Evaluation of bioequivalence of five 0.1 mg dutasteride capsules compared to one 0.5 mg dutasteride capsule: a randomized study in healthy male volunteers

Michael J Fossler, David A Collins, Hiroko Ino, Nobuaki Sarai, Ramiya Ravindranath, Chester L Bowen, Olivia Burns, Michael J Fossler, David A Collins, Hiroko Ino, Nobuaki Sarai, Ramiya Ravindranath, Chester L Bowen, Olivia Burns

Abstract

Objective: To evaluate the bioequivalence of five 0.1 mg dutasteride capsules to one 0.5 mg dutasteride capsule in healthy adult male subjects under fasting conditions.

Methods: This was a single-center, open-label, randomized, single dose, two-way cross-over study (ClinicalTrials.gov identifier NCT01929330). Thirty-six healthy male subjects aged 18-65 years received 5 × 0.1 mg dutasteride softgel capsules and 1 × 0.5 mg dutasteride softgel capsule in a randomized order, with a minimum washout of 28 days between each drug administration. Serial blood samples were collected for the measurement of serum dutasteride concentrations by a validated HPLC-MS/MS method. Dutasteride pharmacokinetic parameters were calculated using non-compartmental analysis. Maximum concentration (Cmax) and area under the concentration-time curve to the last quantifiable concentration (AUC[0-t]) were compared between treatments. Safety and tolerability were monitored throughout the study.

Results: Five 0.1 mg dutasteride capsules were demonstrated to be bioequivalent to 1 × 0.5 mg dutasteride capsule, as the 90% confidence intervals for Cmax and AUC were within the accepted bioequivalence range of 0.80-1.25. The geometric least squares means ratios and associated 90% confidence intervals for 5 × 0.1 mg capsules vs 1 × 0.5 mg capsule were 1.01 (0.97-1.05) for Cmax and 0.91 (0.84-1.00) for AUC(0-t). Adverse events (AEs) were reported for 42% (15/36) and 36% (12/33) of subjects in the 5 × 0.1 mg and 1 × 0.5 mg dosing sessions, respectively. The most frequent AE for both treatments was headache. No subject had a serious AE.

Conclusions: Five 0.1 mg dutasteride capsules were shown to be bioequivalent to one 0.5 mg dutasteride capsule in healthy adult male subjects under fasted conditions, suggesting that the two dose strengths can be interchanged. Both treatments were generally well tolerated in healthy male subjects.

Keywords: Bioequivalence; Clinical trial; Dutasteride; Male; Pharmacokinetics.

Figures

Figure 1.
Figure 1.
Flow of participants through the study. Reference = 1 × 0.5 mg dutasteride capsule. Test = 5 × 0.1 mg dutasteride capsules. *The three withdrawn subjects each received the test formulation in Treatment period 1.
Figure 2.
Figure 2.
Mean serum dutasteride concentration by planned relative time. (a) Reference = 1 × 0.5 mg dutasteride capsule. (b) Test = 5 × 0.1 mg capsules. The circles represent the mean plasma concentration at each time point. The grey shaded area represents ± 1 SD around the mean. The lower limit of quantification was 25.0 pg/mL.

References

    1. Kaufman KD. Androgen metabolism as it affects hair growth in androgenetic alopecia. Dermatol Clin 1996;14:697–711
    1. Sinclair R. Male pattern androgenetic alopecia. BMJ 1998;317:865–9
    1. Olsen EA. Androgenetic alopecia. In: Olsen EA, ed. Disorders of hair growth: diagnosis and treatment. New York, NY: McGraw-Hill, 1994. pp 257–83
    1. Jenkins EP, Andersson S, Imperato-McGinley J, et al. . Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase. J Clin Invest 1992;89:293–300
    1. Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem 1994;63:25–61
    1. Sawaya ME, Price VH. Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia. J Invest Dermatol 1997;109:296--300
    1. Thigpen AE, Silver RI, Guileyardo JM, et al. . Tissue distribution and ontogeny of steroid 5 alphareductase isozyme expression. J Clin Invest 1993;92:903–10
    1. Frye SV. Discovery and clinical development of dutasteride, a potent dual 5alpha-reductase inhibitor. Curr Top Med Chem 2006;6:405–21
    1. Wu C, Kapoor A. Dutasteride for the treatment of benign prostatic hyperplasia. Expert Opin Pharmacother 2013;14:1399–408
    1. Olsen EA, Hordinsky M, Whiting D, et al. . The importance of dual 5α-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol 2006;55:1014–23
    1. Eun HC, Kwon OS, Yeon JH, et al. . Efficacy, safety, and tolerability of dutasteride 0.5 mg once daily in male patients with male pattern hair loss: a randomized, double-blind, placebo-controlled, phase III study. J Am Acad Dermatol 2010;63:252–8
    1. Gubelin Harcha W, Barboza Martínez J, Tsai TF, et al. . A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia. J Am Acad Dermatol 2014;70:489–98
    1. AVODART® (dutasteride) Soft Gelatin Capsules. Prescribing Information. GlaxoSmithKline, The GSK group of companies, 2014. . Accessed July 13, 2015
    1. Andriole GL, Kirby R. Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol 2003;44:82–8

Source: PubMed

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