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Carlos Besses - One of the best experts on this subject based on the ideXlab platform.
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treatment of essential thrombocythemia in europe a prospective long term observational study of 3649 high risk patients in the evaluation of Anagrelide efficacy and long term safety study
Haematologica, 2018Co-Authors: Gunnar Birgegård, Carlos Besses, Martin Griesshammer, Luigi Gugliotta, Claire N Harrison, Mohamed Hamdani, Jingyang Wu, Heinrich Achenbach, Jeanjacques KiladjianAbstract:Evaluation of Anagrelide (Xagrid®) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia patients treated with cytoreductive therapy. The primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: Anagrelide (Xagrid®) (n=804), other cytoreductive therapy (n=2666), or Anagrelide + other cytoreductive therapy (n=141). The median age was 56 vs. 70 years for Anagrelide vs. other cytoreductive therapy. Event rates (patients with events/100 patient-years) were 1.62 vs. 2.06 for total thrombosis and 0.15 vs. 0.53 for venous thrombosis. Anagrelide was more commonly associated with hemorrhage (0.89 vs. 0.43), especially with anti-aggregatory therapy (1.35 vs. 0.33) and myelofibrosis (1.04 vs. 0.30). Other cytoreductive therapies were more associated with acute leukemia (0.28 vs. 0.07) and other malignancies (1.29 vs. 0.44). Post hoc multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age ≥65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age ≥65, time since diagnosis, and platelet count increase. Safety analysis reflected published data, and no new safety concerns for Anagrelide were found. Live births occurred in 41/54 pregnancies (76%). clinicaltrials.gov Identifier: 00567502.
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combination therapy of hydroxycarbamide with Anagrelide in patients with essential thrombocythemia in the evaluation of xagrid r efficacy and long term safety study
Haematologica, 2014Co-Authors: Luigi Gugliotta, Jonathan Smith, Jeanjacques Kiladjian, Carlos Besses, Ruth Coll, Brihad Abhyankar, Martin Griesshammer, Claire N Harrison, Gunnar BirgegårdAbstract:Available information is limited regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid® Efficacy and Long-term Safety study. Of 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + Anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167, 54.9%) and Anagrelide (n=123, 40.5%). Median weekly doses of hydroxycarbamide and Anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581×109/L and 411×109/L before and after starting hydroxycarbamide + Anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts less than 400×109/L increased from 33 (21.6%) to 74 (48.4%; P <0.0001), and with platelet counts less than 600×109/L, from 82 (53.6%) to 132 (86.3%; P <0.0001). Hydroxycarbamide + Anagrelide was discontinued in 158 patients: 76 (48.1%) stopped hydroxycarbamide, 59 (37.3%) stopped Anagrelide, 19 (12.0%) stopped both and 4 (2.5%) had another therapy added. The most frequent reasons for discontinuation were intolerance/side-effects, lack of efficacy, and therapeutic strategy. Combination therapy, usually hydroxycarbamide + Anagrelide, is used in approximately 10% of all high-risk patients with essential thrombocythemia and may be a useful approach in treating patients for whom monotherapy is unsatisfactory. ( [Clinicaltrials.gov][1] identifier:[NCT00567502][2] ) [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00567502&atom=%2Fhaematol%2F99%2F4%2F679.atom
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comparison of pharmacokinetic parameters of Anagrelide in healthy japanese and caucasian volunteers
Blood, 2012Co-Authors: Shinichiro Okamoto, Jonathan Smith, Yuzuru Kanakura, Ian Hodgson, Steven Troy, Brihad Abhyankar, Carlos BessesAbstract:Abstract 5066 Aim: Currently, it is not fully elucidated how ethnicity influences the pharmacokinetic (PK) profile of Anagrelide. The aim of this retrospective analysis was to compare the PK profile of Anagrelide in healthy Japanese and Caucasian volunteers. Methods: Retrospective analyses were conducted on two phase I studies with Anagrelide: a study of healthy Japanese volunteers (study A) and healthy Caucasian volunteers (study B). In study A, healthy males received Anagrelide (0. 5, 1. 0 or 2. 0 mg) or placebo under fasted or fed conditions. In study B, healthy volunteers received a single 1. 0 mg dose under fasted conditions. PK analysis of Anagrelide was conducted as part of these original studies. The calculated PK parameters were maximum plasma concentration (Cmax), time for Cmax (tmax), area under plasma concentration from time zero to time infinity (AUC0-inf) and terminal-phase disposition half-life (t1/2). Results: PK data for healthy Japanese males (n=6) aged 20–35 years, with a body weight of 50–80 kg and receiving 1. 