January 2001 and May 2009. Total monthly costs attributable to each cost component were described across all regimens and for bortezomib-, thalidomide- and lenalidomide-based treatment regimens. RESULTS: Mean monthly total costs (€3,981) varied depending on the sequence of therapy (range: €442-€31,318). Significant cost drivers across all regimens included costs of therapy and hospital admissions. The acquisition costs for novel agents in particular accounted for 32% of mean total monthly costs. Prognostic factors associated with increased mean total monthly costs in multivariate regression analysis included low platelet counts (P = 0·01) and worsening performance status (P < 0·001). Mean total monthly costs of bortezomib- and lenalidomide-based regimens were significantly higher than those for thalidomide-based regimens in second, third and fourth treatment line. WHAT IS NEW AND CONCLUSIONS: Real-world costs during treatment of relapsed/refractory multiple myeloma vary greatly. Cost drivers include hospital admissions and acquisition costs of novel agents. Costs also vary by prognostic factors and treatment-related resource use. Future studies assessing the costs of combination therapy consisting of two or more novel agents are encouraged.

Serum free light chains in myeloma patients with an intact M protein by immunofixation: potential roles for response assessment and prognosis during induction therapy with novel agents.

The ascertainment of serum free light chain (sFLC) levels has been shown to be valuable in screening for the presence of plasma cell dyscrasia as well as for baseline prognosis in newly diagnosed patients. For patients with amyloidosis and those with oligo-secretory or non-secretory multiple myeloma (MM), serial measurement of sFLC has also been shown to be valuable in monitoring disease status. However, in patients with a measureable, intact monoclonal protein by immunofixation (M protein), the serial measurement of sFLC remains undefined and is currently not recommended in professional guidelines. Herein, we provide data comparing sFLC with M protein as biomarkers of response in newly diagnosed patients with MM undergoing induction therapy with the novel agents thalidomide, lenalidomide and/or bortezomib. We show that although M protein appears to outperform sFLC comparatively over the course of induction therapy, the addition of FLC to M protein further informs the characterization of residual disease status post-induction. Moreover, sFLC at the time of stem cell mobilization appears to hold prognostic power for survival endpoints following high-dose chemotherapy/autologous stem cell transplant (HDC/SCT). These findings suggest potentially novel roles for sFLC in patients with MM with an intact M protein receiving novel agent-based induction strategies followed by HDC/SCT.

Ideal vial size for bortezomib: real-world data on waste and cost reduction in treatment of multiple myeloma in Brazil.

OBJECTIVES: Single-size vials of drugs may be a source of waste and increase in treatment costs. Bortezomib, indicated for multiple myeloma (MM) treatment, is available in 3.5-mg vials, a quantity higher than the average dose commonly prescribed. This analysis aimed to demonstrate, through real-world data, which would be the optimal vial presentation for bortezomib in Brazil and quantify the reduction in medication waste related to this option. METHODS: From November 2007 to October 2009 all patients with MM treated with bortezomib were identified via the Evidências database. Analysis of prescribed, dispensed, and wasted doses, their costs and projections of the ideal vial size were performed. RESULTS: Thirty-five patients (mean body surface area of 1.73 m(2)) received 509 infusions in 131 cycles of treatment (average of 3.77 cycles per patient). The average dose prescribed was 2.1 mg per infusion (95% confidence interval [CI] 1.97-2.26) with average waste of 39.5% of the vial content (95% CI 35.35-43.76). The mean waste per patient per day was 1.38 mg (95% CI 1.24-1.52). If a 3-mg vial were available, the average drug waste per patient per day would be 0.88 mg (95% CI 0.74-1.03) or 36.2% less. With a 2.5-mg vial the waste would be 1.05 mg (95% CI 0.81-1.29) or 23.9% less. If two presentations were available (2.5 mg and 0.5 mg), the waste would be 0.52 mg (95% CI 0.4-0.63) or 62.5% less. Considering the price of the different vials to be proportional to the original 3.5-mg vial, the cost would be also reduced by the same rates described above. CONCLUSIONS: A simple adjustment in vial size may reduce the waste of bortezomib by 36% to 62% and can also reduce the cost of treatment.

Management of relapsed or refractory multiple myeloma in French hospitals and estimation of associated direct costs: a multi-centre retrospective cohort study.

