Anagrelide Hydrochloride Research Articles

Cardiovascular Safety of Anagrelide Hydrochloride versus Hydroxyurea in Essential Thrombocythaemia

Essential thrombocythaemia (ET) is a rare myeloproliferative neoplasm. This multicentre, Phase 3b, randomised, open-label, non-inferiority study investigated the cardiac safety, efficacy and tolerability of first-line treatment with anagrelide or hydroxyurea in high-risk ET patients for up to 3 years. Eligible patients aged ≥ 18 years with a diagnosis of high-risk ET confirmed by bone marrow biopsy within 6 months of randomisation received anagrelide (n = 75) or hydroxyurea (n = 74), administered twice daily. Treatment dose for either compound was titrated to the lowest dose needed to achieve a response. Planned primary outcome measures were change in left ventricular ejection fraction from baseline over time and platelet count at Month 6. Planned secondary outcome measures were platelet count change from baseline at Months 3 and 36; percentage of patients with complete or partial response; time to complete or partial response; number of patients with thrombohaemorrhagic events; and changes in white blood cell count or red blood cell count over time. Neither treatment altered cardiac function. There were no significant differences in adverse events between treatment groups, and no reports of malignant transformation. The incidence of disease-related thrombotic or haemorrhagic events was numerically higher in anagrelide-treated patients. Both treatments controlled platelet counts at 6 months, with the majority of patients experiencing complete or partial responses. In conclusion, these results suggest that long-term treatment with anagrelide is not associated with adverse effects on cardiac function. This is one of the few studies using left ventricular ejection fraction assessment and central biopsy reading to confirm the diagnosis of ET.Trial registration number: Clinicaltrials.gov NCT00202644

PB2196 ANTIPLATELET THERAPY IN ESSENTIAL THROMBOCYTHEMIA: LABORATORY STUDY OF LOW‐DOSE ASPIRIN

Background:The essential thrombocythemia (ET) is a myeloid neoplasm characterized by platelet hyperreactivity and thrombosis. The daily low‐dose aspirin (ASA) is a cornerstone in the prevention of the thrombotic events. In the ET an accelerated platelet turnover translates in a renewal of the drug target shortening the duration of cyclooxygenase (COX‐1) inhibition and may dictate new dosing strategies particularly in ASA “low‐responders” patients.Aims:Therefore, we evaluated platelet count, β‐thromboglobulin (β‐TG) and platelet factor 4 (PF4), as markers of platelet activation, the platelet function activity (PFA), as indicator of ASA platelet sensitivity, the clotting time (CT), clot formation time (CFT) and maximum clot formation/firmness (MCF), as indicators of aspirinated platelet contribution to clot firmness.MethodsWe studied 60 patients (20 men, 40 women; mean age 51 years, range 32‐70) with ET according to WHO criteria. The mean duration of disease was 11 years. All patients were on ASA 100 mg once daily. Of the 60 patients, 45 were on anagrelide hydrochloride (daily dose 1.5 mg) (10 men, 35 women), 15 were on hydroxyurea (daily dose 2 mg) (10 men 5 women). None had inherited or acquired thrombotic risk factors. Sixty subjects served as controls. Platelets were measured by automated analyzer. β‐TG and PF4 were determined by ELISA. ASA platelet sensitivity and CT, CFT and MCF were measured by Platelet Function Analyzer (PFA‐100) and by ROTEM delta, respectively.Results:The mean platelet count was 455 ± 200 × 109/L. All patients had normal β‐TG and PF4 (12 ± 5 IU/ml and 4 ± 1 IU/ml), prolonged C/EPI closure time (T, unit: s, n.v. 84‐160 s) (249 ± 40 s), normal CT (CT, unit: s. n.v. 100‐240 s) (110 ± 20 s), normal CFT (CFT, unit: s, n.v. 30‐110 s) (45 ± 5 s) and normal MCF (MCF, unit: mm, n.v. 50‐72 mm) (61 ± 2 mm).Summary/Conclusion:These findings suggest that in ET patients the daily low‐dose ASA represents an optimal dosing strategy.

