Pharmacokinetic Comparison of 2 Formulations of Anastrozole (1 mg) in Healthy Korean Male Volunteers: A Randomized, Single-Dose, 2-Period, 2-Sequence, Crossover Study

Noh, Yook-Hwan; Ko, Young-Ju; Cho, Sang-Heon; Ghim, Jong-Lyul; Choe, Sangmin; Jung, Jin Ah; Kim, Un-Jib; Jin, Seok-Joon; Park, Hyun-Jung; Song, Geun-Seog; Lim, Hyeong-Seok; Bae, Kyun-Seop

doi:10.1016/j.clinthera.2012.01.008

« Previous Next »Clinical Therapeutics
Volume 34, Issue 2 , Pages 305-313, February 2012

Pharmacokinetic Comparison of 2 Formulations of Anastrozole (1 mg) in Healthy Korean Male Volunteers: A Randomized, Single-Dose, 2-Period, 2-Sequence, Crossover Study

Yook-Hwan Noh, MD
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea
Young-Ju Ko, MD
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea
Sang-Heon Cho, MD, PhD
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea
Jong-Lyul Ghim, MD, PhD
- Department of Clinical Pharmacology, Busan Paik Hospital, Busan, Korea
Sangmin Choe, MD, PhD
- Clinical Trials Center, Pusan National University Hospital, Busan, Korea
Jin Ah Jung, MD, PhD
- Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Korea
Un-Jib Kim, MD
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea
Seok-Joon Jin, MD
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea
Hyun-Jung Park
- Clinical Trial Center, Asan Medical Center, Seoul, Korea
Geun-Seog Song, PhD
- Regulatory and Clinical Development Division, Pharmaceutical BU, CJ Cheiljedang Co., Ltd., Seoul, Korea
Hyeong-Seok Lim, MD, PhD
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea
- Address correspondence to: Hyeong-Seok Lim, MD, PhD, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Korea, 138-736
Kyun-Seop Bae, MD, PhD
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea

Accepted 3 January 2012. published online 27 January 2012.

Abstract

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.

Key words: anastrozole , bioequivalence , formulation , nonlinear mixed-effect modeling , pharmacokinetic properties , simulation