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Ghose A.K.,Teva Branded Pharmaceutical Products R and D Inc. | Ott G.R.,Teva Branded Pharmaceutical Products R and D Inc. | Hudkins R.L.,Teva Branded Pharmaceutical Products R and D Inc.
ACS Chemical Neuroscience | Year: 2017

At the discovery stage, it is important to understand the drug design concepts for a CNS drug compared to those for a non-CNS drug. Previously, we published on ideal CNS drug property space and defined in detail the physicochemical property distribution of CNS versus non-CNS oral drugs, the application of radar charting (a graphical representation of multiple physicochemical properties used during CNS lead optimization), and a recursive partition classification tree to differentiate between CNS- and non-CNS drugs. The objective of the present study was to further understand the differentiation of physicochemical properties between CNS and non-CNS oral drugs by the development and application of a new CNS scoring scheme: Technically Extended MultiParameter Optimization (TEMPO). In this multiparameter method, we identified eight key physicochemical properties critical for accurately assessing CNS druggability: (1) number of basic amines, (2) carbon-heteroatom (non-carbon, non-hydrogen) ratio, (3) number of aromatic rings, (4) number of chains, (5) number of rotatable bonds, (6) number of H-acceptors, (7) computed octanol/water partition coefficient (AlogP), and (8) number of nonconjugated C atoms in nonaromatic rings. Significant features of the CNS-TEMPO penalty score are the extension of the multiparameter approach to generate an accurate weight factor for each physicochemical property, the use of limits on both sides of the computed property space range during the penalty calculation, and the classification of CNS and non-CNS drug scores. CNS-TEMPO significantly outperformed CNS-MPO and the Schrödinger QikProp CNS parameter (QP_CNS) in evaluating CNS drugs and has been extensively applied in support of CNS lead optimization programs. © 2016 American Chemical Society.

Meltzer E.O.,Allergy and Asthma Medical Group and Research Center | Jacobs R.L.,Biogenics Research Institute | LaForce C.F.,North Carolina Clinical Research | Kelley C.L.,Teva Branded Pharmaceutical Products R and D Inc. | And 2 more authors.
Allergy and Asthma Proceedings | Year: 2012

Intranasal corticosteroids are recommended as first-line therapy for the treatment of the symptoms of persistent allergic rhinitis (AR). Since the phase-out of chlorofluorocarbon nasal aerosols, intranasal corticosteroids have been available only as aqueous nasal sprays. This study was designed to assess the efficacy, safety, and quality-of-life benefits of beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol in subjects with perennial AR (PAR). After a 7- to 21-day placebo run-in period, eligible subjects aged ≥12 years with PAR were randomized to 6 weeks of once-daily treatment with BDP nasal aerosol at 320 μg or placebo. Reflective and instantaneous total nasal symptom scores (rTNSS and iTNSS, respectively), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, and physician-assessed total nasal symptom score were evaluated. The primary end point was change from baseline in average morning (A.M.) and evening (P.M.) subject-reported rTNSS over the 6-week treatment period. Safety and tolerability were also assessed. Treatment with BDP nasal aerosol showed significantly greater improvement in average A.M. and P.M. rTNSS compared with placebo (mean treatment difference,-0.84; 95% confidence interval, -1.2, -0.5; p < 0.001). Greater improvements in rTNSS were reported as early as day 1 and were maintained throughout the 6-week treatment period with the exception of day 2. Greater improvements were seen for all four individual nasal symptoms (nasal congestion, nasal itching, rhinorrhea, and sneezing) with BDP nasal aerosol compared with placebo. Similarly, significant improvements were seen in average A.M. and P.M. iTNSS (p < 0.001) and RQLQ score (p = 0.001) with BDP nasal aerosol compared with placebo. In addition, BDP nasal aerosol treatment was well tolerated, and its safety profile was comparable to that of placebo. This clinical study indicated that treatment with BDP nasal aerosol provides statistically significant and clinically meaningful nasal symptom relief accompanied by improved quality of life in subjects with PAR. Additionally, treatment with BDP nasal aerosol was well tolerated with a safety profile comparable to that of placebo. Copyright © 2012, OceanSide Publications, Inc.