Study to Evaluate the Effect of Omeprazole on the Pharmacokinetics of SPD422 (Anagrelide Hydrochloride) in Healthy Adult Participants

Study to Evaluate the Effect of Omeprazole on the Pharmacokinetics of SPD422 (Anagrelide Hydrochloride) in Healthy Adult Participants

Morning Vs Bedtime Aspirin Intake in Patients with Essential Thrombocythemia

The essential thrombocythemia (ET) is a myeloid neoplasm characterized by platelet hyperreactivity and thrombotic risk. The treatment with aspirin (ASA) is recommended in ET patients at risk of first-time or recurrent thrombotic events. An unexplored topic is the optimal timing of once daily ASA intake. On the basis of the presumptions that 1) platelet aggregation is higher in the morning and that 2) the platelet inhibitory effect of ASA is not sustained during the usual 24-hour (h) dosing interval and that 3) a higher gastric mucosal resistance in the evening, we evaluated platelet count, β-thromboglobulin (β-TG) and platelet factor 4 (PF4), as markers of platelet activation, the clotting time (CT), clot formation time (CFT) and maximum clot formation/firmness (MCF), as indicators of aspirinated platelet contribution to clot formation/firmness. We studied 60 patients (20 men, 40 women; mean age 51 years, range 32-70) with ET according to WHO criteria. The mean duration of disease was 11 years. All patients were on ASA 100 mg once daily. Of these, 30 took ASA on awakening and 30 took ASA at bedtime. Of the 60 patients, 45 were on anagrelide hydrochloride (daily dose 1.5 mg) (10 men, 35 women), 15 were on hydroxyurea (daily dose 2 mg) (10 men 5 women). None had inherited or acquired thrombotic risk factors. Sixty subjects served as controls. Platelets were measured by automated analyzer. β-TG and PF4 were determined by ELISA. CT, CFT and MCF were measured by ROTEM delta. The mean platelet count was 455±200x109/L. The awakening ASA patients had normal β-TG and PF4 (12±5 IU/ml and 4±1 IU/ml), normal CT (CT, unit: s. n.v. 100-240 s) ( 110±20 s), normal CFT (CFT, unit: s, n.v. 30-110 s) (45±5 s) and normal MCF (MCF, unit: mm, n.v. 50-72 mm) (61±2 mm), whereas the bedtime ASA patients had high β-TG and PF4 (200±15 IU/ml vs 20±11 IU/ml and 170±50 IU/ml vs 6±2 IU/ml, respectively) (p<.0001 and p<.0001, respectively), shortened CT (CT, unit: s. n.v. 100-240 s) ( 80±10 s), CFT (CFT, unit: s, n.v. 30-110 s) (15±5 s) and MCF (MCF, unit: mm, n.v. 50-72 mm) (40±2 mm). These findings suggest that in ET patients the optimal timing of once daily ASA intake is in the morning. DisclosuresNo relevant conflicts of interest to declare.

The Functional Platelet Response to Aspirin in Patients with Essential Thrombocythemia

The essential thrombocythemia (ET) is a myeloid neoplasm characterized by platelet hyperreactivity and thrombosis. The daily low-dose aspirin (ASA) is a cornerstone in the prevention of the thrombotic events. In the ET an accelerated platelet turnover translates in a renewal of the drug target shortening the duration of cyclooxygenase (COX-1) inhibition and may dictate new dosing strategies particularly ASA low-responders patients. Therefore, we evaluated platelet count, β-thromboglobulin (β-TG) and platelet factor 4 (PF4), as markers of platelet activation, the platelet function activity (PFA), as indicator of ASA platelet sensitivity and the clotting time (CT), as indicator of aspirinated platelet contribution to clot formation. We studied 60 patients (20 men, 40 women; mean age 51 years, range 32-70) with ET according to WHO criteria. The mean duration of disease was 11 years. All patients were on ASA 100 mg once daily. Of the 60 patients, 45 were on anagrelide hydrochloride (daily dose 1.5 mg) (10 men, 35 women), 15 were on hydroxyurea (daily dose 2 mg) (10 men 5 women). None had inherited or acquired thrombotic risk factors. Sixty subjects served as controls. Platelets were measured by automated analyzer. β-TG and PF4 were determined by ELISA. ASA platelet sensitivity and CT were measured by Platelet Function Analyzer (PFA-100) and by ROTEM delta, respectively. The mean platelet count was 455±200x109/L. All patients had normal β-TG and PF4 (12±5 IU/ml and 4±1 IU/ml), prolonged C/EPI closure time (T, unit: s, n.v. 84-160 s) (249±40 s), normal CT (CT, unit: s. n.v. 100-240 s) ( 110±20 s). These findings suggest that in ET patients the daily low-dose ASA represents an optimal dosing strategy. Disclosures No relevant conflicts of interest to declare.

