Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other antineoplastic agents, ATC Code: L01XX35.

The specific mechanism of action by which anagrelide reduces platelet count is not yet fully understood although it has been confirmed that anagrelide is platelet selective from in vitro and in vivo study information.

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.

Clinical efficacy and safety
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 disorders (MPDs). 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.

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.

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.
Paediatric population
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.

This medicinal product has been authorised under “Exceptional Circumstances”.
This means that due to the rarity of this disease it has not been possible to obtain complete information on this medicine.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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 Cmax by 29%, although it had no effect on the AUC.

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.

Paediatric population
Pharmacokinetic data from fasting children and adolescents (age range 7 - 14 years) with essential thrombocythaemia indicate that dose and body weight normalised exposure, Cmax 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.

Older people
Pharmacokinetic data from fasting older 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 older patients, but that the Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the older patients. These differences were likely to be caused by lower presystemic metabolism of anagrelide to 3-hydroxy anagrelide in the older patients.