Bioequivalence Assessment of an Oral Fixed-Dose Formulation of Dutasteride-Tamsulosin 0.5 mg/0.4 mg: A Randomized, Single-Blind, Single-Dose, 2-Period Crossover Study in Mexican Population Under Fasted Conditions.

The aim of the present study was to compare the bioavailability and to demonstrate the bioequivalence between a dutasteride-tamsulosin 0.5 mg/0.4 mg capsule formulation and the regulatory reference drug (Combodart®, GlaxoSmithKline). A randomized, single-blind, single-dose, 2-way crossover study under fasting conditions, with at least a 28-day washout period was carried out in healthy volunteers. Plasma concentrations of drugs were determined by high-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic analysis included maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC) from time 0 to 72 hours, and AUC from baseline to infinity. The test formulation was considered bioequivalent if the geometric mean ratios (test/reference) were within the predetermined range of 80% to 125%. Safety and tolerability were evaluated by clinical assessment. The confidence intervals for the log-transformed test/reference ratios for dutasteride, Cmax (95.4-109.2) and AUC from baseline to 72 hours (93.2-109.1), and for tamsulosin, Cmax (101.9-119.8), AUC from baseline to the last quantifiable concentration (91.4-106.3) and AUC from baseline to infinity (90.9-103.3), were within the allowed limit specified by the regulatory authorities (80%-125%). In addition, both test and reference drugs were safe and tolerated. These results demonstrated the bioequivalence of test product (Dakart®) compared with Combodart®.

Impact of dutasteride on spermatogenesis and oxidative status in rats / Impacto de dutasteride en la espematogénesis y el estrés oxidativo en ratas

OBJECTIVES: Although the association between 5 alpha reductase inhibitors used for the treatment of both androgenetic alopecia and benign prostatic hyperplasia and their side effects is well established, the impact of dutasteride on testicular structure is not clear. To evaluate the alterations in spermatogenesis and serum FSH, LH, testosterone and dihydrotestosterone concentrations along with the oxidative status in testes and blood of the rats treated with daily dutasteride. METHODS: A total of 18 male Sprague-Dawley rats have been divided into 2 groups as control (n=8) and dutasteride (n=10). After chronically administered, rats were sacrificed and their testes were harvested for histopathological and biochemical evaluation. Johnsen's criteria were used to assess spermatogenesis. Serum hormone concentrations and levels of reactive oxygen species (ROS) in both testicular tissue and serum were measured by ECLIA and ELISA, respectively. Results were compared with Mann- Whitney U test. RESULTS: DHT (7.35 ± 0.35 vs. 10.54 ± 0.95, p < 0.001) and LH levels (0.32 ± 0.009 vs. 0.43 ± 0.01, <0.001) were significantly lower in treatment group compared with controls whereas testosterone levels were higher in dutasteride arm (3.41 ± 1.12 vs. 1.52 ± 0.34, p < 0.001). Johnsen score, serum FSH levels, serum and tissue ROS levels were similar between the two groups. CONCLUSIONS: According to our results, administration of dutasteride does not appear to modify spermatogenesis and oxidative burden in rats. Further investigations are required to confirm our findings