Gross G.N.,Dallas Allergy and Asthma Center | Ford L.B.,Asthma and Allergy Center | Kelley L.,Teva Branded Pharmaceutical Products R and D Inc. | Tantry S.K.,Teva Branded Pharmaceutical Products R and D Inc.
Allergy and Asthma Proceedings | Year: 2013

Some patients with allergic rhinitis (AR) may prefer a "dry" intranasal corticosteroid aerosol to avoid certain sensory perceptions such as the "wet feeling in the nose" and the "dripping down the throat" associated with aqueous nasal sprays. A nonaqueous hydrofluoroalkane-propelled beclomethasone dipropionate (BDP) nasal aerosol with an established efficacy and safety profile was approved to treat the nasal symptoms associated with AR in adult and adolescent patients. This study was designed to evaluate ease of use and patient satisfaction with the BDP nasal aerosol device in patients with perennial AR (PAR). In this phase 3, randomized, double-blind, parallel-group, placebo-controlled study, eligible patients (≥12 years of age) with PAR were randomly assigned to receive BDP nasal aerosol at 320 micrograms/day or placebo for 6 weeks. At the end of the treatment period, patients assessed device ease of use and satisfaction with the device using a questionnaire with a 5-point representative scale (not at all, not very, neither nor, somewhat, very [certain/easy/satisfactory]). Nearly all patients (89.7%) reported that the BDP nasal aerosol device with integrated dose counter was "very easy" or "somewhat easy" to use. The majority of patients (87.5%) also indicated that it was "very easy" or "somewhat easy" to tell when the device was empty, compared with only 42.3% who were "very certain" or "somewhat certain" of being able to tell when previously used aqueous nasal spray devices were empty. Overall, patient satisfaction with the BDP nasal aerosol device was high: 65.7% responded that they were "very satisfied" or "somewhat satisfied" and only 3.6% were "not satisfied at all" or "not very satisfied." These results indicate that the majority of patients considered the BDP nasal aerosol device easy to use and reported a high degree of satisfaction with the device compared with other nasal sprays they had used in the past. Copyright © 2013, OceanSide Publications, Inc.

Ratner P.H.,Sylvana Research Associates | Melchior A.,Teva Branded Pharmaceutical Products R and D Inc. | Dunbar S.A.,Teva Branded Pharmaceutical Products R and D Inc. | Tantry S.K.,Teva Branded Pharmaceutical Products R and D Inc. | Dorinsky P.M.,Teva Branded Pharmaceutical Products R and D Inc.
Clinical Therapeutics | Year: 2012

