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Benign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP(®) 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500 µL) via solid-phase extraction (Oasis(®) HLB), with (13)C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150 × 3 mm, 2.6 µm), using a gradient run of 19 min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289 → 97), DHT (m/z 291 → 255), androstenedione (m/z 287 → 97), dutasteride (m/z 529 → 461), finasteride (m/z 373 → 317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

The aim of the present work was to study the in vitro/in vivo characteristics of dutasteride loaded biodegradable microspheres designed for sustained release of dutasteride over four weeks. An O/W emulsion-solvent evaporation method was used to incorporate dutasteride, which is of interest in the treatment of benign prostatic hyperplasia (BPH), into poly(lactide-co-glycolide) (PLGA). A response surface method (RSM) with central composite design (CCD) was employed to optimize the formulation variables. A prolonged in vitro drug release profile was observed, with a complete release of the entrapped drug within 28 days. The pharmacokinetics study showed sustained plasma drug concentration-time profile of dutasteride loaded microspheres after subcutaneous injection into rats. The in vitro drug release in rats correlated well with the in vivo pharmacokinetics profile. The pharmacodynamics evaluated by determination of the BPH inhibition in the rat models also showed a prolonged pharmacological response. These results suggest the potential use of dutasteride loaded biodegradable microspheres for the management of BPH over long periods.

Background and Objectives: The combination of dutasteride and tamsulosin may be more effective for the treatment of symptomatic benign prostatic hyperplasia than either treatment alone. We report the results of three pharmacokinetics and tolerability studies, which used a dutasteride/tamsulosin HCl (0.5 mg/0.2 mg) fixed-dose combination (FDC) capsules containing a small dutasteride soft gelatin capsule (smaller than commercial Avodart™) and modified-release tamsulosin pellets that have different amounts of enteric coating. These studies compared the test products to commercial Avodart™ (dutasteride 0.5 mg) and two different commercial tamsulosin HCl 0.2 mg products, Harnal™ Capsules or Harnal-D™ Tablets, which are reportedly bioequivalent to each other., Methods: All three studies were randomized single-dose studies in healthy male adults. Study 1 [N = 86 (NCT01254071)] was a two-period crossover study of a dutasteride/tamsulosin HCl FDC versus coadministered Avodart™ and Harnal-D™ Tablets. The pharmacokinetics of both dutasteride and tamsulosin were studied. Study 2 [N = 27 (NCT01471678)] was a four-period crossover study of dutasteride/tamsulosin HCl FDC formulations versus Avodart™ and Harnal™ Capsules or Harnal-D™ Tablets. Only the pharmacokinetics of tamsulosin were studied. Study 3 [N = 40 (NCT01495026)] was a two-period study of dutasteride/tamsulosin HCl FDC formulations versus coadministered Avodart™ and Harnal-D™ Tablets. In this study, only the pharmacokinetics of tamsulosin were studied. Study 2 assessed fed-state pharmacokinetics. Studies 1 and 3 assessed fed- and fasted-state pharmacokinetics., Results: All dutasteride/tamsulosin HCl FDC formulations and coadministered treatments were well-tolerated. In Study 1, the FDC dutasteride was bioequivalent to Avodart™ coadministered with tamsulosin under fed and fasted conditions. In Study 1, the FDC tamsulosin had a slower release than commercial Harnal-D™ Tablets coadministered with dutasteride (fed and fasted state). In Study 2, the FDC tamsulosin containing 15 % by weight enteric-coated tamsulosin pellets was bioequivalent to Harnal™ Capsules coadministered with dutasteride in the fed state. In Study 3, the FDC containing 15 % by weight enteric-coated tamsulosin pellets combined with uncoated tamsulosin pellets (coated:uncoated = 10:90) were bioequivalent to Harnal-D™ Tablets coadministered with dutasteride in the fasted state but not the fed state., Conclusions: The FDC formulations were well-tolerated and some FDC formulations were comparable with concomitant administration of commercially available dutasteride and tamsulosin.