0 mg Anagrelide in study A were compared with PK data for healthy Caucasian volunteers (n=10, 8 male and 2 female) aged 40–69 years, with a body weight of 56–100 kg and receiving 1. 0 mg Anagrelide in study B. Single-dose PK parameters under fasted conditions across both studies are shown in the Table for Anagrelide and its metabolite 2-amino-5, 6-dichloro-3, 4-dihydroquinazilone (RL603). Compared with Caucasian volunteers, healthy Japanese volunteers exhibited similar Cmax, and slightly higher AUC0-inf for Anagrelide. In contrast, Cmax and AUC0-inf for the inactive metabolite RL603 were considerably higher in Japanese volunteers. Five adverse events (AEs) were reported in 3 volunteers in study A and 9 AEs in 3 volunteers in study B: 5 and 3 AEs, respectively, were considered possibly related to treatment. The most commonly reported AEs were headache and nausea. No serious AEs were observed during either study. Discussion: The PK analyses conducted on volunteers receiving a single 1 mg dose showed that under fasted conditions Anagrelide was rapidly absorbed with similar Cmax and tmax between Japanese and Caucasian volunteers. The slightly higher AUC0-inf of Anagrelide in Japanese volunteers may be an artefact of the high inter-subject variability, which is common with drugs such as Anagrelide that exhibit extensive pre-systemic metabolism. It remains unclear as to why Japanese volunteers had higher RL603 Cmax and AUC0-inf values than Caucasian individuals. Analyses of PK data from studies of patients with essential thrombocythaemia (ET) (Okamoto et al, manuscript in preparation; Besses et al, Int J Clin Pharmacol Ther, 2012, manuscript in press) noted that compared with non-Japanese patients, Japanese patients also had slightly higher Cmax (2. 81±0. 99 vs 5. 88±4. 58 ng/mL) and AUC (6. 8±2. 4 vs 16. 3±6. 5 ng·h/mL) for Anagrelide. Overall, across both ethnic groups, patients with ET had higher Anagrelide exposures than healthy volunteers. However, within the Japanese population, Cmax and AUC0-inf values were only slightly higher in patients with ET than in volunteers, which may suggest that the PK exposures of Anagrelide did not differ substantially between these Japanese cohorts. Conclusion: Anagrelide exhibits high inter- and intra-subject variability, which makes it difficult to compare PK exposures in studies with small populations. The PK data across all these studies indicate that the first-pass metabolism of Anagrelide may be marginally lower in the Japanese population than in Caucasian individuals; however these differences do not translate to different clinical outcomes with respect to the observed treatment-related AEs associated with Anagrelide therapy. Despite the small differences observed in metabolism of Anagrelide, it is well tolerated in Japanese populations and ethnicity-specific dosing regimens are not required. Disclosures: Kanakura:Shire: Consultancy. Hodgson:Shire Pharmaceutical Development Ltd: Employment. Troy:Shire Development, LLC: Employment. Abhyankar:Shire Pharmaceuticals: Employment. Smith:Shire Pharmaceuticals: Employment. Besses:Shire: Honoraria; Novartis: Honoraria.
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pharmacokinetics and tolerability of Anagrelide hydrochloride in young 18 50 years and elderly 65 years patients with essential thrombocythemia
Principles and Practice of Constraint Programming, 2012Co-Authors: Carlos Besses, Wolfgang Zeller, Alberto Alvarezlarran, Ruth Coll, Steven M Troy, Jaideep Purkayastha, Patrick T Martin, Christian FreitagAbstract:Objective To ascertain the role of patient age as an influencing factor in the pharmacokinetics of Anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (≥ 65 years) patients with essential thrombocythemia (ET). Method This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of Anagrelide and its active metabolite, 3-hydroxy-Anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily Anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy-Anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. Results A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized Anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCτ), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCτ: 10.3 vs. 6.4 ng×h/ml; p = 0.01). In contrast, the dose-normalized 3-hydroxy-Anagrelide Cmax and AUCτ were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCτ: 17.4 vs. 27.6 ng×h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of Anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-Anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. Conclusions To conclude, the differences observed in Anagrelide and 3-hydroxy-Anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET.
