Kooperativer Bibliotheksverbund

In: Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, Wiley, Vol. 38, No. 2 ( 2018-02)

Abstract: Lacosamide is a new‐generation antiepileptic drug ( AED ) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy ( CRRT ) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT . We describe a single patient admitted to the study center with status epilepticus and multiorgan failure. The patient required both continuous venovenous hemofiltration ( CVVH ) and several AED s. He was receiving intravenous lacosamide 200 mg twice/day at steady state prior to sampling. Plasma lacosamide concentrations were derived using a validated high‐performance liquid chromatography method. Parameters were calculated using Phoenix WinNonlin 7.1 software. The peak concentration at steady state was 7.7 mg/L, the trough concentration was 5.9 mg/L (goal 5–12 mg/L). The volume of distribution was 0.7 L/kg, the elimination half‐life was 21 hours, and the sieving coefficient was 0.8 (± 0.06). Lacosamide was cleared by CVVH as demonstrated by the sieving coefficient, but plasma concentrations remained within goal range throughout the dosing interval. These results may suggest that lacosamide 200 mg twice/day is a useful dosing strategy for critically ill patients who require CVVH .

Type of Medium: Online Resource

ISSN: 0277-0008 , 1875-9114

URL: Issue

URL: Article

DOI: 10.1002/phar.2018.38.issue-2

DOI: 10.1002/phar.2063

Language: English

Publisher: Wiley

Publication Date: 2018

detail.hit.zdb_id: 2061167-5

SSG: 15,3

In: Acta Haematologica, S. Karger AG, Vol. 143, No. 6 ( 2020), p. 567-573

Abstract: Background: Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown. Methods: We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution. Results: Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2–8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission [CR], 6 CR with incomplete hematologic recovery [CRi] , 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and BCR-ABL1 PCR. Conclusions: Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.

Type of Medium: Online Resource

ISSN: 0001-5792 , 1421-9662

URL: Article

DOI: 10.1159/000506346

Language: English

Publisher: S. Karger AG

Publication Date: 2020

detail.hit.zdb_id: 1481888-7

detail.hit.zdb_id: 80008-9

In: Biologics: Targets and Therapy, Informa UK Limited, Vol. Volume 14 ( 2020-02), p. 23-34

Type of Medium: Online Resource

ISSN: 1177-5491

URL: Journal

URL: Article

DOI: 10.2147/BTT

DOI: 10.2147/BTT.S202746

Language: English

Publisher: Informa UK Limited

Publication Date: 2020

detail.hit.zdb_id: 2415708-9

In: Blood Advances, American Society of Hematology, Vol. 4, No. 22 ( 2020-11-24), p. 5681-5689

Abstract: TP53 mutations are associated with poor outcomes in acute myeloid leukemia (AML). The prognostic impact of mutant TP53 (TP53mut) variant allelic frequency (VAF) is not well established, nor is how this information might guide optimal frontline therapy. We retrospectively analyzed 202 patients with newly diagnosed TP53-mutated AML who underwent first-line therapy with either a cytarabine- or hypomethylating agent (HMA)–based regimen. By multivariate analysis, TP53mut VAF & gt;40% was independently associated with a significantly higher cumulative incidence of relapse (P = .003) and worse relapse-free survival (P = .001) and overall survival (OS; P = .003). The impact of TP53mut VAF on clinical outcomes was driven by patients treated with a cytarabine-based regimen (median OS, 4.7 vs 7.3 months for VAF & gt;40% vs ≤40%; P = .006), whereas VAF did not significantly affect OS in patients treated with HMA. The addition of venetoclax to HMA did not significantly affect OS compared with HMA without venetoclax, both in the entire TP53-mutated population and in patients stratified by TP53mut VAF. Among patients with TP53mut VAF ≤40%, OS was superior in those treated with higher-dose cytarabine, whereas OS was similarly poor for patients with TP53mut VAF & gt;40% regardless of therapy. The best long-term outcomes were observed in those with 1 TP53 mutation with VAF ≤40% who received a frontline cytarabine-based regimen (2-year OS, 38% vs 6% for all others; P & lt; .001). In summary, TP53mut VAF provides important prognostic information that may be considered when selecting frontline therapy for patients with newly diagnosed TP53-mutated AML.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2020003120

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 2876449-3

In: Journal of Oncology Pharmacy Practice, SAGE Publications, Vol. 24, No. 2 ( 2018-03), p. 110-115

