Clinical Therapeutics/Volume 31, Number 10, 2009
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 Li Chen, MD1,2; Xuehua Jiang, PhD1; Liang Huang, MD2; Ke Lan, PhD1; Haiying Wang, MD2; Lina Hu, MD2; Jing Ren, PhD1; Xihong Li, PhD2; and Qin Zou, MD2 1Key
Laboratory of Drug Targeting and Novel Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu, China; and 2West China Second University Hospital, Sichuan University, Chengdu, China ABSTRACT Background: Finasteride, an inhibitor of the steroid 5α-reductase, has been approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia. An orally disintegrating tablet (ODT) 5-mg formulation of finasteride was recently developed. Information regarding its pharmacokinetics and bioequivalence was required to assess the efficacy and safety of this formulation before marketing it in China. Objectives: The aims of this study were to compare the bioavailability of finasteride ODTs and standard tablets in healthy adult male Han Chinese volunteers and to determine whether any observed differences exceeded Chinese regulatory guidelines for bioequivalence. Methods: This single-dose, randomized, open-label, 2-way crossover trial was conducted in China. Healthy adult male Han Chinese volunteers were enrolled. Participants were randomly assigned to receive 10 mg of either the ODT or standard tablet formulation, followed by a 1-week washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties, including Cmax, AUC0–24, and AUC0–∞, blood samples were obtained at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 5, 8, 11, 14, and 24 hours after administration. The formulations were to be considered bioequivalent if calculations of the 90% CI for the ratio of the means of the measures for the test and reference formulations fell within bioequivalence limits, 80% to 125%, for logarithmic (log) transformation of Cmax and AUC, and if Schuirmann’s two 1-sided tests showed P < 0.05. Tolerability was assessed using vital sign measurements (ie, blood pressure, body temperature, heart rate, and respiratory rate), laboratory analysis (ie, he2242
matology, blood biochemistry, hepatic function, and urinalysis), and interviews with participants. Results: Twenty-four men (mean [SD] age, 22.0 [1.2] years [range, 20–24 years]; weight, 63.5 [4.6] kg [range, 55–70 kg]; height, 172.8 [4.4] cm [range, 164–180 cm]) were enrolled in this study, and 24 (12 each randomized to receive the ODT or standard tablet first) completed it. No period or sequence effects were observed. The 90% CIs for the log-transformed Cmax, AUC0–24, and AUC0–∞ values were 86.8 to 106.8, 95.1 to 119.1, and 96.2 to 117.5, respectively (all, P < 0.05). The Wilcoxon rank sum test of Tmax found a significant difference between the ODT formulation (mean [SD], 2.40 [0.47] hours) and standard tablet formulation (1.98 [0.63] hours). No adverse events were reported by the volunteers or found in clinical laboratory testing during the study. Conclusions: In this single-dose study, based on the rate and extent of absorption, the ODT (ie, test) and standard tablet (ie, reference) formulations of finasteride met the regulatory criteria for bioequivalence in these fasting healthy adult male Han Chinese volunteers. However, a significant difference was found for Tmax between the test and reference formulations. Both formulations were well tolerated. ClinicalTrials. gov identifier: 2005L02216 (Clin Ther. 2009;31: 2242–2248) © 2009 Excerpta Medica Inc. Key words: bioavailability, bioequivalence, finasteride, human, pharmacokinetics. Accepted for publication June 30, 2009. doi:10.1016/j.clinthera.2009.10.015 0149-2918/$ - see front matter © 2009 Excerpta Medica Inc. All rights reserved.
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INTRODUCTION Finasteride is an inhibitor of the steroid 5α-reductase that has been approved in the United States, Australia, and Europe for the treatment of benign prostatic hyperplasia and androgenetic alopecia.1,2 Its pharmacokinetic properties in healthy white adult volunteers have been reported.3–6 Finasteride is well absorbed after oral administration, and the presence of food has no effect on total bioavailability.5 Finasteride undergoes hepatic metabolism, yielding the essentially inactive metabolites ω-OH finasteride, ω-aldehyde finasteride, and ω-oic acid finasteride, which are excreted in bile and urine.6 The t1/2 was reported to be 4.7 to 7.1 hours or longer in men aged >70 years.5,6 Most men who require treatment for benign prostatic hyperplasia are aged >60 years.7 Orally disintegrating tablets (ODTs) may suit them because of the ease of administration, pleasant taste, and absence of a need to swallow pills.8,9 Therefore, finasteride ODTs were developed to meet the clinical requirements of elderly men with benign prostatic hyperplasia. The present study was conducted to compare the bioavailability of finasteride ODTs* and standard finasteride tablets† in healthy adult male Han Chinese volunteers, and determine whether any observed differences exceeded Chinese regulatory guidelines for bioequivalence.