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Pharmacokinetics and tolerability of Anagrelide hydrochloride in young (18 - 50 years) and elderly (≥ 65 years) patients with essential thrombocythemia.
International journal of clinical pharmacology and therapeutics, 2012Co-Authors: Carlos Besses, Wolfgang Zeller, Ruth Coll, Steven M Troy, Jaideep Purkayastha, Patrick T Martin, Alberto Alvarez-larrán, Christian FreitagAbstract:Objective To ascertain the role of patient age as an influencing factor in the pharmacokinetics of Anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (≥ 65 years) patients with essential thrombocythemia (ET). Method This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of Anagrelide and its active metabolite, 3-hydroxy-Anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily Anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy-Anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. Results A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized Anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCτ), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCτ: 10.3 vs. 6.4 ng×h/ml; p = 0.01). In contrast, the dose-normalized 3-hydroxy-Anagrelide Cmax and AUCτ were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCτ: 17.4 vs. 27.6 ng×h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of Anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-Anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. Conclusions To conclude, the differences observed in Anagrelide and 3-hydroxy-Anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET.
Ayalew Tefferi - One of the best experts on this subject based on the ideXlab platform.
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decreased survival and increased rate of fibrotic progression in essential thrombocythemia chronicled after the fda approval date of Anagrelide
American Journal of Hematology, 2019Co-Authors: Ayalew Tefferi, Natasha Szuber, Rangit Vallapureddy, Kebede H Begna, Mrinal M Patnaik, Michelle A Elliott, Christopher C Hook, Alexandra P Wolanskyj, Curtis A Hanson, Rhett P KetterlingAbstract:: First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and Anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of Anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for Anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of Anagrelide. Whether or not Anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.
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Decreased survival and increased rate of fibrotic progression in essential thrombocythemia chronicled after the FDA approval date of Anagrelide.
American Journal of Hematology, 2018Co-Authors: Ayalew Tefferi, Natasha Szuber, Rangit Vallapureddy, Kebede H Begna, Mrinal M Patnaik, Michelle A Elliott, Christopher C Hook, Alexandra P Wolanskyj, Curtis A Hanson, Rhett P KetterlingAbstract:: First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and Anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of Anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for Anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P
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Anagrelide associated cardiomyopathy in polycythemia vera and essential thrombocythemia
Blood, 2004Co-Authors: Donald J Jurgens, Alvaro Morenoaspitia, Ayalew TefferiAbstract:Introduction: Anecdotal reports of “idiopathic” cardiomyopathy (ICM) in patients receiving Anagrelide therapy have surfaced but not formally studied. We undertook a tertiary-center comprehensive study of ICM that was diagnosed in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET). Methods: Standard criteria were used for the diagnosis of both ET and PV. A diagnosis of ICM required echocardiogram documentation of a reduced left ventricular systolic ejection fraction (EF Results: Initial data inquiry yielded a total of 434 patients whose medical histories were thoroughly reviewed for the presence of an echocardiogram-documented ICM that post-dated a diagnosis of either ET or PV. Nine such patients (7 females; age range 46–78 years) were identified. Anagrelide therapy, at standard doses (median 2 mg/day), was temporally associated with ICM in 4 of the 9 patients while treatment in the remaining 5 patients consisted of either phlebotomy alone (3 patients) or other cytoreductive agents (2 patients). A similar database inquiry at Mayo Clinic Jacksonville identified 2 more patients with ICM that was temporally associated with Anagrelide treatment. A normal echocardiogram was documented in 3 of the 6 patients with Anagrelide-associated ICM at 2, 15, and 39 months prior to treatment (table 1). Anagrelide therapy was immediately discontinued when ICM was diagnosed in 5 of the 6 patients and after further worsening of EF on continued Anagrelide therapy in the sixth patient (first patient in table 1). All 6 patients with Anagrelide-associated ICM experienced symptomatic improvement after drug discontinuation but the corresponding improvement in EF, after a period of 0.2–16 months, was often suboptimal (table 1). In contrast, ICM not associated with Anagrelide therapy remained unchanged both in terms of symptoms and EF in all 5 cases. Conclusion: Anagrelide-induced cardiomyopathy might occur in some patients with either PV or ET. Prompt recognition and drug discontinuation has the potential to adequately reverse the situation in some but not all patients.