OBJETIVOS: Aunque la asociación entre los inhibidores de la 5'alfa reductasa y el tratamiento de la alopecia y de la hiperplasia benigna de próstata esta bien establecido, el impacto de dutasteride en la estructura testicular no esta claro. El objetivo de este trabajo es evaluar las alteraciones en la espermatogénesis y concentraciones de FSH, LH, testosterona y dihidrotestosterona junto con el estado oxidativo del testículo y en sangre de ratas con la administración diaria dedutasteride. MÉTODOS: Un total de 18 ratas Sprague Dawle fueron divididas en 2 grupos: control (n = 8) y dutasteride (n = 10). Después de una administración crónica de dutasteride, las ratas fueron sacrificadas y los testículos se analizaron del punto de vista anatomopatológico y bioquímico. Los criterios de Johnsen fueron utilizados para valorar la espermatogénesis. Los niveles séricos hormonales y de especias reactivas del oxigeno en el tejido testicular y serum fueron medidos con ECLIA y ELISA respectivamente. Los resultados se compararon con Test Mann-Whitney. RESULTADOS: Los niveles de DHT (7,35 ± 0,35 vs. 10,54 ± 0,95, p < 0,001) y LH (0,32 ± 0,009 vs. 0,43 ± 0,01, < 0,001) fueron significativamente menores en el grupo tratamiento en comparación con los controles, mientras que los niveles de testosterona fueron mas elevados en el brazo de dutasteride (3,41 ± 1,12 vs. 1,52 ± 0,34, p < 0,001). El score de Johansen los niveles séricos de FSH y de ROS fueron similares entre ambos grupos. CONCLUSIONES: De acuerdo con nuestros resultados, la administración de dutasterida no parece modificar la espermatogénesis y la carga oxidativa en ratas. Mas investigaciones son necesarias para confirmar nuestros hallazgos

Pharmacokinetic Study of a Soft Gelatin Capsule and a Solid-Supersaturatable SMEDDS Tablet of Dutasteride in Beagle Dogs.

BACKGROUND AND OBJECTIVE: Dutasteride, an analog of testosterone, a 5α-reductase inhibitor is widely used in the treatment of moderate to severe symptomatic benign prostatic hyperplasia. The aim of this study was to compare the pharmacokinetic characteristics of dutasteride in beagle dogs after oral administration of a conventional soft gelatin capsule (Avodart®) and a novel solid-supersaturatable soft-microemulsifying drug delivery system (SMEDDS) tablet. METHODS: In this comparative dissolution study, the dissolution of dutasteride was pH-independent for both formulations. Noncompartmental analysis and modeling approaches were carried out to determine the pharmacokinetic parameters of dutasteride. RESULTS: Approximately 90% of the drug dissolved in all media within 15 min, indicating that there was little difference in the dissolution rate of the solid-supersaturatable SMEDDS tablets and that of the commercial soft gelatin capsules. Using t test analysis, no statistically significant difference was detected in the pharmacokinetic parameters of the two formulations. The test/reference geometric mean ratios were 1.087 (90% confidence intervals 0.8529-1.3854) for the area under the plasma concentration versus time curve from 0 to the last time point (48 h) with a measurable concentration and 1.094 (90% confidence intervals 0.8909-1.3454) for maximum plasma concentration. Unfortunately, the bioequivalent criterium (0.8-1.25) was not met due to the small sample size, but the results of this study suggest a possible bioequivalence of dutasteride in the two formulations. CONCLUSION: Based on the results of this study, the development of a tablet dosage form of dutasteride using a solid-supersaturatable SMEDDS should be considered for humans.

Solid dispersion of dutasteride using the solvent evaporation method: Approaches to improve dissolution rate and oral bioavailability in rats.

The aim of this study was to develop a dutasteride (DUT) solid dispersion (SD) using hydrophilic substances to enhance its dissolution (%) and oral bioavailability in rats. DUT-SD formulations were prepared with various co-polymers using a solvent evaporation method. The physical properties of DUT-SD formulations were confirmed using field emission scanning electron microscopy (FE-SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and attenuated total reflectance Fourier transform infrared (ATR-FT-IR) spectroscopy. The toxicity and oral bioavailability of DUT-SD formulations were evaluated. Tocopheryl polyethylene glycol-1000-succinate (TPGS) was chosen as the solubilizer; and methylene chloride, and Aerosil® 200 or microcrystalline cellulose (MCC) were chosen as the solvent and carrier, respectively, based on a solubility test and pre-dissolution study. The dissolution levels of DUT-SD formulations were 86.3 ±â€¯2.3% (F15) and 95.1 ±â€¯1.9% (F16) after 1 h, which were higher than those of the commercial product, i.e., Avodart® (75.8 ±â€¯1.5%) in 0.1 N HCl containing 1% (w/v) sodium lauryl sulfate (SLS). The F16 formulation was found to be stable, after assessing its dissolution (%) and drug content (%) for 6 months. The DUT-SD formulations resulted in relative bioavailability (BA) values of 126.4% (F15) and 132.1% (F16), which were enhanced compared to that of Avodart®. Dissolution (%) and relative BA values were both increased by hydrogen interaction between TPGS and DUT. This study might contribute to a new formulation (powder) whose oral bioavailability is greater than that of Avodart® (soft capsule), which could facilitate to the use of the SD system during the production process.