MATERIALS AND METHODS This single-dose, randomized, open-label, 2-way crossover study was conducted at West China Second University Hospital of Sichuan University, Chengdu, China. The ethics and research committee at Sichuan University approved and registered the clinical study protocol, and the study was conducted in accordance with the principles of the Declaration of Helsinki and its amendments. Finasteride 5-mg ODTs (batch 031204; expiration date: December 1, 2006; 3-year term of validity) and finasteride 5-mg standard tablets (batch 251910; expiration date: March 20, 2007; 3-year term of validity) were used in this study. Both drugs were provided by the manufacturers at no cost.
*Manufactured by Conquer Medicine Company, Ltd. (Chongqing, China). † Trademark: Proscar ® (Merck Sharp & Dohme Pty, Ltd., South Granville, New South Wales, Australia).
Estrone, used as an internal standard for LC-MS analysis of finasteride, was purchased from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). Methanol and ammonium acetate, used for the mobile phase of LC-MS, were purchased from Tedia Company, Inc. (Fairfield, Ohio). Analytical pure ethyl acetate, used as liquid–liquid extraction solvent in sample preparation, was purchased from Fangzhou Chemical Company (Chengdu, China).
Inclusion and Exclusion Criteria This study aimed to evaluate the bioequivalence of the 2 formulations. To reduce the influence of individual factors, so that the dosage form would be the greatest influence on the pharmacokinetic profile of finasteride, the age range of eligible patients was limited. Healthy adult male Han Chinese volunteers (aged 20–24 years) were recruited using printed advertisements; it should be noted that most of the prospective volunteers who responded to the advertisements were aged 20 to 25 years. Eligible participants had no significant cardiac, hepatic, renal, pulmonary, neurologic, gastrointestinal, or hematologic disease, as determined by medical history, physical examination, and laboratory tests (ie, hematology, blood biochemistry, hepatic function, and urinalysis), including HIV and hepatitis B virus surface antigen serology. Inclusion and exclusion criteria met the requirements established in the Chinese guidelines for clinical bioequivalence testing.10 The volunteers were instructed to abstain from using any drug, including over-the-counter and herbal products, for ≥2 weeks before the study began, and during the study period; they were also asked to abstain from smoking and from the use of alcohol- and caffeine-containing food and beverages for ≥48 hours before the study period.
Study Design and Drug Administration This study included 2 treatment periods separated by a 1-week washout period, which was >7 times the t1/2 of 4.7 to 7.1 hours. Participants arrived at the study site the day before the beginning of the trial. A table of random numbers, generated by SPSS version 10.0 (SPSS Inc., Chicago, Illinois), was used to assign subjects in a 1:1 ratio (groups A and B) to receive a single 10-mg oral dose of finasteride ODT (2 ODTs placed on the tongue and swallowed after disintegration in the saliva for group A) or standard tablet (2 tablets given 2243
Clinical Therapeutics with 250 mL of water for group B). When ODT was administered, oral sensations and the time for the entire tablet to disintegrate in the mouth were reported by volunteers and recorded by investigators. A 1-week washout period followed administration of the initial formulation, after which the alternate formulation was administered in a similar fashion. Participants were not permitted to eat or drink anything other than water for 12 hours before study drug administration. The dietary, smoking, and drug/ herbal product restrictions were continued throughout the testing period.
Blood Sampling and Assay Methods After the 12-hour overnight fast and before drug administration, a catheter (BD Autoguard Shielded IV, Becton, Dickinson and Company, Franklin Lakes, New Jersey) was placed in a suitable forearm vein and a 4-mL blood sample was drawn into a heparinized tube (Vacutainer, Becton, Dickinson and Company). Additional blood samples (4 mL) were drawn at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 5, 8, 11, 14, and 24 hours after study drug administration. The space in the catheter used was smaller than the volume of the samples11; therefore, catheter flushing and discards were not part of the study protocol. It was determined that the duration of sampling would have to be at least as long as the t1/2 range. Immediately after collection, blood samples were centrifuged (model EBA21, Hettich Laboratories AG, Hettich, Germany) at 1500gg for 10 minutes at room temperature (20°C), and plasma was separated and stored at –80°C in coded polypropylene tubes (Haimen Company, Jiangsu, China). After the end of the washout period, the participants returned to the study site, where the alternate formulation was administered, and samples were drawn and analyzed as before.