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long term use of Anagrelide in young patients with essential thrombocythemia
Blood, 2001Co-Authors: Elizabeth C Storen, Ayalew TefferiAbstract:Anagrelide is a novel platelet-lowering agent that has recently been approved for use in essential thrombocythemia (ET) and related disorders. Short-term drug efficacy and toxicity data have previously been presented. The purpose of this study was to obtain additional information regarding long-term Anagrelide use. This is a retrospective series of 35 young patients (17 to 48 years) with ET who received Anagrelide treatment before 1992. Initial drug dosage ranged between 1 and 10 mg/d, and the median maintenance dosage was 2.5 mg/d. The overall initial response rate of 94% included 74% complete remissions and 20% partial remissions. Of the 33 responding patients, 27 (82%) remained on Anagrelide therapy for a median of 10.8 years (range, 7 to 15.5). Of these, 66% maintained a complete and 34% a partial remission over the study period. In general, the reporting of somatic side effects decreased over time, and anemia was the only new side effect that emerged after long-term therapy. Eight patients (24%) experienced a more than 3 g/dL decrease in hemoglobin level. Despite active therapy, 20% of the patients experienced a total of 10 thrombotic episodes, and a similar proportion experienced major hemorrhagic events. All thrombohemorrhagic complications occurred at a platelet count of more than 400 × 109/L. It is concluded that long-term treatment of ET with Anagrelide is associated with decreased reporting of initial side effects and the development of mild-to-moderate anemia. Complete normalization of platelet counts may be needed to minimize residual thrombohemorrhagic risk during therapy.
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bone marrow effects of Anagrelide therapy in patients with myelofibrosis with myeloid metaplasia
British Journal of Haematology, 1999Co-Authors: Soo Young Yoon, Chin Yang Li, Ruben A Mesa, Ayalew TefferiAbstract:In a prospective study investigating the therapeutic role of Anagrelide in myelofibrosis with myeloid metaplasia, 20 patients received Anagrelide in daily oral doses of 0.5–3 mg. 17 patients were evaluable and received Anagrelide for a median of 2 years (range 0.5–4 years). No patient had a clinically appreciable benefit. Bone marrow (BM) examinations at baseline and after 6 and 12 months of treatment were available for 17, 17 and 12 patients, respectively. In all evaluable cases, BM megakaryocyte number increased after 6 months of Anagrelide treatment. Also, Ulex europaeus agglutinin-1 staining of megakaryocytes revealed a left-shifted maturation pattern in most patients with a platelet response to Anagrelide. However, megakaryocyte staining intensity for transforming (TGF-β) and platelet-derived (PDGF) growth factors was not affected consistently by treatment. No patient had a 2 grade change in either BM fibrosis or osteosclerosis. These in-vivo data support our previous in-vitro observations that Anagrelide interferes with megakaryocyte maturation rather than proliferation. Lack of a positive treatment effect is consistent with the finding that Anagrelide did not significantly alter megakaryocyte expression of TGF-β and PDGF.
Gunnar Birgegård - One of the best experts on this subject based on the ideXlab platform.