Relative Bioavailability of Fixed-Dose Combinations of Tamsulosin and Dutasteride: Results From 2 Randomized Trials in Healthy Male Volunteers.

The relative bioavailabilities of dutasteride/tamsulosin hydrochloride 0.5 mg/0.2 mg fixed-dose combination (FDC) capsules compared with coadministered reference products (1 dutasteride 0.5-mg capsule [Avodart® ] + 1 tamsulosin hydrochloride 0.2-mg orally disintegrating tablet [Harnal D® ]) were investigated in 2 clinical trials under fasted and fed conditions (ClinicalTrials.gov NCT02184585 and NCT02509104). Both trials were open-label, randomized, single-dose, crossover studies in healthy male adults aged 18-65 years. Trial 1 evaluated 2 formulations (FDC1 and FDC2), and trial 2 evaluated a third formulation (FDC3). The primary end points were dutasteride area under the concentration-time curve from time 0 to t (AUC(0-t) ) and peak plasma concentration (Cmax ) and tamsulosin AUC(0-∞) , AUC(0-t) , and Cmax . The formulations were considered to be bioequivalent if the 90%CIs for the geometric mean ratios for each end point were within the range of 0.80-1.25. For FDC1 in trial 1, bioequivalence criteria were not met for dutasteride Cmax or AUC in the fasted state or for tamsulosin Cmax in the fasted or fed states. For FDC2 in trial 1, all bioequivalence criteria were met except for tamsulosin Cmax in the fasted state. For FDC3 in trial 2, bioequivalence criteria were met for all dutasteride and tamsulosin end points in both the fed and fasted states. Safety profiles were similar for all FDC formulations and combination treatments.

Dutasteride in Androgenetic Alopecia: An Update.

BACKGROUND: Androgenetic alopecia is a common condition characterized by thinning of scalp hair. Conversion of testosterone to dihydrotestosterone, a more potent androgen, by the enzyme 5-α-reductase is responsible for underlying pathogenesis. Dutasteride, a synthetic 4-azasteroid, is a selective and competitive inhibitor of both type-1 and type-2 isoenzymes of 5-α-reductase. Finasteride and minoxidil are the only approved drugs for androgenetic alopecia. Dutasteride has been demonstrated to be effective in several randomized, double-blind, placebo controlled trials in androgenetic alopecia. In this review, after the pharmacology of dutasteride, the authors have discussed the status of dutasteride in androgenetic alopecia and have compared its efficacy with that of finasteride. OBJECTIVE: This article aims to review the current status of dutasteride in androgenetic alopecia. The structure, mechanism of action, pharmacokinetics and side effects are discussed along with its comparison with finasteride in androgenetic alopecia. METHOD: The main sources of our information were Medline Pubmed, Google scholar and Scopus including original articles and review articles. The keywords 'dutasteride', 'dutasteride in androgenetic alopecia' were used for search. CONCLUSION: Like finasteride, dutasteride is now becoming popular treatment option in AGA, due to its good response shown by various randomized control studies and meta-analysis. Also, in most of these studies, dutasteride was found to be better than finasteride with comparable adverse effects. Therefore, dutasteride could become a treatment of choice for AGA in near future.

Bioequivalence Studies of a Reformulated Dutasteride and Tamsulosin Hydrochloride Combination Capsule and a Commercially Available Formulation.

A dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg combination (DTC) capsule (Duodart® ) was reformulated to reduce the capsule size and enhance product stability. Bioequivalence of the reformulated DTC capsule with the commercial formulation was evaluated in 2 single-dose, open-label, randomized, 2-way crossover studies in healthy adult male volunteers. Subjects in a fasted or fed state received a single oral dose of either the reformulated DTC or the commercial formulation followed by a 28-day washout period between treatments. Blood samples were taken predose and up to 72 hours postdose for pharmacokinetic (PK) analysis of dutasteride and tamsulosin serum concentrations. From the serum concentration-vs-time data, a noncompartmental method was used to calculate the maximum observed serum concentration (Cmax ) and area under the serum concentration-time curve (AUC0-t ) for dutasteride and tamsulosin, and AUC0-∞ for tamsulosin. The 90% confidence intervals for the ratios of the Cmax and AUC0-t (for dutasteride and tamsulosin) and for AUC0-∞ (for tamsulosin) were all completely contained within the range of 80% to 125%; therefore, the reformulated DTC capsule is bioequivalent to the commercial formulation under both fed and fasted states.

Impact of Formulation on the Pharmacokinetics of Dutasteride: Results from Two Phase I Studies.

BACKGROUND AND OBJECTIVES: Dutasteride is currently marketed by GlaxoSmithKline (GSK), either as monotherapy or as a fixed-dose combination with tamsulosin. As part of the project to develop the fixed-dose combination product, alternative formulations of dutasteride were prepared by GSK, and their pharmacokinetic properties were investigated. METHODS: Two single-centre, open-label, active-comparator, randomised, three-period crossover studies were performed. The first study evaluated the relative bioavailability of dutasteride 0.5 mg soft gelatin capsule (marketed formulation, reference) versus a dutasteride 0.5 mg hard gelatin capsule and a dutasteride 0.5 mg tablet. The second assessed the relative bioavailability of dutasteride 0.5 mg from soft gelatin capsules containing 300 or 100 mg of mono- and diglycerides of caprylic acid/capric acid (MDC8, an emulsifying agent) versus the marketed formulation. RESULTS: In the first study (n = 36), compared with the marketed soft gelatin capsule formulation, the bioavailability (least squares [LS] means ratio) of the tablet formulation was 76 % (90 % CI 0.68-0.84), and that of the hard gelatin capsule was 73 % (90 % CI 0.66-0.82). Peak exposures were also lower for the tablet (73 %; 90 % CI 0.66-0.81) and hard capsule (71 %; 90 % CI 0.64-0.79) relative to the marketed soft gelatin capsule. In the second study (n = 37), compared with the marketed soft gelatin formulation, the bioavailability (LS means ratio) of the 300 mg MDC8 capsule formulation was 95 % (90 % CI 0.88-1.03), and that of the 100 mg MDC8 capsule formulation was 93 % (90 % CI 0.86-1.00). Peak exposures were also lower for the 300 mg MDC8 (90 %; 90 % CI 0.81-0.99) and 100 mg MDC8 (87 %; 90 % CI 0.79-0.96) formulations. CONCLUSIONS: The bioavailability of, and peak exposure to, dutasteride are influenced by the formulation of the administered medication. These studies demonstrate the importance of formulation for obtaining the optimal pharmacokinetic properties of dutasteride.

Design of a gelatin microparticle-containing self-microemulsifying formulation for enhanced oral bioavailability of dutasteride.

In this study, a gelatin microparticle-containing self-microemulsifying formulation (SMF) was developed using a spray-drying method to enhance the oral delivery of the poorly water-soluble therapeutic dutasteride. The effect of the amount of gelatin and the type and amount of hydrophilic additives, namely, Gelucire(®) 44/14, poloxamer 407, sodium lauryl sulfate, Soluplus(®), Solutol™ HS15, and D-α-tocopheryl polyethylene glycol 1000 succinate, on the droplet size, dissolution, and oral absorption of dutasteride from the SMF was investigated. Upon dispersion of the gelatin microparticle-containing SMF in water after spray-drying, the mean droplet size of the aqueous dispersion was in the range of 110-137 nm. The in vitro dissolution and recrystallization results showed that gelatin could be used as a solid carrier and recrystallization inhibitor for the SMF of dutasteride. Furthermore, combination of the gelatin microparticle-containing SMF and Soluplus enhanced the dissolution properties and oral absorption of dutasteride. The results of our study suggest that the gelatin microparticle-containing SMF in combination with Soluplus could be useful to enhance the oral absorption of dutasteride.