WHAT IS KNOWN AND BACKGROUND: For relapsed or refractory multiple myeloma (RRMM), a series of novel agents (thalidomide, bortezomib and lenalidomide) has emerged during the latest decade, but their use in routine clinical practice is not well documented as well as the cost of RRMM. OBJECTIVE: Our aim is to review the therapeutic management of such patients in France and to estimate the associated costs. METHODS: A retrospective cohort study, based on chart reviews, was conducted in French Haematology Departments over the period 2004-2007 and the associated direct costs estimated. RESULTS: One hundred and two patients with a relapse after first-line therapy were selected from five centres. The average follow-up from diagnosis or the date of first relapse to death or to the latest news was respectively 56.25 and 23.53 months. Novel agents were used in 73% of all cases, and in all cases of first relapse. Thalidomide and bortezomib were respectively the most frequently used second-line (57%) and third-line treatments (44%). The average number of lines of treatment received per patient as from first relapse was 2.75 (min 1; max 8) and the mean direct cost per month was estimated at 3130 € after the first relapse. This cost was represented in greater part by the cost of chemotherapy drugs (66%). WHAT IS NEW AND CONCLUSION: The use of novel agents such as thalidomide, bortezomib and lenalidomide for RRMM is highly prevalent in France from the first relapse. The associated medical cost is substantial mainly due to the cost of the new agents.

The cost-effectiveness of bortezomib in relapsed/refractory multiple myeloma: Swedish perspective.

OBJECTIVES: To estimate the cost-effectiveness of bortezomib (BTZ) compared with dexamethasone (DEX) and lenalidomide plus dexamethasone (LEN/DEX) for the treatment of relapsed/refractory multiple myeloma in Sweden. METHODS: We used partitioned survival analysis to assess survival data decomposed into three states: (i) alive before disease progression; (ii) alive after progression; and (iii) dead. The effects of treatment on time to progression and overall survival (OS) were obtained from published reports of the APEX, MM-009, and MM-010 randomized clinical trials. Costs included drug and administration costs, adverse events, treatment of relapses, and end-of-life costs. Utility estimates were derived from the literature. RESULTS: BTZ mean OS was 57.4 months compared with 44.6 and 54.1 months for DEX and LEN/DEX, respectively. Mean lifetime direct medical costs per patient were approximately 2010 SEK 1,904,462, 1,278,854, and 2,450,588 for BTZ, DEX, and LEN/DEX, respectively. Mean incremental cost per quality-adjusted life-year of BTZ compared to DEX was 2010 SEK 902,874 (€95,073) (95% CI: 514,791, 962,416) and was dominant with respect to LEN/DEX. CONCLUSION: BTZ and LEN/DEX are projected to prolong survival relative to DEX. From a Swedish perspective, BTZ is cost-effective compared to DEX and LEN/DEX.

Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma.

BACKGROUND: Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties. METHODS: This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75-100 mg/m2 cisplatin combined with 300-400 mcg talabostat bid for 6, 21-day cycles. The primary endpoint was overall response. The rate of complete responses, duration of overall objective response, progression-free survival (PFS), and overall survival were the secondary endpoints. RESULTS: Six objective partial responses were recorded in the 74 patients (8.1%) in the intention-to-treat population. Five of these responses involved the 40 evaluable patients (12.5%). Thirty-one percent of patients reported SAEs to the combination of talabostat and cisplatin. CONCLUSION: Acceptable tolerability was observed in the intention-to-treat population and antitumor activity was observed in 12.5% of evaluable patients, which is not greater than historical expectation with cisplatin alone.

Bortezomib: a novel chemotherapeutic agent for hematologic malignancies.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage and administration, place in therapy, and cost of bortezomib in the treatment of multiple myeloma and mantle cell lymphoma are reviewed. SUMMARY: Bortezomib is a modified dipeptidyl boronic acid that disrupts essential intracellular pathways by inhibiting proteasomes. The drug is metabolized by cytochrome P-450 isoenzymes 3A4, 2C19, and 1A2 to four inactive metabolites. Bortezomib was initially developed for the treatment of multiple myeloma based on the findings of early in vitro studies of patients with multiple myeloma who received at least one prior course of treatment; the drug received approval for the treatment of mantle cell lymphoma based on a single, noncomparative, Phase II study of previously treated patients. Significant toxicities have been reported with the use of bortezomib, including peripheral neuropathy, neutropenia, and thrombocytopenia. The dosage of bortezomib recommended by the manufacturer is 1.3 mg/m(2) per dose administered as an i.v. bolus injection twice weekly on days 1, 4, 8, and 11 of a three-week cycle. It is not necessary to adjust the dosage of bortezomib in patients with renal impairment. Bortezomib is being investigated as a treatment for several other malignant conditions. The current wholesale price of bortezomib is $1,322.40 for a single-use vial containing 3.5 mg of bortezomib lyophilized powder, with one course of treatment costing approximately $27,500 in drug cost alone. CONCLUSION: Bortezomib, an antineoplastic agent that reversibly inhibits the 26S proteasome, offers an important treatment option for patients with multiple myeloma or mantle cell lymphoma.