Thromboreductin Mechanism of Action

Pharmacotherapeutic group: Other antineoplastic substances. ATC code: L01XX35.
Pharmacology: Pharmacodynamics: Mechanism of action: Anagrelide causes a dose dependent and selective decrease in platelet count in humans; the specific mechanism of action is not yet fully understood.
Anagrelide is an inhibitor of cyclic AMP PDE III.
In vitro studies on megakaryocytopoiesis in humans have demonstrated that the inhibiting effect on platelet production is caused by a delay in maturation and a reduction of size and ploidy of megakaryocytes. Biopsies of bone marrow of treated patients gave evidence for similar in vivo effects.
Pharmacodynamic effects: 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 maximum 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.
A 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.
At therapeutic doses, anagrelide does not cause significant changes in white blood cells and coagulation parameters, but may cause minor changes in red blood cells.
At high, non-therapeutic doses anagrelide inhibits c-AMP phosphodiesterase and ADP- and collagen induced thrombocyte aggregation.
Pharmacokinetics: Absorption: 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 C_max of anagrelide by 14%, but increases the AUC by 20%. Food also decreased the C_max of the active metabolite, 3-hydroxy anagrelide, by 29%, although it had no effect on the AUC.
Biotransformation: 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 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, an active metabolite of anagrelide, were reduced by 13%, 14%, and 18%, respectively.
Elimination: 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.
Paediatric population: Pharmacokinetic data from fasting children and adolescents (age range 7-16 years) with essential thrombocythaemia indicate that dose normalised exposure, C_max and AUC, of anagrelide were higher in children/adolescents as compared to adults. There was also a trend to higher exposure to the active metabolite.
Elderly: Pharmacokinetic data from fasting elderly patients with ET (age range 65 through 75 years) compared to fasting adult patients (age range 22 through 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 oral administration of anagrelide in dogs, subendocardial haemorrhage and focal myocardial necrosis was observed at 1 mg/kg/day (12 to 16-fold the maximum therapeutic dose) or higher in males and females with males being more sensitive. The no observed effect level (NOEL) for male dogs (0.3 mg/kg/day) corresponds to 0.1, 0.1, and 1.6-fold the AUC in humans for anagrelide at 2 mg/day, and the metabolites BCH24426 and RL603, respectively.
Reproductive toxicity: Fertility: In male rats, anagrelide at oral doses up to 240 mg/kg/day (>1,000 times a 2 mg/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 (10 mg/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.
Embryofoetal development studies: 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 (3 mg/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 2 mg/day.
Anagrelide at ≥60 mg/kg increased parturition time and mortality in the dam and foetus respectively. At the NOEL dose (30 mg/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.
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 findings were observed and related or attributed to an exaggerated pharmacological effect. Among them, the incidence of adrenal phaeochromocytomas was increased relative to the control group 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 the 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.