s have been identified (RL603 and 3-hydroxy anagrelide).
There were no apparent differences between patient groups (pediatric versus adult patients) for tmax and t1/2 for anagrelide, 3-hydroxy anagrelide, or RL603.
Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the Cmax by 14%, but increased the AUC by 20%.
Pharmacokinetic (PK) data from pediatric (age range 7-14 years) and adult (age range 16-86 years) patients with thrombocythemia secondary to a myeloproliferative disorder (MPD), indicate that dose- and body weight-normalized exposure, Cmax and AUCτ , of anagrelide were lower in the pediatric patients compared to the adult patients (Cmax 48%, AUCτ 55%).
Pharmacokinetic data from fasting elderly patients with ET (age range 65-75 years) compared to fasting adult patients (age range 22-50 years) indicate that the Cmax and AUC of anagrelide were 36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients.
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment (creatinine clearance <30ml/min) showed no significant effects on the pharmacokinetics of anagrelide.
A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic impairment showed an 8-fold increase in total exposure (AUC) to anagrelide.
CLINICAL STUDIESA 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 three clinical trials. Patients with OMPD included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unknown myeloproliferative disorders.
Clinical Studies
Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:
ET:
• Platelet count ≥ 900,000/µL on two 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
CML:
• Persistent granulocyte count ≥ 50,000/µL without evidence of infection
• Absolute basophil count ≥ 100/µL
• Evidence for hyperplasia of the granulocytic line in the bone marrow
• Philadelphia chromosome is present
• Leukocyte alkaline phosphatase ≤ lower limit of the laboratory normal range
PV†:
• A1 Increased red cell mass
• A2 Normal arterial oxygen saturation
• A3 Splenomegaly
• B1 Platelet count ≥ 400,000/µL, in absence of iron deficiency or bleeding
• B2 Leukocytosis (≥ 12,000/µL, in the absence of infection)
• B3 Elevated leukocyte alkaline phosphatase
• B4 Elevated serum B12
Diagnosis positive if A1, A2, and A3 present; or, if no splenomegaly, diagnosis is positive if A1 and A2 are present with any two of B1, B2, or B3.
MMM:
• Myelofibrotic (hypocellular, fibrotic) bone marrow
• Prominent megakaryo |