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No effect of Anagrelide on bone marrow fibrosis in patients with chronic myeloproliferative disorders, estimated with hyaluronan and reticulin staining
2020Co-Authors: Magnus Hultdin, Jörgen Samuelsson, Gunnel Sundstrom, Berith Lundström, Gunnar Birgegård, Anders Wahlin, Anna Engström-laurentAbstract:No effect of Anagrelide on bone marrow fibrosis in patients with chronic myeloproliferative disorders, estimated with hyaluronan and reticulin staining
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treatment of essential thrombocythemia in europe a prospective long term observational study of 3649 high risk patients in the evaluation of Anagrelide efficacy and long term safety study
Haematologica, 2018Co-Authors: Gunnar Birgegård, Carlos Besses, Martin Griesshammer, Luigi Gugliotta, Claire N Harrison, Mohamed Hamdani, Jingyang Wu, Heinrich Achenbach, Jeanjacques KiladjianAbstract:Evaluation of Anagrelide (Xagrid®) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia patients treated with cytoreductive therapy. The primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: Anagrelide (Xagrid®) (n=804), other cytoreductive therapy (n=2666), or Anagrelide + other cytoreductive therapy (n=141). The median age was 56 vs. 70 years for Anagrelide vs. other cytoreductive therapy. Event rates (patients with events/100 patient-years) were 1.62 vs. 2.06 for total thrombosis and 0.15 vs. 0.53 for venous thrombosis. Anagrelide was more commonly associated with hemorrhage (0.89 vs. 0.43), especially with anti-aggregatory therapy (1.35 vs. 0.33) and myelofibrosis (1.04 vs. 0.30). Other cytoreductive therapies were more associated with acute leukemia (0.28 vs. 0.07) and other malignancies (1.29 vs. 0.44). Post hoc multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age ≥65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age ≥65, time since diagnosis, and platelet count increase. Safety analysis reflected published data, and no new safety concerns for Anagrelide were found. Live births occurred in 41/54 pregnancies (76%). clinicaltrials.gov Identifier: 00567502.
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combination therapy of hydroxycarbamide with Anagrelide in patients with essential thrombocythemia in the evaluation of xagrid r efficacy and long term safety study
Haematologica, 2014Co-Authors: Luigi Gugliotta, Jonathan Smith, Jeanjacques Kiladjian, Carlos Besses, Ruth Coll, Brihad Abhyankar, Martin Griesshammer, Claire N Harrison, Gunnar BirgegårdAbstract:Available information is limited regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid® Efficacy and Long-term Safety study. Of 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + Anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167, 54.9%) and Anagrelide (n=123, 40.5%). Median weekly doses of hydroxycarbamide and Anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581×109/L and 411×109/L before and after starting hydroxycarbamide + Anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts less than 400×109/L increased from 33 (21.6%) to 74 (48.4%; P <0.0001), and with platelet counts less than 600×109/L, from 82 (53.6%) to 132 (86.3%; P <0.0001). Hydroxycarbamide + Anagrelide was discontinued in 158 patients: 76 (48.1%) stopped hydroxycarbamide, 59 (37.3%) stopped Anagrelide, 19 (12.0%) stopped both and 4 (2.5%) had another therapy added. The most frequent reasons for discontinuation were intolerance/side-effects, lack of efficacy, and therapeutic strategy. Combination therapy, usually hydroxycarbamide + Anagrelide, is used in approximately 10% of all high-risk patients with essential thrombocythemia and may be a useful approach in treating patients for whom monotherapy is unsatisfactory. ( [Clinicaltrials.gov][1] identifier:[NCT00567502][2] ) [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00567502&atom=%2Fhaematol%2F99%2F4%2F679.atom
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Long-term management of thrombocytosis in essential thrombocythaemia
Annals of Hematology, 2009Co-Authors: Gunnar BirgegårdAbstract:Essential thrombocythaemia (ET) is an acquired myeloproliferative disorder with a prolonged clinical course and a near-normal life expectancy. Therapy is stratified according to risk of thrombohaemorrhagic events. In high-risk patients, platelet reduction is generally recommended. In intermediate-risk patients, therapy should be considered depending on the severity of associated risk factors, especially cardiovascular. In low-risk patients, a watch-and-wait approach is appropriate. Hydroxycarbamide is generally first-line therapy. Concerns for possible leukemogenicity make Anagrelide or interferon-α possible choices in younger patients and those who are resistant or intolerant to hydroxycarbamide. Each pharmacotherapy is associated with specific long-term risks and benefits. The potential risk of major bleeding is the main drawback of aspirin. Hydroxycarbamide is an established, effective drug for ET, but it may increase the risk of transformation to acute myeloid leukaemia and may give mucocutaneous ulcers. Anagrelide is a licensed treatment that also reduces platelet counts and is generally well tolerated, with evidence that some common side effects diminish over time. Anagrelide can have cardiac effects due to inhibition of phosphodiesterase III and therefore requires cautious use in patients with cardiac insufficiency. There is no evidence of leukaemogenicity with Anagrelide or interferon-α therapy. Interferon-α is the only treatment suitable for use during pregnancy, although it is not licensed in ET. While it is effective for platelet reduction, the use of interferon-α is restricted by psychiatric side effects. Our knowledge of the optimum pharmacotherapy for each patient with ET continues to evolve through research and clinical trials, particularly into the molecular basis of the disease.
