Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents, ATC Code: L01XX35.

Mechanism of action
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.

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 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.

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
In an open-label clinical study in 8 children and 10 adolescents (including patients who were anagrelide treatment naïve or who had been receiving anagrelide for up to 5 years pre-study), median platelet counts were decreased to controlled levels after 12 weeks of treatment. The average daily dose tended to be higher in adolescents.

In a paediatric registry study, median platelet counts were reduced from diagnosis and maintained for up to 18 months in 14 paediatric patients with ET (4 children, 10 adolescents) with anagrelide treatment. In earlier, open-label studies, median platelet count reductions were observed in 7 children and 9 adolescents treated for between 3 months and 6.5 years.

The average total daily dose of anagrelide across all studies in paediatric patients with ET was highly variable, but overall the data suggest that adolescents could follow similar starting and maintenance doses to adults and that a lower starting dose of 0.5 mg/day would be more appropriate for children over 6 years (see sections 4.2, 4.4, 4.8, 5.2). In all paediatric patients, careful titration to a patient- specific daily dose is needed.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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 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.

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 Cmax 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.

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.

Additionally these results show no evidence of auto-induction of the anagrelide clearance.

Linearity
Dose proportionality has been found in the dose range 0.5 mg to 2 mg.
Paediatric population
Pharmacokinetic data from exposed fasting children and adolescents (age range 7 through 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.

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 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.