Determination of Plasma Finasteride Concentrations Plasma finasteride concentrations were determined without group and period masking using the LC-MS method coupled with liquid–liquid extraction by acetic ether developed in our laboratory.12 The method was found to have a linear range of 0.5 to 200 ng/mL and an r value of 0.9990 or better. Inaccuracy was <9.1% and imprecision was <5.9% at all tested concentrations. The extraction recovery and standard deviation were 60.1% to 65.4% for finasteride and 2244
79.1% for the internal standard. The analyte was stable in human plasma following 3 freeze–thaw cycles, for 24 hours in room temperature, for up to 8 weeks following storage at –80°C, and for 24 hours after being processed. The method was validated as recommended by the Chinese guidelines on clinical bioequivalence testing.10
Tolerability Assessment Tolerability assessments included subject interviews and adverse-event monitoring (especially about breast discomfort and exanthema, which are the most commonly reported adverse events with finasteride, as described in the manufacturer instructions for standard finasteride8), clinical laboratory testing (ie, hematology, blood biochemistry, hepatic function, and urinalysis), electrocardiogram findings, and vital sign measurements (including axillary temperature, respiratory rate, heart rate, and seated blood pressure with a sphygmomanometer [HEM7000, Omron Company Ltd., Osaka, Japan]) during the study period, without group masking, by one of the investigators (X.L.), who was the physician in charge at the clinical care units in West China Second University Hospital. Laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) were performed at baseline and after completion of the study.
Pharmacokinetic and Statistical Analyses Using a power analysis (expected value, ≥1 – β = 0.8), it was determined that the power of the ANOVA was >0.8 with a 90% CI, according to US and Chinese guidelines for bioequivalence testing,10,13 indicating that 24 subjects would be sufficient for the purposes of the study. Cmax and Tmax were determined using visual inspection of the finasteride plasma concentration– time data from individual volunteers. The AUC was calculated using noncompartmental analysis to the final measurable sample (AUC0–24) using the linearlog trapezoidal method. The linear trapezoidal rule was used until Cmax was reached, and the logarithmic trapezoidal rule was used thereafter.14 AUC0–∞ was calculated as the sum of AUC0–24 and C24/ke, where C24 represented the last measurable concentration, ke was estimated from the terminal log decay phase using linear regression, and t1/2 was estimated as 0.693/ke. After logarithmic transformation of the data, Cmax, AUC0–24, and AUC0–∞ values were subjected to ANOVA Volume 31 Number 10
L. Chen et al. for a 2 × 2 crossover design to assess effects due to periods, formulation, and sequence using an F test; P < 0.05 was considered to be significant. The logtransformed pharmacokinetic parameters were examined using the two 1-sided t tests described by Schuirmann,15 in which P < 0.05 was the benchmark for acceptance of bioequivalence. Mean ratios for test/ reference values for Cmax, AUC0–24, and AUC0–∞ were calculated. The formulations were to be considered bioequivalent if calculations of a 90% CI for the ratio of the means of the measures for the test and reference formulations fell within bioequivalence limits (80%– 125%) for logarithmic transformation of Cmax and AUC. The Wilcoxon rank sum test was used to determine statistically significant differences in Tmax. This was the definition according to the US Food and Drug Administration,13 as well as Chinese regulations.10 All pharmacokinetic and statistical analyses were performed using DAS version 2.0 (Drug and Statistics, Anhui, China).
Table I. The figure shows the mean finasteride concentration–time profiles after administration of the 2 formulations. Table II shows the 90% CIs of the ratios (ODTs/ standard tablets) for the log-transformed Cmax (as an index of rate of absorption), AUC0–24, and AUC0–∞ (as an index of extent of absorption); the probability of exceeding the limits of acceptance for bioavailability (Schuirmann’s two 1-sided tests); and the power of the test. The 90% CIs for the log-transformed Cmax, AUC0–24, and AUC0–∞ values were 86.8 to 106.8, 95.1 to 119.1, and 96.2 to 117.5, respectively (all, P < 0.05), meeting the predetermined criteria for bioequivalence. The mean relative bioavailabilities (test/ reference) for Cmax, AUC0–24, and AUC0–∞ were 96.8%, 107.1%, and 107.3%, respectively. Similar results were found for these data without log transformation. The Wilcoxon rank sum test of Tmax found a significant difference between the ODT formulation and the standard tablet formulation (P < 0.021).
