Pharmacokinetic analysis and bioequivalence of Finasteride and Doxazosin formulated in a single tablet in comparison with the corresponding single agents
DOI:
https://doi.org/10.34119/bjhrv6n2-023Keywords:
Doxazosin, Finasteride, pharmacokinetics, benign prostatic hyperplasia, therapeutic equivalence, bioequivalenceAbstract
The most commonly agents used to treat benign prostatic hyperplasia (BPH) in clinical practice are finasteride and doxazosin employed alone or in combination. Randomized clinical trials have shown that combination therapy with finasteride and doxazosin is superior to finasteride alone or placebo. However, decreased patient compliance may lead to unsatisfactorily therapeutic results. The aim of this study was to assess whether the combined pharmacokinetic profile for both finasteride and doxazosin was not significantly altered when these agents were co-administered, in comparison with their use as single agents. This was a randomized 6 sequences and 3 periods, crossover, comparative study of three medications: finasteride (5 mg), doxazosin (2 mg) (references), and the fixed combination containing 5 mg of finasteride and 2 mg of doxazosin in a single tablet (test). Plasma samples obtained from 30 eligible subjects were analyzed simultaneously for finasteride and doxazosin by HPLC coupled to a LC-MS/MS having cyproterone acetate and terazosin as internal standards. The statistical analysis showed no significant differences for AUC0-72h (finasteride: 245.3±87.8 vs. test: 240.5±93.1 and doxazosin: 183.0±42.9 vs. test: 188.8±45.6 ng.h.mL-1), AUC0-∞ (finasteride: 247.4±92.1 vs. test: 40.47±93.1 and doxazosin: 190.3±44.3 vs. test: 188.8±45.6 ng.h.mL-1), and Cmax (finasteride: 34.2±7.1 vs. test: 29.9±6.2 and doxazosin: 16.3±3.6 vs. test: 14.9±3.3 ng/mL). The mean ratios of AUC0-72h/AUC0-∞ for finasteride and doxazosin were 99.99% and 99.98%, respectively, indicating that the sampling time was adequate for both drugs. In summary, the current pharmacokinetic study demonstrated bioequivalence between the single agents and the corresponding agents in combination and provided further evidence for the lack of pharmacokinetic interaction between finasteride and doxazosin.
References
Thorpe A, Neal D. Benign prostatic hyperplasia. Lancet. 2003;361(9366):1359-67.
Naslund MJ, Miner M. A review of the clinical efficacy and safety of 5alpha-reductase inhibitors for the enlarged prostate. Clin Ther. 2007;29(1):17-25.
O'Leary MP. Lower urinary tract symptoms/benign prostatic hyperplasia: maintaining symptom control and reducing complications. Urology. 2003;62(3 Suppl 1):15-23.
Tacklind J, Fink HA, Macdonald R, Rutks I, Wilt TJ. Finasteride for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2010(10):CD006015.
MacDonald R, Wilt TJ, Howe RW. Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects. BJU Int. 2004;94(9):1263-70.
McVary KT. A review of combination therapy in patients with benign prostatic hyperplasia. Clin Ther. 2007;29(3):387-98.
Bautista OM, Kusek JW, Nyberg LM, McConnell JD, Bain RP, et al. Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial. Control Clin Trials. 2003;24(2):224-43.
Nichol MB, Knight TK, Wu J, Barron R, Penson DF. Evaluating use patterns of and adherence to medications for benign prostatic hyperplasia. J Urol. 2009;181(5):2214-21; discussion 21-2.
Al-Dirbashi OY, Aboul-Enein HY, Jacob M, Al-Qahtani K, Rashed MS. UPLC-MS/MS determination of doxazosine in human plasma. Anal Bioanal Chem. 2006;385(8):1439-43.
Phapale PB, Lee HW, Lim MS, Kim EH, Kim SD, et al. Rapid determination of finasteride in human plasma by UPLC-MS/MS and its application to clinical pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878(20):1718-23.
Chen L, Jiang X, Huang L, Lan K, Wang H, et al. Bioequivalence of a single 10-mg dose of finasteride 5-mg oral disintegrating tablets and standard tablets in healthy adult male Han Chinese volunteers: a randomized sequence, open-label, two-way crossover study. Clin Ther. 2009;31(10):2242-8.
Chytil L, Strauch B, Cvacka J, Maresova V, Widimsky J, Jr., et al. Determination of doxazosin and verapamil in human serum by fast LC-MS/MS: application to document non-compliance of patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878(30):3167-73.
Erceg M, Cindric M, Pozaic Frketic L, Vertzoni M, Cetina-Cizmek B, et al. A LC-MS-MS method for determination of low doxazosin concentrations in plasma after oral administration to dogs. J Chromatogr Sci. 2010;48(2):114-9.
RESOLUÇÃO-RE nº 1.170, DE 19 DE ABRIL DE 2006, (2006).
RESOLUÇÃO-RE Nº 899, DE 29 DE MAIO DE 2003, (2003).
Vashi V, Chung M, Hilbert J, Lawrence V, Phillips K. Pharmacokinetic interaction between finasteride and terazosin, but not finasteride and doxazosin. J Clin Pharmacol. 1998;38(11):1072-6.
Chung M, Vashi V, Puente J, Sweeney M, Meredith P. Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation. Br J Clin Pharmacol. 1999;48(5):678-87.
de Menezes FG, Ribeiro W, Ifa DR, de Moraes ME, de Moraes MO, et al. Bioequivalence study of finasteride. Determination in human plasma by high-pressure liquid chromatography coupled to tandem mass spectrometry. Arzneimittelforschung. 2001;51(2):145-50.
Barry MJ, Fowler FJ, Jr., O'Leary MP, Bruskewitz RC, Holtgrewe HL, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 1992;148(5):1549-57; discussion 64.
Barry MJ, Williford WO, Fowler FJ, Jr., Jones KM, Lepor H. Filling and voiding symptoms in the American Urological Association symptom index: the value of their distinction in a Veterans Affairs randomized trial of medical therapy in men with a clinical diagnosis of benign prostatic hyperplasia. J Urol. 2000;164(5):1559-64.
Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CM, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med. 1996;335(8):533-9.
Kirby RS, Roehrborn C, Boyle P, Bartsch G, Jardin A, et al. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology. 2003;61(1):119-26.
Kane SV. Systematic review: adherence issues in the treatment of ulcerative colitis. Aliment Pharmacol Ther. 2006;23(5):577-85.