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Progression of bone marrow fibrosis in patients with essential thrombocythemia and polycythemia vera during Anagrelide treatment.
Medical Oncology, 2008Co-Authors: Magnus Hultdin, Gunnel Sundstrom, Berith Lundström, Gunnar Birgegård, Anders Wahlin, Jan Samuelsson, Anna Engström-laurentAbstract:Anagrelide is a second-line option for reduction of thrombocythemia in patients with chronic myeloproliferative disorders (CMPDs). A multicenter, open, phase II study of Anagrelide treatment in 60 patients during 2 yr was performed by the Swedish Myeloproliferative Disorder Study Group. Adequate bone marrow biopsies were obtained from 53 of the CMPD patients [36 essential thrombocythemia (ET), 16 polycythemia vera (PV), 1 chronic idiopathic myelofibrosis (CIMF)] before treatment and compared with biopsies from 30 healthy volunteers and 34 patients with acute myeloid leukemia (AML). Higher reticulin and hyaluronan (HYA) scores were found before Anagrelide therapy in the CMPD patients than in the normal controls (p
Petro E Petrides - One of the best experts on this subject based on the ideXlab platform.
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Molecular and Preclinical Aspects of Anagrelide Action
Molecular Basis of Chronic Myeloproliferative Disorders, 2020Co-Authors: Petro E PetridesAbstract:Anagrelide is the most important contribution to the therapeutic options in the Phnegative cMPDs over the last decade. The substance belongs to the group of imidazole (2,l-b)chinazoline-2-compounds (Fig. 15.1). Anagrelide, which is orally bioavailable, has a relatively poor solubility in water.
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Anagrelide: what was new in 2004 and 2005?
Seminars in thrombosis and hemostasis, 2020Co-Authors: Petro E PetridesAbstract:Anagrelide is an established platelet-reducing drug. Although there are gaps in the understanding of its mechanism of action, two randomized comparisons with other drugs used for therapy of patients with essential thrombocythemia (ET) have been performed. Recent progress has been made in this field with the development of better determination techniques, with the characterization of metabolites, and with studies of their mechanism of action on megakaryocytes and platelets. More data are now available from various noncomparative clinical trials on its clinical efficacy and safety. Only few investigations are available that document its long-term effects. Although the drug should not be used during pregnancy, there are a few studies that report that pregnant women have taken this drug without harm to the newborn. Studies have also investigated the effects of Anagrelide on platelets, indicating that platelet function is as important as platelet counts in ET. Preliminary analyses of the mechanism of action of Anagrelide have revealed that the drug interferes with the signal transduction of the thrombopoietin receptor. Results of the first phase III trial (PT1) that compared Anagrelide/aspirin with hydroxyurea/aspirin have sparked an intense discussion, given that the combination of Anagrelide and aspirin causes more bleeding complications in the gastrointestinal tract. It has been speculated that the higher number of transient ischemic attacks in this study arm is not caused by thrombotic events but by small bleedings that would be responsible for transient hemorrhagic attacks. More insights are expected from the recently completed ANAHYDRET trial that compared monotherapy with hydroxyurea and Anagrelide.