Background: Beclomethasone dipropionate (BDP) is an anti-inflammatory corticosteroid that is rapidly metabolized to the pharmacologically active monoester, beclomethasone-17-monopropionate (17-BMP). Recently, a hydrofluoroalkane (HFA)-propelled nasal aerosol formulation of BDP was developed to treat allergic rhinitis. However, the pharmacokinetic profile of BDP HFA nasal aerosol has not been previously investigated. Objective: This study evaluated and compared the systemic levels of 17-BMP and BDP after a single dose of intranasally administered or orally inhaled BDP HFA in healthy subjects. Methods: In this single-center, randomized, open-label, 3-period crossover study, healthy subjects received single doses of intranasal BDP HFA (80 and 320 μg) and orally inhaled BDP HFA (320 μg). The primary pharmacokinetic parameters assessed were area under the concentration-time curve until the last measurable value (AUC last) and C max for 17-BMP. For AUC last and C max, point estimates for treatment differences and CIs were calculated on the log scale and then exponentiated to provide estimates of the geometric mean ratios (GMRs) and associated CIs. Results: Thirty subjects were randomized to receive study medication (aged 18-45 years, 66.7% male). Mean plasma concentrations of 17-BMP after intranasal administration of BDP HFA (for both 80- and 320-μg doses) were substantially lower than that of orally inhaled BDP HFA (320 μg) across all time points. Mean AUC last values of 17-BMP for intranasal 80 μg, intranasal 320 μg, and orally inhaled 320 μg were 295.8, 1139.7, and 4140.3, respectively. Mean C max values were 92.1, 262.7, and 1343.7 pg/mL, respectively. The GMR of AUC last for 17-BMP with intranasal BDP HFA 320 μg versus orally inhaled BDP HFA 320 μg was 0.275, indicating substantially lower systemic bioavailability with intranasal administration than with oral inhalation. Similarly, the GMR of AUC last for 17-BMP with intranasal BDP HFA 80 μg versus 320 μg was 0.260, suggesting approximate dose proportionality (4-fold difference). Pharmacokinetic results for BDP were similar to those seen for 17-BMP. All doses of intranasal and orally inhaled BDP HFA were well tolerated, and no treatment-related adverse events were reported. Conclusions: The results of this study suggest that 80 and 320 μg BDP HFA nasal aerosols have substantially lower systemic bioavailability than 320 μg orally inhaled BDP HFA in healthy subjects. All treatments were well tolerated. identifier: NCT01537692. © 2012 Elsevier HS Journals, Inc.

Hexner E.,University of Pennsylvania | Roboz G.,New York Medical College | Hoffman R.,Mount Sinai School of Medicine | Luger S.,University of Pennsylvania | And 5 more authors.
British Journal of Haematology | Year: 2014

Summary: JAK2-V617F is central to the pathogenesis of myeloproliferative neoplasms. We examined whether lestaurtinib decreased JAK2-V617F allele burden and evaluated its clinical benefits and tolerability in patients with polycythaemia vera (PV) and essential thrombocythaemia (ET). This phase 2, open-label, multicentre study was designed to detect ≥15% reduction in JAK2-V617F allele burden in 15% of patients. Eligible patients received lestaurtinib 80 mg twice daily for 18 weeks and could participate in a 1-year extension phase of treatment. Of 39 enrolled patients, 27 (69%) had PV; 12 (31%) had ET. While the pre-specified responder rate of 15% was not met, lestaurtinib modestly reduced JAK2-V617F allele burden and reduced spleen size in a subset of patients. Of 37 patients in the full efficacy analysis, 5 (14%) responded clinically. Every patient had ≥1 adverse event, most commonly gastrointestinal (95%). Fifteen patients (38%) experienced serious adverse events; 23 (59%) withdrew due to adverse events. This is the first reported study of JAK2-inhibitor treatment in patients with PV/ET and highlights both the need for further studies to assess the role of JAK2 inhibition in treatment of PV/ET and the use of JAK2-V617F as a biomarker for response. This trial was registered at as NCT00586651. © 2013 John Wiley & Sons Ltd.

Flinn I.W.,Sarah Cannon Research Institute Tennessee Oncology | Van Der Jagt R.,University of Ottawa | Kahl B.S.,University of Wisconsin - Madison | Wood P.,Princess Alexandra Hospital | And 14 more authors.
Blood | Year: 2014

This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety ofbendamustineplusrituximab(BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatmentnaive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n 5 224) or standard therapy (R-CHOP/R-CVP, n 5 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P 5 .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P 5 .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. © 2014 by The American Society of Hematology.