Spotlight on anagrelide hydrochloride for the treatment of essential thrombocythemia

Spotlight on anagrelide hydrochloride for the treatment of essential thrombocythemia

Final Results from the Phase 3 Traial Areta Comparing a Novel, Extended-Release Anagrelide Formulation to Placebo in Essential Thrombocythemia Patients with Defined Risk Status

▪Background: Anagrelide hydrochloride (ana), is a well-known compound used to selectively normalize platelet counts (plc) by inhibiting megakaryocyte development and maturation. Common side-effects of licensed formulations may be largely due to peak plasma concentrations of ana and its 3OH-metabolite, whereas efficacy is proportional to the Area under the curve (AUC). A novel extended-release formulation (ana retard, AR) has superior pharmacokinetics (Petrides 2015) and has been demonstrated to be equally effective as the licensed formulation (Gisslinger 2016). Here, we investigate a "treat-early" concept in non-high risk ET patients.Study design:AR was compared to placebo in a phase 3, randomized, parallel group, multicenter, subject- and sponsor-blinded trial in patients diagnosed with ET according WHO 2008 and a defined risk status including JAK2 mutation, protein C/S or antithrombin III deficiency, factor V Leiden or prothrombin mutation, cardiovascular risk factors. The primary endpoint was time to first ET-related event adjudicated by a blinded expert panel, or progressive thrombocytosis (plc≥1000G/L or plc increase >300G/L within 3 months) requiring medical intervention. Secondary endpoints included plc response and change of risk status.Results: 146 patients were randomized and dosed (all Caucasian, mean age 43 years, 74% females), and 112 completed the first year with drop-out rates of 22% in AR and 25% in placebo. Only 49% of placebo patients vs. 74% of AR patients consented to enter the extension phase. Consequently, over the entire study duration, median exposure times differed significantly with 123 weeks for AR and 62 weeks for placebo. The primary endpoint was met in all analysis sets, with p<0,0008 and 13 vs. 26 ET related events and/or progressive thrombocytosis in the ITT analysis. The progression to high-risk status was 11,7% for AR vs. 26,1% for placebo (p<0,005). AR proofed highly efficacious in normalizing plc: within 2 weeks of therapy mean baseline plc of around 750G/L were consistently below 400G/L (83% complete, 12% partial responders). The maintenance dose was the highest tolerated dose able to maintain plc in range; for 73% of AR patients this was achieved with a single 2mg tablet given once-daily. Remaining patients received doses up to 4 tablets per day. AR showed an acceptable safety profile consistent with the SmPC of licensed ana formulations.Conclusions: Long term treatment of ET patients with defined risk status, using this novel modified-release anagrelide formulation proofed well tolerable, normalized plc in a vast majority, significantly reduced progression to high-risk status and most importantly was associated with significantly less clinical ET related events. These data have important implications for the optimal management of ET and support a "treat-early" approach.ReferencesResults of a phase I, single dose, randomized, 3-way crossover study, to assess the bioavailability of a novel anagrelide extended release (ER) formulation in comparison to a commercially available anagrelide reference product (CARP) in healthy volunteers, Petrides P, Zagrijtschuk O, Klade C, DGHO, 2015Phase 3 trial TEAM-ET in 106 high-risk Essential Thrombocythemia patients, demonstrating non-inferiority of Anagrelide Retard, a novel, extended-release anagrelide formulation, to the licensed comparatorGisslinger H, Radinoff A, Karyagina E,Kyrcz-Krzemień S, Abdulkadyrov K, Gerbutavicius R,Melikyan A, Burgstaller S, Hus M, Kłoczko J, Yablokova V, Tzvetkov N, Całbecka M, Shneyder T, Warzocha K, Jurgutis M, Kaplanov K, Hodisch J, Klade C, Buxhofer-Ausch V, European School of Hematology EHA 21st Congress, 2016 DisclosuresGisslinger:AOP Orphan Pharmaceuticals AG, Novartis, Celgene, Baxalta: Consultancy, Honoraria, Research Funding. Klade:AOP Orphan: Employment. Kyrcz-Krzemien:AOP Orphan Pharmaceuticals AG, Novartis, BMS, Medac: Honoraria. Warzocha:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Hodisch:AOP Orphan Pharmaceuticals: Employment. Widmann:AOP Orphan Pharmaceuticals: Employment. Kralovics:Qiagen: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Research Funding. Schwarz:AOP Orphan Pharmaceuticals: Consultancy. Kiladjian:Novartis: Research Funding; AOP Orphan: Research Funding.