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pharmacokinetics of a novel Anagrelide extended release formulation in healthy subjects food intake and comparison with a reference product
Clinical pharmacology in drug development, 2018Co-Authors: Petro E Petrides, Rudolf Widmann, Christian Schoergenhofer, Bernd Jilma, Christoph KladeAbstract:Anagrelide is an established therapy for essential thrombocythemia. Common adverse effects have been linked to peak plasma concentrations of Anagrelide and its 3OH metabolite. Our study was performed to investigate the pharmacokinetics (PK) of a novel Anagrelide extended-release (AER) formulation and its active metabolites. Thirty healthy volunteers were randomized to receive either 2 mg AER (under fasting and fed conditions) or 2 mg commercially available reference product (CARP) in an open-label, 3-way crossover trial with washout periods of 6 days. Plasma concentrations of Anagrelide and its active metabolites were assessed by tandem mass spectrometry. The PK differed significantly between all treatment periods. Bioavailability of AER was 55% of the CARP under fasting conditions and 60% under fed conditions. C-max, AUCt, and AUC infinity were significantly higher and T-max and T-1/2 were significantly shorter after the CARP compared with AER. Food had a significant impact on the PK of AER, increasing the C-max and AUC(t) while reducing the T-1/2, plateau, and mean residence time. Both formulations were well tolerated, with a trend toward more frequently occurring adverse events after the CARP. The PK of AER and the CARP differed significantly in all parameters. Food enhanced the bioavailability of AER.
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Anagrelide a novel platelet lowering option in essential thrombocythaemia treatment experience in 48 patients in germany
European Journal of Haematology, 2009Co-Authors: Petro E Petrides, Maria K Beykirch, Oliver M TrappAbstract:: We report on our treatment experience in Germany with Anagrelide, a novel platelet lowering agent, in 48 patients (27 females, 21 males) with essential thrombocythaemia. Their age was between 19 and 79 yr when Anagrelide therapy was initiated. Sixteen patients were previously untreated, 15 pretreated with hydroxyurea and 17 had multiple pretreatments. Forty-one of the 48 patients had either microvascular, thromboembolic or bleeding complications. About 50% received low dose acetylsalicylic acid as an adjunct. Their platelet count prior to therapy ranged from 850,000/microl to 3,100,000/microl. Eighty-seven per cent of the patients treated with Anagrelide were complete hematological responders, while 13% responded only partially or failed to respond. Twelve of our patients (25%) developed short-term (from a few days to a maximum of 4 wk) side effects including headache (most frequent), palpitations, tachycardia or nausea. Eight patients reported long-term (more than 1 month) adverse effects. However, in only 5 of all 48 patients (10%) were these side effects not acceptable so that treatment had to be discontinued. We have now treated patients for up to 7 yr (median maintenance dose 2.5 mg/d). Preliminary evidence suggests that Anagrelide mediated platelet count reduction also prevents recurrence of thromboembolic complications. Hence, Anagrelide has the potential to become the first-line platelet-lowering treatment in myeloproliferative disorders with high platelet counts.
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pharmacokinetics bioequivalence tolerability and effects on platelet counts of two formulations of Anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation
Clinical Therapeutics, 2009Co-Authors: Petro E Petrides, Heinz Gisslinger, Michael Steurer, Werner Linkesch, Gunther Krumpl, Agnes Schuller, Rudolf WidmannAbstract:Abstract Background: Anagrelide hydrochloride is an anti-thrombotic agent indicated for the treatment of essential thrombocythemia (ET). In various previously published clinical trials of 2 branded formulations of Anagrelide in patients with ET at high risk for thrombohemorrhagic events, the rates of adverse events and discontinuation were strikingly divergent between brands. Because the formulations and manufacturers differed, the differences in tolerability, as well as platelet counts, might have been related to differences in pharmacokinetic properties between the 2 formulations. Objectives: The present series of investigations (1) determined the pharmacokinetic profile of Anagrelide and its metabolites; (2) compared the pharmacokinetic profiles of the test and reference formulations of Anagrelide; (3) investigated the in vitro release of Anagrelide as a marker of intragastric Anagrelide release of the test and reference formulations; and (4) compared the platelet-reducing effects of the test and reference formulations in patients with thrombocythemia in 2 longitudinal studies over 4 weeks. Methods: A series of 4 in vivo studies and 1 in vitro study were conducted. In a pilot, prospective, singledose study in healthy volunteers, the pharmacokinetic properties (C max , T max , and AUC 0-∞ ) of a test formulation of Anagrelide were assessed using high-performance liquid chromatography analysis of plasma samples. Based on the results from that study, a single-dose, randomized, double-blind, 2-period