Iyer R.R.,Teva Branded Pharmaceutical Products R and D Inc. | Pluciennik A.,Thomas Jefferson University | Napierala M.,University of Alabama at Birmingham | Napierala M.,Polish Academy of Sciences | Wells R.D.,Texas A&M University
Annual Review of Biochemistry | Year: 2015

DNA mismatch repair is a conserved antimutagenic pathway that maintains genomic stability through rectification of DNA replication errors and attenuation of chromosomal rearrangements. Paradoxically, mutagenic action of mismatch repair has been implicated as a cause of triplet repeat expansions that cause neurological diseases such as Huntington disease and myotonic dystrophy. This mutagenic process requires the mismatch recognition factor MutSβ and the MutLα (and/or possibly MutLγ) endonuclease, and is thought to be triggered by the transient formation of unusual DNA structures within the expanded triplet repeat element. This review summarizes the current knowledge of DNA mismatch repair involvement in triplet repeat expansion, which encompasses in vitro biochemical findings, cellular studies, and various in vivo transgenic animal model experiments. We present current mechanistic hypotheses regarding mismatch repair protein function in mediating triplet repeat expansions and discuss potential therapeutic approaches targeting the mismatch repair pathway. Copyright © 2015 by Annual Reviews. All rights reserved.

Given J.,Allergy and Respiratory Center | Taveras H.,Teva Branded Pharmaceutical Products RandD Inc. | Iverson H.,Teva Branded Pharmaceutical Products RandD Inc. | Lepore M.,Teva Branded Pharmaceutical Products RandD Inc.
Allergy and Asthma Proceedings | Year: 2013

Metered-dose inhalers (MDIs) allow patients who require therapy for various respiratory diseases to deliver these therapies directly to the airways via inhalation. MDIs are designed to contain more propellant than required for administration of the labeled number of actuations; therefore, the amount of active medication/actuation remaining after administration of the labeled number of actuations may result in a lower than therapeutic dose of active medication. An MDI with an integrated dose counter provides the only reliable means by which a patient can track the amount of medication remaining in the MDI. This study evaluated the functionality, reliability, accuracy, and patient satisfaction with albuterol sulfate hydrofluoroalkane (HFA) MDI with a new integrated dose counter in the clinical setting. Patients aged 4 years with asthma, chronic obstructive pulmonary disease, or both, participated in this phase 4, prospective, open-label study. Treatment was twice-daily dosing with albuterol HFA MDI at 90 micrograms with dose counter for either 5 or 7 weeks. Concordance/agreement between daily patient recordings of actuations and counter readings was assessed with five discrepancy types: fire not count (undercount; primary end point), count not fire (overcount), fire count up within a dose (counter reading increased, instead of decreased, after MDI was actuated), count unknown fire (counter number at the beginning of a dosing session was less than counter number at the end of the previous session), and count up unknown fire (counter number at the beginning of a dosing session was greater than counter number at the end of the previous session). Responses to twelve questions designed to evaluate confidence, ease of use, and patient satisfaction were also analyzed. Overall discrepancy rate was 1.87 per 200 actuations. Primary end point (fire not count rate) was 0.30 per 200 actuations. Overall, 95-97% of patients were 'very satisfied' or 'somewhat satisfied' with the albuterol HFA MDI with dose counter, its ease of use, and the ability to tell when it should be replaced. The albuterol HFA MDI with new integrated dose counter functioned reliably and accurately in the clinical setting. Overall patient satisfaction was high with the albuterol HFA MDI with new integrated dose counter and the device was shown to function reliably and accurately. identifier: NCT01302587. Copyright © 2013, OceanSide Publications, Inc., U.S.A.

Darwish M.,Science Med Bridge LLC | Bond M.,Teva Branded Pharmaceutical Products R and D Inc. | Hellriegel E.,Teva Branded Pharmaceutical Products R and D Inc. | Robertson P.,Teva Branded Pharmaceutical Products R and D Inc. | Chovan J.P.,Teva Branded Pharmaceutical Products R and D Inc.
Cancer Chemotherapy and Pharmacology | Year: 2015

