Agrylin Mechanism of Action

Pharmacotherapeutic group: Other Antineoplastic Agents. ATC Code: L01XX35.
Pharmacology: Pharmacodynamics: 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.
The safety and efficacy of anagrelide as a platelet lowering agent have been evaluated in four open-label, non-controlled clinical trials (study numbers 700-012, 700-014, 700-999 and 13970-301) including more than 4000 patients with myeloproliferative neoplasms (MPNs). In patients with essential thrombocythaemia complete response was defined as a decrease in platelet count to ≤600 x 10⁹/L or a ≥50% reduction from baseline and maintenance of the reduction for at least 4 weeks. In studies 700-012, 700-014, 700-999 and study 13970-301, the time to complete response ranged from 4 to 12 weeks. Clinical benefit in terms of thrombohaemorrhagic events has not been convincingly demonstrated.
Paediatric patients: An open label clinical study with a 3 month treatment period did not raise any safety concerns for anagrelide in 17 children/adolescent patients with ET (age range 7-14 years) compared to 18 adult patients. Earlier during clinical development a limited number (12) of children (age range 5-17 years) with essential thrombocythaemia were treated with anagrelide.
Effects on Heart Rate and QTc Interval: The effect of two dose levels of anagrelide (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval was evaluated in a double-blind, randomised, placebo- and active controlled, cross-over study in healthy adult men and women.
A dose-related increase in heart rate was observed during the first 12 hours, with the maximum increase occurring around the time of maximal concentrations. The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.
An apparent transient increase in mean QTc was observed for both doses during periods of increasing heart rate and the maximum change in mean QTcF (Fridericia correction) was +5.0 msec occurring at 2 hours for 0.5 mg and +10.0 msec occurring at 1 hour for 2.5 mg. The evidence suggests that this increase in QTc may be due to the physiological effect of the increasing heart rate and the corresponding QT-RR hysteresis, rather than a direct effect on repolarisation.
Pharmacokinetics: 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 a 0.5 mg dose; the plasma half-life is short, approximately 1.3 hours. Dose proportionality has been found in the dose range 0.5 mg to 2 mg.
Anagrelide is primarily metabolised by CYP1A2; less than 1% is recovered in the urine as anagrelide. Two major urinary metabolites, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline and 3-hydroxy anagrelide have been identified. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in urine is approximately 18-35% of the administered dose.
Pharmacokinetic data from healthy subjects established that food decreases the C_max of anagrelide by 14%, but increases the AUC by 20%. Food had a more significant effect on the active metabolite and decreased the C_max by 29%, although it had no effect on the AUC.
The effect of omeprazole, a CYP1A2 inducer, on the pharmacokinetics of anagrelide was investigated in 20 healthy adult subjects following multiple, once daily 40-mg doses. The results showed that in the presence of omeprazole, AUC_(0-∞), AUC_(0-t), and C_max of anagrelide were reduced by 27%, 26%, and 36%, respectively; and the corresponding values for 3-hydroxy anagrelide, a metabolite of anagrelide, were reduced by 13%, 14%, and 18%, respectively.
As expected from its half-life, there is no evidence for anagrelide accumulation in the plasma. Additionally these results show no evidence of auto-induction of the anagrelide clearance.
Special Populations: Paediatric patients: Pharmacokinetic data from fasting children and adolescents (age range 7-14 years) with essential thrombocythaemia indicate that dose and body weight normalised exposure, C_max and AUC, of anagrelide were lower in children/adolescents compared to adults. There was also a trend to lower exposure to the active metabolite. These observations may be a reflection of more efficient metabolic clearance in younger subjects.
Elderly: 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 C_max and AUC of anagrelide were 36% and 61% higher respectively in elderly patients, but that the C_max 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.
Toxicology: Preclinical safety data: Repeated dose toxicity: Following repeated administration of anagrelide, at doses of 1 mg/kg/day or higher, subendocardial haemorrhage and focal myocardial necrosis occurred in dogs.
Reproductive toxicity: Maternally toxic dosages of anagrelide (60 mg/kg/day and above) in rats and rabbits were associated with increased embryo resorption and foetal mortality.
Mutagenic and carcinogenic potential: 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.
Currently there is no clinical evidence that these findings are of relevance to human use.