Final Results of Anagrelide Controlled-Release (GALE-401) Safety, Efficacy and Pharmacokinetics in Subjects with Myeloproliferative Neoplasms (MPN)-Related Thrombocytosis

Introduction: Agrylin® (United States) and Xagrid® (European Union) are immediate release (IR) preparations of anagrelide hydrochloride that block megakaryocyte differentiation and proliferation and inhibit the action of cyclic AMP phosphodiesterase. Anagrelide was developed as an inhibitor of platelet aggregation but was found to reduce platelet count at lower doses than the amount needed for platelet aggregation. This led to the development of a controlled release formulation of anagrelide (GALE-401). Early healthy volunteer results demonstrated platelet lowering activity and a pharmacokinetic profile with lower Cmax compared to anagrelide IR. The current study, GALE-401-201, was undertaken in subjects with MPN-related thrombocytosis and the final safety, efficacy, and pharmacokinetics are reported here.Methods: GALE-401-201 is a phase 2 open-label, single arm, clinical proof-of-concept study in chronic myelogenous leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF) or essential thrombocythemia (ET). Eligible subjects must not be refractory to anagrelide IR and must have a platelet count ≥ 600 K/μL. GALE-401 was administered orally at a starting dose of 0.5 mg twice daily and titrated to a dose that maintained a platelet count of 150-400 K/μL. Platelet response was defined by World Health Organization 2008 (complete response, ≤ 400 K/μL or partial response ≤ 600 k/μL or ≥ 50% reduction from baseline), safety assessments were graded by CTCAE version 4.03, and the pharmacokinetic profile was assessed at the starting dose, weekly sampling during dose titration, and at the final titrated dose using a non-linear mixed effect modeling.Results: Eighteen subjects were enrolled, median age 64 years (range, 40-79), 10 females/8 males, 14 ET, 3 PV, and 1 PV/ET. Three groups of anagrelide subjects were enrolled: naïve, intolerant and tolerant subjects with 10, 5, and 3 subjects, respectively. Baseline mutation of JAK2 V617F was present in 12 (66.7%) subjects, CALR in 3 (16.7%) subjects, and thrombopoietin receptor gene (MPL) in 1 (5.6%) subject. After a median duration of 7 months on GALE-401, an overall response rate of 14 of 18 subjects (77.8%; 7 CRs and 7 PRs) was observed across the anagrelide subject groups with median GALE-401 dose of 2 mg daily (range, 0-5 mg). The median duration of response (CR or PR) is 6.3 months (ongoing) with a median time to first objective response of 3.1 weeks (range, 1.1-5.0 weeks). JAK2 V617F was present at baseline in 7 (38.9%) and CALR mutation 1 (5.6%) of ET subjects who demonstrated a clinical response. Majority of the AEs, regardless of relationship were of Grade 1/2 in severity. Treatment related Grade 3/4 adverse events occurred in 2 subjects; Grade 3 (anemia, pancreatitis, increased creatinine, headache); Grade 4 (cholestatic jaundice). Grade 3/4 events were not correlated with higher anagrelide doses. A logistical regression evaluating the relationship between adverse events severity versus dose, anagrelide maximum plasma concentration (Cmax occurring between the time of the adverse event occurrence and up to 7 days prior) versus adverse events, did not reveal a clear positive correlation. Further exposure-adverse events analyses in addition to pharmacokinetic parameters will be presented.Conclusions: In this pilot clinical proof-of-concept study, GALE-401 produces an overall response rate at a dose comparable to anagrelide IR in a diverse group of subjects both treated and untreated with anagrelide IR. The majority of adverse events were mild to moderate in nature, and the adverse events severity was not correlated with dose or plasma concentration. A comparative controlled study evaluating GALE-401 with anagrelide IR in a well-defined MPN population, such as anagrelide treatment naïve ET, will be further needed to fully elucidate the safety and efficacy profile of GALE-401. DisclosuresTroung:Galena Biopharma, Inc.: Research Funding. Saltzman:Galena Biopharma, Inc.: Research Funding. Jawien:Galena Biopharma, Inc.: Research Funding. Lyons:Galena Biopharma, Inc.: Research Funding; Amgen: Consultancy. Berenzon:Galena Biopharma, Inc.: Research Funding. Mena:Galena Biopharma, Inc.: Research Funding. Wingate-Pearse:Galena Biopharma, Inc.: Employment. Barriere:Galena Biopharma, Inc.: Other: Contract Research Organization. Beeson:Galena Biopharma, Inc.: Other: Contract Research Organization. Glidden:Galena Biopharma, Inc.: Consultancy, Equity Ownership, Patents & Royalties: N/A. Choy:Galena Biopharma, Inc.: Employment.