RESULTS Twenty-four men (mean [SD] age, 22.0 [1.2] years [range, 20–24 years]; weight, 63.5 [4.6] kg [range, 55–70 kg]; height, 172.8 [4.4] cm [range, 164–180 cm]) were enrolled in this study, and 24 completed it (12 each randomized to receive the test or reference formulation first). The mean (SD) age of group A (ODT, then standard tablets) was 22.3 (1.1) years; in group B (standard tablets, then ODT), it was 21.8 (1.2) years. Weight and body mass index were also similar between groups: 64.2 (5.1) kg and 21.5 (1.0) kg/m2 in group A and 62.8 (4.3) kg and 21.1 (0.9) kg/m2 in group B, respectively. A washout period of 7 days was adequate for total elimination of finasteride between the 2 administration periods. The mean disintegration time in the mouth was 29 (10) seconds.
Pharmacokinetic Properties The mean (SD) Cmax with the ODT formulation was 87.9 (14.7) ng/mL, and the Tmax was 2.40 (0.47) hours. With the standard tablets, the corresponding values were 93.1 (15.9) ng/mL and 1.98 (0.63) hours, respectively. The terminal t1/2 values with the ODT and standard tablet formulations were 7.45 (1.32) and 7.15 (1.37) hours, respectively. In the ANOVA, no period or sequence effects were observed for any pharmacokinetic property. The pharmacokinetic parameters of the 2 formulations are summarized in October 2009
Tolerability All volunteers reported a pleasant taste and mouth feel after being given the ODT formulation. No adverse events were found on clinical or laboratory testing or reported by the participants.
DISCUSSION In this open-label study, a single 10-mg dose of finasteride 5-mg ODTs was found to meet the regulatory requirements for assuming bioequivalence; however, regulatory bioequivalence does not prove clinical equivalence. The test dose of the present study (10 mg) was twice the daily dose recommended for the treatment of benign prostatic hyperplasia (5 mg/d),8 and 10 times the daily dose recommended for androgenetic alopecia (1 mg/d).16 The test dose was well tolerated, supporting the findings of previously reported trials and the manufacturer’s instructions for the reference formulation (ie, the standard tablets).7 Theoretically, ODTs ought to have a faster absorption rate than standard tablets because of the rapid rates of disintegration and stomach emptying. However, the mean Tmax value with the ODT formulation in the present study was numerically higher than and statistically different from that observed with the reference formulation (2.40 vs 1.98 hours; P = 0.020). A slow dissolu2245
Table I. Pharmacokinetic properties of finasteride 5-mg oral disintegrating tablet (ODT) and reference fomulation after a single 10-mg administration in healthy adult male Chinese volunteers (N = 24). All values are mean (SD). Variable
Group A = 2 finasteride 5-mg ODTs (manufactured by Conquer Medicine Company, Ltd., Chongqing, China) in the first period, then 2 finasteride 5-mg standard tablets (trademark: Proscar ®, Merck Sharp & Dohme Pty, Ltd., South Granville, New South Wales, Australia) in the second period; group B = 2 finasteride 5-mg standard tablets in the first period, then 2 finasteride 5-mg ODTs in the second period.
ODT Standard tablet
Plasma Finasteride Concentration (ng/mL)
100 90 80 70 60 50 40 30 20 10 0 0
Time After Administration (h) Figure. Mean (SD) plasma concentration–time profiles after administration of a single 10-mg oral dose of 2 formulations of finasteride 5-mg tablets to 24 healthy male adult Han Chinese volunteers. The limit of quantification was 0.5 ng/mL. ODT = oral disintegrating tablet (manufactured by Conquer Medicine Company, Ltd., Chongqing, China); standard tablet = Proscar ® (trademark of Merck Sharp & Dohme Pty, Ltd., South Granville, New South Wales, Australia).
