Pharmacology: The mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in white cell counts or coagulation parameters and may have a small but clinically insignificant effect on red cell parameters. Platelet aggregation is inhibited in people at doses higher than those required to reduce platelet count. Anagrelide inhibits cyclic AMP phosphodiesterase, as well as ADP- and collagen-induced platelet aggregation.
Following oral administration of 14C-anagrelide in people, >70% of radioactivity was recovered in urine. Based on limited data, there appears to be a trend toward dose linearity between doses of 0.5 and 2 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hrs. The available plasma concentration-time data at steady state in patients showed that anagrelide does not accumulate in plasma after repeated administration. The drug is extensively metabolized; <1% is recovered in the urine as anagrelide.
When a 0.5-mg dose of anagrelide was taken after food, its bioavailability (based on AUC values) was modestly reduced by an average of 13.8% and its plasma half-life slightly increased (to 1.8 hrs), when compared to the drug administered to the same subjects in the fasted state. The peak plasma level was lowered by an average of 45% and delayed by 2 hrs.
Clinical Studies: A total of 942 patients with myeloproliferative disorders including 551 patients with essential thrombocythemia (ET), 117 patients with polycythemia vera (PV), 178 patients with chronic myelogenous leukemia (CML), and 96 patients with other myeloproliferative disorders (OMPD), were treated with anagrelide in 3 clinical trials. Patients with OMPD included 87 patients who had myeloid metaplasia with myelofibrosis (MMM) and 9 patients who had unknown myeloproliferative disorders.
Patients with ET, PV, CML or MMM were diagnosed based on the following criteria: ET: Platelet count ≥900,000/microliter on 2 determinations; profound megakaryocytic hyperplasia in bone marrow; absence of Philadelphia chromosome; normal red cell mass; normal serum iron and ferritin and normal marrow iron stores.
PV*: A1 increased red cell mass; A2 normal arterial oxygen saturation; A3 splenomegaly; B1 platelet count ≥400,000/microliter, in absence of iron deficiency or bleeding; B2 leucocytosis (≥12,000/microliter in the absence of infection); B3 elevated leucocyte alkaline phosphatase; B4 elevated serum B12.
*Diagnosis is positive if A1, A2 and A3 are present; or, if no splenomegaly, diagnosis is positive if A1 and A2 are present with any 2 of B1, B2 or B3.
CML: Persistent granulocyte count ≥50,000/microliter without evidence of infection; absolute basophil count ≥100/microliter; evidence for hyperplasia of the granulocytic line in the bone marrow; Philadelphia chromosome present; leucocyte alkaline phosphatase less than or equal to the lower limit of laboratory normal range.
MMM: Myelofibrotic (hypocellular, fibrotic) bone marrow; prominent megakaryocytic metaplasia in the bone marrow; splenomegaly; moderate to severe normochromic, normocytic anemia; white cell count may be variable (80,000-100,000/microliter); increased platelet count; variable red cell mass, teardrop poikilocytes; normal to high leucocyte alkaline phosphatase; absence of Philadelphia chromosome.
Patients were enrolled in clinical trials if their platelet count was ≥900,000/microliter on 2 occasions or ≥650,000/microliter on 2 occasions with documentation of symptoms associated with thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML and OMPD patients was 65, 67, 40 and 44 weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with anagrelide starting at doses of 0.5-2 mg every 6 hrs. The dose was increased if the platelet count was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000-400,000/microliter). The criteria for defining subjects as "responders" were reduction in platelets for at least 4 weeks to ≤600,000/microliter or by at least 50% from baseline value. Subjects treated for <4 weeks were not considered evaluable. The results are depicted as follows: (See figure.)
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Click on icon to see table/diagram/image
Agrylin was effective in phlebotomized patients as well as in patients with other concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus and alkylating agents.