Efficacy and safety of anagrelide in treatment of essential thrombocythemia: multicenter, randomized controlled clinical trial

To evaluate the efficacy and safety of anagrelide in essential thrombocythemia (ET). Patients who diagnosed as ET according to the World Health Organization classification were enrolled. Each patient was assigned to take anagrelide hydrochloride capsule or hydroxyurea tablet by random 1∶1 ratio. Dose of anagrelide started at 2 mg/d, then increased gradually and the maximum dose was 10 mg/d until the platelet counts dropped to (100-400) × 10⁹/L, one month later gradually reduced to maintain dose. The dose of hydroxyurea was 1000 mg/d at beginning, then increased gradually, when platelet counts dropped to (100-400)×10⁹/L and kept for one month, reduced to maintain dose as 10 mg·kg⁻¹·d⁻¹. The observation period was 12 weeks. A total of 222 patients were enrolled in seventeen centers (including 113 patients treated with anagrelide and 109 with hydroxyurea). Therapy efficacy can be evaluated in 198 patients (including 97 patients administered with anagrelide and 101 with hydroxyurea). At 12th weeks of therapy, the hematologic remission rate was 87.63% (85/97) in anagrelide group and 88.12% (89/107) in hydroxyurea group, the differences between the two groups were not significant (P=0.173). Treatment with anagrelide lowered the platelet counts by a median of 393 (362-1 339) × 10⁹/L from a median of 827 (562-1657) × 109/L at the beginning of the observation to 400(127-1130)×10⁹/L after 12 weeks (P<0.001), which were similar to the treatment result of hydroxyurea by a median drop of 398 (597-1846)× 10⁹/L (P=0.982). The median time to achieving response of anagrelide group was 7 (3-14) days, superior to that of hydroxyurea for 21 (14-28) significantly (P=0.003). Frequency of anagrelide related adverse events was 65.49 % (74/113), including cardiopalmus (36.28% ), headache (21.24% ), fatigue (14.16% ) and dizzy (11.50% ). Anagrelide was effective in patients with ET which had similar hematologic remission rate to hydroxyurea and could take effect more quickly than hydroxyurea. Incidence of adverse events was undifferentiated between anagrelide and hydroxyurea, but anagrelide treatment had tolerable adverse effects and no hematologic toxicity.

Pharmacokinetics and tolerability of anagrelide hydrochloride in young (18 – 50 years) and elderly (? 65 years) patients with essential thrombocythemia

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). 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. 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. 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.

Development and Validation of a Stability-Indicating RP-HPLC Method for the Quantitative Analysis of Anagrelide Hydrochloride

