Chemical formula: C₁₀H₇Cl₂N₃O Molecular mass: 256.088 g/mol PubChem compound: 135409400
The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis, ultimately leading to reduced platelet production.
In vitro studies of human megakaryocytopoiesis established that anagrelide’s inhibitory actions on platelet formation in man are mediated via retardation of maturation of megakaryocytes, and reducing their size and ploidy. Evidence of similar in vivo actions was observed in bone marrow biopsy samples from treated patients.
Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III.
Following oral administration of anagrelide in man, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects, peak plasma levels occur about 1 hour after administration. Pharmacokinetic data from healthy subjects established that food decreases the Cmax of anagrelide by 14%, but increases the AUC by 20%. Food also decreased the Cmax of the active metabolite, 3-hydroxy-anagrelide, by 29%, although it had no effect on the AUC.
Anagrelide is primarily metabolised by CYP1A2 to form, 3-hydroxy anagrelide, which is further metabolised via CYP1A2 to the inactive metabolite, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline.
The plasma half-life of anagrelide is short, approximately 1.3 hours and as expected from its half-life, there is no evidence for anagrelide accumulation in the plasma. Less than 1% is recovered in the urine as anagrelide. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in urine is approximately 18-35% of the administered dose.
Additionally these results show no evidence of auto-induction of the anagrelide clearance.
Dose proportionality has been found in the dose range 0.5 mg to 2 mg.
Pharmacokinetic data from exposed fasting children and adolescents (age range 7-16 years) with essential thrombocythaemia indicate that dose normalised exposure, Cmax and AUC, of anagrelide tended to be higher in children/adolescents compared with adults. There was also a trend to higher dose-normalised exposure to the active metabolite.
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. These differences were likely to be caused by lower presystemic metabolism of anagrelide to 3-hydroxy anagrelide in the elderly patients.
Following repeated oral administration of anagrelide in dogs, subendocardial haemorrhage and focal myocardial necrosis was observed at 1mg/kg/day or higher in males and females with males being more sensitive. The no observed effect level (NOEL) for male dogs (0.3mg/kg/day) corresponds to 0.1, 0.1, and 1.6-fold the AUC in humans for anagrelide at 2mg/day, and the metabolites BCH24426 and RL603, respectively.
In male rats, anagrelide at oral doses up to 240 mg/kg/day (>1000 times a 2mg/day dose, based on body surface area) was found to have no effect on fertility and reproductive performance. In female rats increases in pre- and post-implantation losses and a decrease in the mean number of live embryos was observed at 30 mg/kg/day. The NOEL (10mg/kg/day) to this effect was 143, 12 and 11-fold higher than the AUC in humans administered a dose of anagrelide 2 mg/day, and the metabolites BCH24426 and RL603, respectively.
Maternally toxic doses of anagrelide in rats and rabbits were associated with increased embryo resorption and foetal mortality.
In a pre- and post-natal development study in female rats, anagrelide at oral doses of ≥10 mg/kg produced a non-adverse increase in gestational duration. At the NOEL dose (3mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 14, 2 and 2-fold higher than the AUC in humans administered an oral dose of anagrelide 2mg/day.
Anagrelide at ≥60 mg/kg increased parturition time and mortality in the dam and foetus respectively. At the NOEL dose (30mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and RL603 were 425-, 31- and 13-fold higher than the AUC in humans administered an oral dose of anagrelide 2 mg/day, respectively.
Studies on the genotoxic potential of anagrelide did not identify any mutagenic or clastogenic effects.
In a two-year rat carcinogenicity study, non-neoplastic and neoplastic findings were observed and related or attributed to an exaggerated pharmacological effect. Among them, the incidence of adrenal phaeochromocytomas was increased relative to control in males at all dose levels (≥ 3 mg/kg/day) and in females receiving 10 mg/kg/day and above. The lowest dose in males (3 mg/kg/day) corresponds to 37 times the human AUC exposure after a 1 mg twice daily dose. Uterine adenocarcinomas, of epigenetic origin, could be related to an enzyme induction of CYP1 family. They were observed in females receiving 30 mg/kg/day, corresponding to 572 times the human AUC exposure after a 1 mg twice daily dose.
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