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Abstract
Background: Anagrelide hydrochloride is an anti-thrombotic agent indicated for the treatment
of essential thrombocythemia (ET). In various previously published clinical trials
of 2 branded formulations of anagrelide in patients with ET at high risk for thrombohemorrhagic
events, the rates of adverse events and discontinuation were strikingly divergent
between brands. Because the formulations and manufacturers differed, the differences
in tolerability, as well as platelet counts, might have been related to differences
in pharmacokinetic properties between the 2 formulations.
Objectives: The present series of investigations (1) determined the pharmacokinetic profile of
anagrelide and its metabolites; (2) compared the pharmacokinetic profiles of the test
and reference formulations of anagrelide; (3) investigated the in vitro release of
anagrelide as a marker of intragastric anagrelide release of the test and reference
formulations; and (4) compared the platelet-reducing effects of the test and reference
formulations in patients with thrombocythemia in 2 longitudinal studies over 4 weeks.
Methods: A series of 4 in vivo studies and 1 in vitro study were conducted. In a pilot, prospective,
singledose study in healthy volunteers, the pharmacokinetic properties (Cmax, Tmax, and AUC0-∞) of a test formulation of anagrelide were assessed using high-performance liquid
chromatography analysis of plasma samples. Based on the results from that study, a
single-dose, randomized, double-blind, 2-period crossover study in healthy volunteers
was conducted to determine bioequivalence of 2 formulations of anagrelide 2 mg/d (taken
as 4 capsules). In vitro dissolution properties of the test or reference formulation
containing 0.5 mg anagrelide as the active ingredient were studied in an assay mimicking
gastrointestinal release. To test for effects on platelet counts of switching from
the reference formulation (previous treatment on stable dose for 3 months) to the
test formulation, two 4-week longitudinal trials were conducted: one in patients with
ET (in Germany), and one in patients with thrombocythemia associated with chronic
myeloproliferative disorders (CMPDs) (in Austria).
Results: The pilot pharmacokinetic study of the test formulation in 16 volunteers (10 women,
6 men; mean [SD] age, 20.5 [1.5] years; weight, 69.0 [10.0 kg) suggested that anagrelide
was metabolized to 3-hydroxyanagrelide (AUC0-∞ 50% compared with anagrelide) and the inactive metabolite 2-amino-5,6-dichloro-,4-dihydroquinazolone.
The subsequent bioequivalence study in 24 volunteers (14 women, 10 men; mean [SD]
age, 23 [4] years; white, 100%; weight, 67.5 [10.2] kg) found that the test formulation
was associated with a significantly lower Cmax (point estimation [PE], 66%; 90% CI, 58%-76%; P < 0.001) and AUC0-∞ (PE, 77%; 90% CI, 68%-86%; P = 0.001). Tmax values for anagrelide and 3-hydroxyanagrelide were 1 hour longer with the test formulation
compared with the reference formulation. The total number of adverse events with the
reference formulation was 46; the test formulation, 29 (P = 0.05). In vitro, anagrelide from the reference formulation was immediately released
(89.1% at 5 minutes), whereas there was a delayed release (93.6% at 30 minutes) from
the test formulation (P < 0.05). In the last 2 studies, 2 cohorts of white patients (cohort 1, 15 patients
with ET; 10 women, 5 men; mean [SD] age, 49.0 [10.7] years [range, 31-66 years]; weight,
73.2 [12.6] kg; cohort 2, 19 patients with thrombocythemia associated with CMPD; 12
women, 7 men; age, 62.6 [12.4] years [range, 38-80 years]; weight, 66.1 [13.3] kg)
who had received treatment for ≥3 months with the reference formulation were switched
to the same dose of the test formulation and maintained on this dose for 4 weeks.
Platelet counts did not change significantly from baseline over 4 weeks and stayed
within a predefined margin of 150 × 103 cells/μL.
Conclusions: The pharmacokinetic properties, adverse event rates, and in vitro dissolution profile
differed between the test and reference anagrelide formulations in these healthy volunteers.
In patients with ET or thrombocythemia associated with CMPD, platelet counts did not
differ significantly from baseline at 4 weeks when subjects were switched from the
reference to the test anagrelide formulation.
Key words:
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Article info
Publication history
Accepted:
November 25,
2008
Identification
Copyright
© 2009 Excerpta Medica Inc. All rights reserved. Published by Elsevier Inc.