crossover study in healthy volunteers was conducted to determine bioequivalence of 2 formulations of Anagrelide 2 mg/d (taken as 4 capsules). In vitro dissolution properties of the test or reference formulation containing 0.5 mg Anagrelide as the active ingredient were studied in an assay mimicking gastrointestinal release. To test for effects on platelet counts of switching from the reference formulation (previous treatment on stable dose for 3 months) to the test formulation, two 4-week longitudinal trials were conducted: one in patients with ET (in Germany), and one in patients with thrombocythemia associated with chronic myeloproliferative disorders (CMPDs) (in Austria). Results: The pilot pharmacokinetic study of the test formulation in 16 volunteers (10 women, 6 men; mean [SD] age, 20.5 [1.5] years; weight, 69.0 [10.0 kg) suggested that Anagrelide was metabolized to 3-hydroxyAnagrelide (AUC 0-∞ 50% compared with Anagrelide) and the inactive metabolite 2-amino-5,6-dichloro-,4-dihydroquinazolone. The subsequent bioequivalence study in 24 volunteers (14 women, 10 men; mean [SD] age, 23 [4] years; white, 100%; weight, 67.5 [10.2] kg) found that the test formulation was associated with a significantly lower C max (point estimation [PE], 66%; 90% CI, 58%-76%; P 0-∞ (PE, 77%; 90% CI, 68%-86%; P = 0.001). T max values for Anagrelide and 3-hydroxyAnagrelide were 1 hour longer with the test formulation compared with the reference formulation. The total number of adverse events with the reference formulation was 46; the test formulation, 29 ( P = 0.05). In vitro, Anagrelide from the reference formulation was immediately released (89.1% at 5 minutes), whereas there was a delayed release (93.6% at 30 minutes) from the test formulation ( P 3 cells/μL. Conclusions: The pharmacokinetic properties, adverse event rates, and in vitro dissolution profile differed between the test and reference Anagrelide formulations in these healthy volunteers. In patients with ET or thrombocythemia associated with CMPD, platelet counts did not differ significantly from baseline at 4 weeks when subjects were switched from the reference to the test Anagrelide formulation.
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pharmacokinetics and tolerability of Anagrelide hydrochloride in young 18 50 years and elderly 65 years patients with essential thrombocythemia
Principles and Practice of Constraint Programming, 2012Co-Authors: Carlos Besses, Wolfgang Zeller, Alberto Alvarezlarran, Ruth Coll, Steven M Troy, Jaideep Purkayastha, Patrick T Martin, Christian FreitagAbstract:Objective To ascertain the role of patient age as an influencing factor in the pharmacokinetics of Anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (≥ 65 years) patients with essential thrombocythemia (ET). Method This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of Anagrelide and its active metabolite, 3-hydroxy-Anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily Anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy-Anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. Results A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized Anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCτ), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCτ: 10.3 vs. 6.4 ng×h/ml; p = 0.01). In contrast, the dose-normalized 3-hydroxy-Anagrelide Cmax and AUCτ were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCτ: 17.4 vs. 27.6 ng×h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of Anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-Anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. Conclusions To conclude, the differences observed in Anagrelide and 3-hydroxy-Anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET.
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Pharmacokinetics and tolerability of Anagrelide hydrochloride in young (18 - 50 years) and elderly (≥ 65 years) patients with essential thrombocythemia.
International journal of clinical pharmacology and therapeutics, 2012Co-Authors: Carlos Besses, Wolfgang Zeller, Ruth Coll, Steven M Troy, Jaideep Purkayastha, Patrick T Martin, Alberto Alvarez-larrán, Christian FreitagAbstract:Objective To ascertain the role of patient age as an influencing factor in the pharmacokinetics of Anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (≥ 65 years) patients with essential thrombocythemia (ET). Method This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of Anagrelide and its active metabolite, 3-hydroxy-Anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily Anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy-Anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. Results A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized Anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCτ), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCτ: 10.3 vs. 6.4 ng×h/ml; p = 0.01). In contrast, the dose-normalized 3-hydroxy-Anagrelide Cmax and AUCτ were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCτ: 17.4 vs. 27.6 ng×h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of Anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-Anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. Conclusions To conclude, the differences observed in Anagrelide and 3-hydroxy-Anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET.