Abstract: Tyrosine kinase inhibitors are increasingly used in the treatment of cancer. Drug interactions involving tyrosine kinase inhibitors are commonly encountered in clinical practice. The objective of this study was to describe the frequency of tyrosine kinase inhibitor-associated drug interactions among a cohort of oncology patients. Methods Adult patients were included who presented to either of two outpatient oncology practices and were prescribed a tyrosine kinase inhibitor during 2 January 2013 to 1 January 2015. Demographic and medication data were abstracted from electronic medical records. Lexicomp®, Micromedex Solutions®, and medication labeling were utilized to identify potential interactions between tyrosine kinase inhibitors and concomitant medications. Interactions were then assessed by the investigators for clinical significance. The primary outcome was the frequency of significant drug interactions involving tyrosine kinase inhibitors and concomitant medications. Secondary outcomes included describing the nature and clinical impact of interactions, and describing interactions by medication class. Results A total of 356 patients were identified for analysis, in whom 244 potential interactions were identified, and 109 (44.7%) of which were considered severe. Decreased tyrosine kinase inhibitor absorption due to acid suppressive therapy and CYP3A4 interactions were the most frequent mechanisms of potential subtherapeutic and supratherapeutic concentrations, respectively. Potential clinical consequences included QTc prolongation ( n = 53, 48.6%), decreased tyrosine kinase inhibitor concentration ( n = 53, 48.6%), and increased tyrosine kinase inhibitor concentration ( n = 3, 2.8%). Conclusions Safer alternative therapy and/or more frequent clinical monitoring should be considered if an interaction poses a significant risk of increased tyrosine kinase inhibitor toxicity or decreased tyrosine kinase inhibitor efficacy. Oncology pharmacists can play a role in screening for tyrosine kinase inhibitor-associated interactions, recommending alternative therapies or dosing strategies, and monitoring tyrosine kinase inhibitor efficacy and toxicity.

Type of Medium: Online Resource

ISSN: 1078-1552 , 1477-092X

URL: Article

DOI: 10.1177/1078155216682311

Language: English

Publisher: SAGE Publications

Publication Date: 2018

detail.hit.zdb_id: 2026590-6

SSG: 15,3

In: Journal of General Internal Medicine, Springer Science and Business Media LLC, Vol. 36, No. 5 ( 2021-05), p. 1390-1394

Type of Medium: Online Resource

ISSN: 0884-8734 , 1525-1497

URL: Article

DOI: 10.1007/s11606-020-06218-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2006784-7

In: JACC: CardioOncology, Elsevier BV, ( 2023-10)

Type of Medium: Online Resource

ISSN: 2666-0873

URL: Article

DOI: 10.1016/j.jaccao.2023.07.006

Language: English

Publisher: Elsevier BV

Publication Date: 2023

detail.hit.zdb_id: 3040527-0

In: Annals of Pharmacotherapy, SAGE Publications, Vol. 52, No. 6 ( 2018-06), p. 527-532

Abstract: Background: The pharmacokinetics and pharmacodynamics of desmopressin are appropriate for adjusted body weight–based dosing, particularly in obese patients. Objective: The objective of this study was to describe desmopressin dosing strategies, with emphasis on hemostatic outcomes among patients without preexisting bleeding disorders. Methods: This was a single-center, retrospective cohort study of patients who received intravenous weight-based desmopressin for a hemostatic indication. Demographics, comorbidities, treatment setting, indication, site of bleeding, and outcomes were collected from the medical record. Primary outcomes included need for procedural intervention to achieve hemostasis, transfusion requirement, and death. Association between desmopressin dose and outcome was evaluated using χ 2 or Fischer’s exact tests and logistic and linear regression models. Multiple regression analysis was conducted to identify other predictors of outcome in the data set. Results: A total of 109 patients were included (n = 26, dose adjustment; n = 83, no dose adjustment). Baseline characteristics were well-matched between groups: mean (SD) age of 57.0 (13.5) years; mean (SD) Charlson Comorbidity Score of 6.5 (2.8); 37% were obese; 76% were critically ill; 81% were actively bleeding without differences in site of bleeding; and crude mortality was 39%. No differences in death, mean units of packed red blood cells transfused, or need for procedural hemostasis were observed between adjusted weight– and actual weight–based desmopressin dosing. Conclusions: When used adjunctively to blood product transfusion in actively bleeding patients, use of adjusted body weight–based desmopressin did not negatively affect clinical outcomes. More data are needed to confirm this dosing strategy.