Preparation and in vivo evaluation of a dutasteride-loaded solid-supersaturatable self-microemulsifying drug delivery system.

The purpose of this study was to prepare a dutasteride-loaded solid-supersaturatable self-microemulsifying drug delivery system (SMEDDS) using hydrophilic additives with high oral bioavailability, and to determine if there was a correlation between the in vitro dissolution data and the in vivo pharmacokinetic parameters of this delivery system in rats. A dutasteride-loaded solid-supersaturatable SMEDDS was generated by adsorption of liquid SMEDDS onto Aerosil 200 colloidal silica using a spray drying process. The dissolution and oral absorption of dutasteride from solid SMEDDS significantly increased after the addition of hydroxypropylmethyl cellulose (HPMC) or Soluplus. Solid SMEDDS/Aerosil 200/Soluplus microparticles had higher oral bioavailability with 6.8- and 5.0-fold higher peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) values, respectively, than that of the equivalent physical mixture. A linear correlation between in vitro dissolution efficiency and in vivo pharmacokinetic parameters was demonstrated for both AUC and Cmax values. Therefore, the preparation of a solid-supersaturatable SMEDDS with HPMC or Soluplus could be a promising formulation strategy to develop novel solid dosage forms of dutasteride.

Improved oral absorption of dutasteride via Soluplus®-based supersaturable self-emulsifying drug delivery system (S-SEDDS).

A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to improve the oral absorption of dutasteride (DTS), a 5α-reductase inhibitor that is poorly water-soluble. A supersaturable system was prepared by employing Soluplus(®) (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) as a precipitation inhibitor with a conventional SEDDS vehicle consisted of Capryol™ 90, Cremophor(®) EL and Transcutol(®) HP (DTS:SEDDS vehicle:Soluplus(®)=1.0:67.6:10.0 w/v/w). In an in vitro dissolution test in a non-sink condition, the drug dissolution rate from SEDDS was rapidly increased to 72% for an initial period of 5min, but underwent rapid drug precipitation within 2h, decreasing the amount of drug dissolved to one-seventh of its original amount. On the other hand, S-SEDDS resulted in a slower crystallization of DTS by virtue of a precipitation inhibitor, maintaining a 3 times greater dissolution rate after 2h compared to SEDDS. In an in vivo pharmacokinetic study in rats, the S-SEDDS formulation exhibited 3.9-fold greater area-under-curve value than that of the drug suspension and 1.3-fold greater than that of SEDDS. The maximum plasma concentration of S-SEDDS was 5.6- and 2.0-fold higher compared to drug suspension and SEDDS, respectively. The results of this study suggest that the novel supersaturable system may be a promising tool for improving the physicochemical property and oral absorption of the 5α-reductase inhibitor.

Effect of tamsulosin on the pharmacokinetics of dutasteride in Chinese male healthy volunteers.

The purpose of this study was to evaluate the effect of tamsulosin (0.2 mg) on the pharmacokinetics of dutasteride (0.5 mg) in a group of healthy Chinese male volunteers. This was an open-label, single-sequence, 3-period, drug-drug interaction phase 1 study. Twenty-four healthy Chinese male volunteers were enrolled and administered a single dose of 0.5 mg dutasteride and, following a 28- to 30-day washout period, 0.2 mg tamsulosin once daily for 7 days. On day 5, subjects received 0.2 mg tamsulosin coadministered with 0.5 mg dutasteride. Serum dutasteride and tamsulosin concentrations were monitored. In the presence or absence of tamsulosin, there were no apparent changes in dutasteride AUC and Cmax . Adverse events reported were mild to moderate in intensity and resolved by the end of the study. In healthy Chinese male volunteers, tamsulosin 0.2 mg at steady state had no apparent effect on dutasteride pharmacokinetics. Dutasteride and tamsulosin when administered alone or in combination were well tolerated.