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Table II. Comparison of 90% CIs for logarithmically transformed Cmax, AUC0–24, and AUC0–∞ of finasteride 5-mg oral disintegrating tablet (ODT) formulation,* and standard finasteride tablet formulation,† after administration of a single 10-mg oral dose in 24 healthy adult male Han Chinese volunteers. Probability of exceeding the limits of acceptance for bioavailability (80%–125%) and power of the study are also shown.
Parameter Cmax AUC0–24 AUC0–∞
Ratio of ODT to Standard Tablet, Mean (SD), %
P < 80%
P > 125%
96.8 (23.7) 107.1 (28.4) 107.3 (24.9)
86.8–106.8 95.1–119.1 96.2–117.5
<0.001 <0.001 <0.001
<0.001 <0.001 <0.001
0.99 0.99 0.99
Schuirmann’s Two 1-Sided Tests
*Manufactured by Conquer Medicine Company, Ltd. (Chongqing, China). † Trademark: Proscar ® (Merck Sharp & Dohme Pty, Ltd., South Granville, New South Wales, Australia).
tion rate of finasteride from the granules of ODTs might explain this difference, at least in part. This pharmacokinetic study was limited by its single-dose design, small sample size, inclusion of only healthy males, and use of subjects who were fasting. Moreover, the participants were all young (mean age, 22.0 years [range, 20–24 years]). The mean terminal t1/2 values of the ODT formulation (7.45 hours) and reference formulation (7.15 hours) were numerically higher than the 6-hour t1/2 reported in previous studies of the standard tablets among Western subjects.7 It has been reported previously that cytochrome P450 3A4 and cytochrome P450 2C19 (CYP2C19) are responsible for the oxidative metabolism of finasteride.17,18 The incidence of poor metabolizer phenotype for CYP2C19 varies significantly in different populations.19 In the Han Chinese population, the frequency of CYP2C19 poor metabolizers is 19.8%.20 However, the proportion of CYP2C19 poor metabolizers enrolled in the present study was higher than that observed in the general population, which may have contributed to the apparent difference in terminal t1/2. Moreover, CYP2C19 gene polymorphisms among the enrolled subjects were not tested. Therefore, the study results should not be extrapolated to other populations, such as older people. Further study would be necessary to determine whether CYP2C19 metabolizer status was responsible for the difference noted in the pharmacokinetic profiles of populations similar to our study sample. October 2009
CONCLUSIONS This single-dose study found that the ODT and standard tablet formulations of finasteride met the regulatory criteria for bioequivalence in these fasting healthy adult male Han Chinese volunteers. However, a significant difference was found for the Tmax between the test and reference formulations. Both formulations were well tolerated.
ACKNOWLEDGMENTS The authors would like to thank the sponsor (Conquer Medicine Company, Ltd., Chongqing, China) for providing the financial support, the test formulation of finasteride, and the finasteride reference standards used in this research. The sponsor had no role in the design, conduct, analysis, or publication of the results. The authors have indicated that they have no conflicts of interest regarding the content of this article.
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14. US Food and Drug Administration. In vivo bioequivalence guidances. Pharmacopeial Forum. 1993;19:6501– 6508. 15. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;15:657–680. 16. Propecia (finasteride) 1 mg [package insert]. http://www.merck. com/product/usa/pi_circulars/p/ propecia/propecia_pi.pdf. Accessed September 18, 2009. 17. Huskey SW, Dean DC, Miller RR, et al. Identification of human cytochrome P450 isozymes responsible for the in vitro oxidative metabolism of finasteride [published cor-
rection appears in Drug Metab Dispos. 1996;24695]. Drug Metab Dispos. 1995;23:1126–1135. 18. Yasumori T, Narita H, Matsuda T, et al. Finasteride 1 mg has no inhibitory effect on omeprazole metabolism in extensive and poor metabolizers for CYP2C19 in Japanese. Eur J Clin Pharmacol. 2006;62:939–946. 19. Wedlund PJ. The CYP2C19 enzyme polymorphism. Pharmacology. 2000; 61:174–183. 20. Xiao ZS, Goldstein JA, Xie HG, et al. Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele. J Pharmacol Exp Ther. 1997;281:604–609.
Address correspondence to: Ke Lan, PhD, West China School of Pharmacy, Sichuan University, No. 17, 3rd Section, RenminNanLu, Chengdu 610041, China. E-mail: [email protected]
, [email protected]
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