Type of Medium: Online Resource

ISSN: 1060-0280 , 1542-6270

URL: Article

DOI: 10.1177/1060028017752354

Language: English

Publisher: SAGE Publications

Publication Date: 2018

detail.hit.zdb_id: 2053518-1

SSG: 15,3

In: Journal of Critical Care, Elsevier BV, Vol. 38 ( 2017-04), p. 73-77

Type of Medium: Online Resource

ISSN: 0883-9441

URL: Article

DOI: 10.1016/j.jcrc.2016.10.015

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 2041640-4

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 33-34

Abstract: Background: TP53 mutations are associated with poor outcomes in acute myeloid leukemia (AML). The prognostic impact of mutant TP53 variant allelic frequency (TP53mut VAF) in AML is not well-established, nor is how this information might guide optimal frontline therapy. Methods: We performed a retrospective study of 202 patients (pts) with TP53-mutated AML receiving frontline therapy and evaluated the impact of TP53mut VAF on cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS) and its interaction with type of therapy received. In cases of multiple TP53 mutations , the highest TP53mut VAF was used for analysis. Treatments were divided into 4 categories: 1.) intermediate or high-dose cytarabine (IDAC/HDAC)-based, 2.) low-dose cytarabine (LDAC)-based, 3.) HMA-based (excluding venetoclax), and 4.) HMA plus venetoclax. Groups 1 and 2 ("cytarabine" group) and groups 3 and 4 ("HMA" group) were combined for some analyses. Response was defined as achievement of CR or CRi. Results: Baseline characteristics of the study population are shown in Table 1. The median TP53mut VAF was 43% (range, 1%-100%), and 48 pts (24%) had & gt;1 TP53 mutation. The impact of TP53mut VAF on response rates was treatment-dependent. In the HMA group, no baseline variables were associated with response. In contrast, by multivariate analysis, independent predictors for response in the cytarabine-treated group included older age (odds ratio [OR] 0.87; P=0.001), & gt;1 TP53 mutation (OR 0.07; P=0.02) and TP53mut VAF & gt;40% (OR 0.09; P & lt;0.001). Among pts with TP53mut VAF & gt;40%, response rates were higher in those who received HMA-based therapy compared to those who received cytarabine-based therapy (54% and 28%, respectively; P=0.008), whereas response rates were not significantly different among pts with VAF ≤40% (44% and 61%, respectively; P=0.12). In the whole cohort stratified by TP53mut VAF & gt;40% vs. ≤40%, the 1-year CIR rates were 85% and 48%, the 1-year RFS rates were 10% and 44%, and the 1-year OS rates were 19% and 35%, respectively. By multivariate analysis, TP53mut VAF & gt;40% vs. ≤40% remained a significant predictor for higher CIR (hazard ratio [HR] 2.25, P=0.003) and worse RFS (HR 2.21, P=0.001) and OS (HR 1.61, P=0.003). The worse outcomes for pts with TP53mut VAF & gt;40% were driven primarily by those who received cytarabine-based therapy. Among pts treated with a cytarabine-based regimen, those with a TP53mut VAF & gt;40% had significantly worse outcomes than those with VAF ≤40% (median OS: 4.8 vs. 7.3 months, respectively; P=0.006), whereas there was no significant difference in outcomes according to VAF among HMA-treated pts (median OS: 5.7 months vs. 7.0 months, respectively; P=0.22) (Figure 1). Pts with VAF ≤40% who received IDAC/HDAC had a median OS of 18.1 months and 2-year OS of 41%; in contrast, those with VAF & gt;40% who received IDAC/HDAC had a median OS of only 5.0 months and 2-year OS of 14% (P=0.02). Among those with TP53mut VAF ≤40%, pts treated with a cytarabine-based regimen had superior OS compared to those who received an HMA-based regimen (1-year OS rates of 44% and 31%, respectively; P=0.04), with the best outcomes in those pts who received IDAC/HDAC-based therapy. Among those with TP53mut VAF & gt;40%, outcomes were similar among the treatment groups, and survival was universally poor with 1-year OS & lt;25% in all groups. Overall, 20 pts with TP53-mutated AML underwent hematopoietic stem cell transplantation (HSCT) in first remission, with a median time to HSCT of 3.6 months. Using a landmark analysis at 3.6 months, HSCT in first remission was associated with a significant improvement in OS (median OS 17.6 months and 2-year OS 50% vs. median OS 9.1 months and 2-year OS 12%, respectively; P=0.006). By multivariate analysis including HSCT as a time-dependent variable, HSCT in first remission was independently associated with improved CIR, RFS, and OS (P & lt;0.001 for all). Transplanted pts with TP53mut VAF ≤40% had a trend towards better OS compared to transplanted pts with VAF & gt;40% (P=0.07). Conclusions: TP53mut VAF is highly prognostic for response, relapse and survival in pts with TP53-mutated AML, particularly for those treated with conventional cytotoxic chemotherapy. Given the treatment-dependent impact of TP53mut VAF on clinical outcomes, VAF should be assessed when considering frontline therapy options. Further development of effective novel therapies is needed for this poor risk subgroup of pts. Disclosures Short: Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Astellas: Research Funding; Amgen: Honoraria. Dinardo:Takeda: Honoraria; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria; Celgene: Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding. Konopleva:Eli Lilly: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Kisoji: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Agios: Research Funding; Cellectis: Research Funding; Forty-Seven: Consultancy, Research Funding; Amgen: Consultancy; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Calithera: Research Funding; Ablynx: Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Andreeff:Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Kadia:Cellenkos: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; Celgene: Research Funding; Novartis: Honoraria; Amgen: Research Funding; Astra Zeneca: Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134312

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7