Pharmacokinetic comparison of 2 formulations of anastrozole (1 mg) in healthy
Korean male volunteers: a randomized, single-dose, 2-period, 2-sequence,
crossover study.
Author(s): Noh YH, Ko YJ, Cho SH, Ghim JL, Choe S, Jung JA, Kim UJ, Jin SJ, Park HJ, Song
GS, Lim HS, Bae KS.
Affiliation(s): Department of Clinical Pharmacology and Therapeutics, College of Medicine,
University of Ulsan, Asan Medical Center, Seoul, Korea.
Publication date & source: 2012, Clin Ther. , 34(2):305-13
BACKGROUND: Anastrozole is an aromatase inhibitor used to treat advanced breast
cancer in postmenopausal women. A generic 1-mg tablet of anastrozole was recently
developed.
OBJECTIVE: The study was designed to provide data to submit to Korean regulatory
authorities to allow marketing of the test formulation. We evaluated the
comparative bioavailability and tolerability of the test and reference
formulations in healthy male adult volunteers.
METHODS: This single-dose, randomized, double-blind, 2-way crossover trial was
conducted in the Clinical Trial Center at the Asan Medical Center (Seoul, Korea).
A total of 24 healthy male Korean volunteers were enrolled. Subjects were
randomized to receive 1 mg of the test or reference formulation, and
pharmacokinetic (PK) parameters were measured. After a 3-week washout period, the
other formulation was administered, and PK parameters were measured again. C(max)
and AUC(last) were determined from blood samples obtained at 0.33, 0.67, 1, 1.5,
2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168, and 216 hours after drug
administration. The formulations were considered bioequivalent if the 90% CIs of
the geometric mean ratios of test-to-reference formulations for AUC(last) and
C(max) were within the bioequivalence limits of 0.8 to 1.25. Nonlinear
mixed-effect modeling and Monte Carlo simulations for both formulations were also
conducted, and the results were used to characterize and compare the PK
properties. Safety profile and tolerability were assessed using measurements of
vital signs, clinical chemistry tests, and interviews.
RESULTS: All enrolled subjects completed the study. A total of 8 adverse events
(AEs) were reported (2 on test formulation, 6 on reference formulation) in 7 of
24 participants. These AEs were headache (n = 1), hordeolum (n = 1), and abnormal
laboratory test values (n = 6). Both formulations were well tolerated, and there
were no serious AEs. Both formulations were best described by a 2-compartment
disposition model with lag phase. The 90% CIs of the geometric mean ratios of
test formulation to reference formulation were 0.96 to 1.08 for C(max) and 0.93
to 1.0 for AUC(last).
CONCLUSION: The test and reference formulations had similar PK parameters and
similar plasma concentration-time profiles. The test formulation of anastrozole
met the Korean regulatory criteria (AUC and C(max)) for assuming bioequivalence.
ClinicalTrials.gov identifier: NCT01105299.
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