A simple, rapid, and stability-indicating reverse-phase liquid chromatographic assay method was developed for Anagrelide Hydrochloride (ANG) in the presence of its degradation products generated from forced decomposition studies. The HPLC separation was achieved on a C18 Inertsil column (250 mm × 4.6 mm i.d. particle size is 5 μm), using solution A, a mixture of 0.03 M potassium di-hydrogen phosphate pH-adjusted to 3.0 using ortho-phosphoric acid (buffer): methanol: acetonitrile (90:5:5, v/v/v), and solution B, which contains a mixture of buffer: acetonitrile (10:90, v/v). The UV detector was operated at 251 nm while column temperature was maintained at 40°C, and the gradient program had the flow rate of 1.0 mL min−1. The developed method was validated as per ICH guidelines with respect to specificity, linearity, precision, accuracy, robustness, and limit of quantification. The method was found to be simple, specific, precise, accurate, and reproducible. Selectivity was validated by subjecting the stock solution of ANG to acidic, basic, photolysis, oxidative, and thermal degradation. The calibration curve was found to be linear in the concentration range of 0.05–152 μg mL−1 (R2 = 0.9991). The peaks of degradation products did not interfere with that of pure ANG. The utility of the developed method was examined by analyzing the tablets containing ANG.

Pharmacokinetics, bioequivalence, tolerability, and effects on platelet counts of two formulations of anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation

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 < 0.001) and AUC 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 < 0.05). In the last 2 studies, 2 cohorts of white patients (cohort 1, 15 patients with ET; 10 women, 5 men; mean [SD] age, 49.0 [10.7] years [range, 31-66 years]; weight, 73.2 [12.6] kg; cohort 2, 19 patients with thrombocythemia associated with CMPD; 12 women, 7 men; age, 62.6 [12.4] years [range, 38-80 years]; weight, 66.1 [13.3] kg) who had received treatment for ≥3 months with the reference formulation were switched to the same dose of the test formulation and maintained on this dose for 4 weeks. Platelet counts did not change significantly from baseline over 4 weeks and stayed within a predefined margin of 150 × 10 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.

Anagrelide for the treatment of essential thrombocythemia: a survey among European hematologists/oncologists

Two hundred and fifty hematologists and oncologists (50 each from France, Germany, Italy, Spain and the United Kingdom) participated in this survey to assess the current management of essential thrombocythemia (ET), with particular reference to the use of anagrelide. Data were collected between October 9 and November 2, 2006 on 2000 patients with ET. Thirty-eight per cent of patients had been tested for the Janus kinase 2 (JAK2) mutation (JAK2V617F), of whom 54% tested positive. JAK2V617F mutation status was not influenced by age, gender or cardiovascular risk. Overall, 297 patients (14·9%) were receiving anagrelide hydrochloride; 16·8% of these patients were aged 18–40 years, 43·1% aged 41–60 years and 40·1% aged over 60 years. Hydroxycarbamide, alone or in combination with aspirin, was the most commonly prescribed treatment in 136/191 (71·2%) patients prior to switching to anagrelide. In conclusion, this survey provides a useful insight into the epidemiology of ET and current prescribing patterns for anagrelide in Europe.

Tissue Plasminogen Activator (t-PA) and Plasminogen Activator Inhibitor-1 (PAI-1) in Essential Thrombocythemia and Polycythemia Vera and Thrombotic Complications.

Thrombotic complications are frequent in patients with essential thrombocythemia (ET) and polycythemia vera (PV). While a thrombin- and tissue plasminogen activator (t-PA)-regulated release of t-PA and plasminogen activator inhibitor-1 (PAI-1), respectively, has been shown and an association between elevated t-PA and PAI-1 and thrombogenesis has been studied for several vascular diseases, few studies have concentrated on the correlation between t-PA and PAI-1 levels and thrombogenesis in these myeloproliferative disorders. Therefore, we investigated prothrombin fragment 1+2 (F1+2), as marker of thrombin generation, and t-PA and PAI-1 in patients with ET and PV and thrombosis. We included 44 patients, 22 ET (5 men and 17 women, mean age 55 years) and 22 PV (17 men and 5 women, mean age 60 years) who fulfilled PVSG. The mean duration of disease was 4.5 years. Most received cytoreduction, such as hydroxyurea (13 ET and 14 PV), interferon-alpha (2 ET), anagrelide hydrochloride (5 ET) or phlebotomy (8 PV). None of studied patients had thrombotic risk factors. Of 44 patients, 25 (12 ET and 13 PV) developed thrombosis, whereas 19 (10 ET and 9 PV) did not. Measurements were assayed by ELISA. All patients had increased F1+2 (2.8±2.8 nmol/L vs 0.7±0.2 nmol/L) (p=0.001). t-PA and PAI-1 were higher in those patients with previous thrombosis than in asymptomatic patients (130±62 ng/ml vs 89±69 ng/ml and 45±20 ng/ml vs 57±27 ng/ml, respectively) (p=0.043 and p=0.085, respectively). A positive correlation there was between F1+2 and t-PA and t-PA and PAI-1 (p<0.0001 and p<0.0001, respectively). These findings suggest that a disfibrinolysis may be in ET and PV and that t-PA and PAI-1 may be predictive additional factors of the thrombotic tendency of these patients.