Purpose: Bendamustine is a unique alkylating agent indicated for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B cell non-Hodgkin's lymphoma. Despite the extensive experience with bendamustine, its pharmacokinetic profile has only recently been described. This overview summarizes the pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and drug-drug interactions of bendamustine in adult and pediatric patients with hematologic malignancies. Methods: A literature search and data on file (including a human mass balance study, pharmacokinetic population analyses in adult and pediatric patients, and modeling analyses) were evaluated for inclusion. Results: Bendamustine concentrations peak at end of intravenous infusion (∼1 h). Subsequent elimination is triphasic, with the intermediate t 1/2 (∼40 min) as the effective t 1/2 since the final phase represents <1 % of the area under the curve. Bendamustine is rapidly hydrolyzed to monohydroxy-bendamustine and dihydroxy-bendamustine, which have little or no activity. Cytochrome P450 (CYP) 1A2 oxidation yields the active metabolites γ-hydroxybendamustine and N-desmethyl-bendamustine, at low concentrations, which contribute minimally to cytotoxicity. Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug-drug interactions with CYP1A2 inhibitors. Systemic exposure to bendamustine 120 mg/m2 is comparable between adult and pediatric patients; age, race, and sex have been shown to have no significant effect on systemic exposure in either population. The effect of hepatic/renal impairment on bendamustine pharmacokinetics remains to be elucidated. Higher bendamustine concentrations may be associated with increased probability of nausea or infection. No clear exposure-efficacy response relationship has been observed. Conclusions: Altogether, the findings support dosing based on body surface area for most patient populations. © 2015 The Author(s).

McCabe J.C.,Teva Branded Pharmaceutical Products RandD Inc. | Koppenhagen F.,Teva Branded Pharmaceutical Products RandD Inc. | Blair J.,Teva Pharmaceutical Industries | Zeng X.-M.,Teva Branded Pharmaceutical Products RandD Inc.
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2012

Background: Inhaler technique and spray characteristics are critical for adequate management of asthma symptoms with pressurized metered-dose inhalers (pMDIs). A lower spray force has been directly associated with a decrease in throat deposition of asthma medication, and a higher spray temperature may alleviate the "cold Freon effect" associated with pMDIs. The objective of the study was to characterize and compare the temperature, maximum spray force, and duration of the emitted plume from two pMDIs: ProAir ® hydrofluoroalkane (HFA) and Ventolin® HFA. Methods: A spray force tester model SFT1000 and thermocouple were used to test 10 units from three separate lots (total of 30 units) of each inhaler type. Three consecutive actuations were tested at a spray distance of 40mm from the edge of the mouthpiece. Room temperature, humidity, and initial weight of the pMDI were recorded. Final weight of each pMDI was recorded to determine the spray weight of individual actuations. pMDIs were primed and operated according to instructions provided in the package insert. Aerodynamic particle size distribution (APSD) was also assessed using a next-generation impactor at a flow rate of 28.3 L/min. Results: Measurements were obtained from three consecutive actuations for each of 30 units of ProAir® HFA and Ventolin® HFA (10 units from three separate lots), resulting in a total of 90 actuations tested for each pMDI. Minimum plume temperatures recorded were 7.2±0.7°C and -35.9±12.7°C, respectively, for ProAir® HFA and Ventolin® HFA. ProAir® HFA produced more than a twofold greater plume duration (385±46 ms vs. 156±58 ms; p<0.001) and a significantly lower mean maximum spray force (33.6±11.4 mN vs. 75.9±12.0 mN; p<0.0001) compared with Ventolin ® HFA. APSD analysis demonstrated that ProAir® HFA produced almost twice as much fine particle (<5μm) dose with lower geometric standard deviation, compared with Ventolin® HFA. Two inhalers produced similar mass median aerodynamic diameters, ranging from 2.3 to 2.4μm. Conclusions: The ProAir® HFA delivers a warmer, lower-impact, and longer-lasting plume compared with Ventolin® HFA, which may provide a more consistent, comfortable experience for patients using a pMDI. ProAir® HFA produces higher fine particle dose than Ventolin® HFA. © 2012 Mary Ann Liebert, Inc.

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