Assessing the Benefit/Risk Balance of Long-Term Anagrelide Hydrochloride (Xagrid®/Agrylin®) Treatment for Essential Thrombocythemia.

Essential thrombocythemia (ET) is a myeloproliferative disorder (MPD) associated with thrombohemorrhagic complications. The disease uncommonly progresses to myelofibrosis or acute leukemia; the risk of transformation may be increased by cytoreductive treatments. Anagrelide (Xagrid®/Agrylin®) is a non-cytotoxic agent that selectively reduces platelet production. A retrospective analysis of an open-label, multi-center trial including MPD patients treated by long-term anagrelide was performed.1 The total safety population comprised 3660 MPD patients (2251 with ET) with a maximum follow-up of 11.4 years. Prior myelosuppressive therapy had been administered in 81% of patients; 33% of these patients were changed to anagrelide because of previous toxicity and 31% because of poor platelet control. Efficacy and safety data hereafter are described for the ET population. There were 934 ET efficacy evaluable patients: with a response seen in 78.7% of them (complete and partial response: 67.2% and 11.5%, respectively). This was similar to that of patients who failed previous therapy (78.8%) or were intolerant (75.6%). After the first year, platelet count decreases were well maintained. Results were similar for both sexes, different age groupings and ethnic origins. AEs occurred in 40.2% of the patients and were generally mild. Anagrelide was discontinued in 38.6% of patients (adverse events accounting for 29.2% of patients stopping treatment). At baseline, 163/934 (17.5%) patients reported ET-related symptoms including GI and other bleedings, arterial or venous thrombosis, angina, pulmonary embolism, transient ischemic attacks, peripheral ischemia and paresthesia. This had reduced to 7.9% (63/796, P<0.001) after 12 weeks and was maintained during follow up (4.3%: 15/470 at 1 year, 3.2%: 6/239 at 2 years, P<0.001.2 Transformation to AML/MDS occurred in 47/2251 (2.1%), but only in subjects who had previously been exposed to cytoreductive treatment. Mortality rate in the safety population was as to be expected in ET patients: 8.8%. Most common reason for death (> or =1%) were CML, reason unknown or unspecified and sepsis. Anagrelide (Xagrid®/Agrylin®) effectively reduces platelet counts and thrombohemorrhagic complications in patients with ET. This is independent of gender, age, ethnic origin and prior therapy. The drug demonstrates a recognized safety profile. Benefits are maintained during long-term follow-up without an increase in disease transformation.

Anagrelide is effective in treating patients with hydroxyurea-resistant thrombocytosis in patients with chronic myeloid leukemia

We report phase II trial results of the use of oral anagrelide hydrochloride for treating 38 patients with hydroxyurea (HU)-resistant thrombocytosis accompanying chronic myeloid leukemia (CML). Anagrelide's efficacy was well established during a phase II study of more than 400 patients with one of the four myeloproliferative disorders: essential thrombocythemia, polycythemia, idiopathic myelofibrosis, and CML. In the last subgroup, there were 114 CML patients with significant thrombocytosis treated with anagrelide. Out of these patients, 38 had symptoms of thrombosis or hemorrhage and had thrombocytosis resistant to HU. They were then treated with anagrelide at an initial dose of 2.0 mg/day, followed by modifications based upon response and toxicity. In all, 71% of these patients responded with platelet reductions of more than 50% in a median time of approximately 4 weeks. The response rate was not influenced by age, gender, or prior thrombosis or hemorrhage. Importantly, the response rate to anagrelide in patients refractory to prior HU was essentially the same as that of the other 76 CML patients. Treatment with anagrelide was well tolerated and without undue toxicity. Reduction of excessive platelet counts by anagrelide sometimes occurring in CML may lead to the prevention of thrombohemorrhagic complications occurring in this clinical setting and is relevant even in those patients in whom imatinib mesylate is primary therapy.