To develop a solid dosage form of dutasteride for improving its oral bioavailability, a novel dry elixir (DE) system was fabricated. DEs incorporating dextrin and/or xanthan gum were prepared using spray-drying and evaluated by morphology, ethanol content, crystallinity, dissolution and oral bioavailability. DEs were spherical with a smooth surface and had an average particle size of 20-25 μm. The ethanol content could be easily varied by controlling the spray-drying temperature. The dissolution profiles of dutasteride from each DE proved to be much faster than that of dutasteride powder due to the amorphous state and a high amount of incorporated ethanol. In particular, the pharmacokinetic profiles of dutasteride were significantly altered depending on the proportions of dextrin and xanthan gum. Blood concentrations of dutasteride from DE formulations were similar to those of market products and much greater than those of native dutasteride. Interestingly, the dissolution and pharmacokinetic profiles were easily controlled by changing the ratio of dextrin to xanthan gum. The data suggests that a DE using dextrin and/or xanthan gum could provide an applicable solid dosage form to improve the dissolution and bio-availability of dutasteride as well as to modulate its pharmacokinetics.

An accurate and precise method was developed and validated using LC-MS/MS to quantify dutasteride in human plasma. The analyte and dutasteride-13C6 as internal standard (IS) were extracted from 300 μL plasma volume using methyl tert-butyl ether-n-hexane (80:20, v/v). Chromatographic analysis was performed on a Gemini C18 (150 × 4.6 mm, 5 µm) column using acetonitrile-5 mm ammonium formate, pH adjusted to 4.0 with formic acid (85:15, v/v) as the mobile phase. Tandem mass spectrometry in positive ionization mode was used to quantify dutasteride by multiple reaction monitoring. The entire data processing was done using Watson LIMS(TM) software, which provided excellent data integrity and high throughput with improved operational efficiency. The calibration curve was linear in the range of 0.1-25 ng/mL, with intra-and inter-batch values for accuracy and precision (coefficient of variation) ranging from 95.8 to 104.0 and from 0.7 to 5.3%, respectively. The mean overall recovery across quality controls was ≥95% for the analyte and IS, while the interference of matrix expressed as IS-normalized matrix factors ranged from 1.01 to 1.02. The method was successfully applied to support a bioequivalence study of 0.5 mg dutasteride capsules in 24 healthy subjects. Assay reproducibility was demonstrated by reanalysis of 103 incurred samples., (Copyright © 2013 John Wiley & Sons, Ltd.)

The present study sought to evaluate the pharmacokinetics of dutasteride-loaded Eudragit E nanoparticle in rats. In addition, the study investigated the effect of increasing drug load on the in vitro solubility and dissolution behavior of dutasteride together with its in vivo oral absorption characteristics. The suspension of dutasteride-loaded Eudragit E nanoparticles prepared by the nanoprecipitation method showed blue opalescence and the particles were uniform in appearance. The entrapment efficiency and the mean particle size of these nanoparticles were in the range of 98.1-99.3% and 120.5-128.4 nm, respectively, and no significant difference in these parameters was observed between the nanoparticles in the sample. Eudragit E nanoparticles containing a drug load of 5% showed an increase in bioavailability by 550% as compared to dutasteride suspension. This finding is attributable to enhanced solubility and dissolution of dutasteride when formulated as nanoparticles. Furthermore, the oral absorption of dutasteride in rats increased as a function of the extent of supersaturation of dutasteride in Eudragit E nanoparticles. Therefore, the preliminary results from our study suggest that dutasteride-loaded Eudragit E nanoparticles may have significant potential for clinical application., (© Georg Thieme Verlag KG Stuttgart · New York.)

The objectives of this study were to develop a novel solid dutasteride formulation with improved physicochemical properties and oral bioavailability, and to examine the correlation between its in vitro dissolution and in vivo pharmacokinetic parameters. Hydroxypropyl-β-cyclodextrin (HP-β-CD) nanostructures with or without hydrophilic additives were manufactured using the supercritical antisolvent process. The dutasteride-loaded HP-β-CD nanoparticles formed aggregates with a mean particle size of less than 160 nm and a specific surface area greater than 100 m(2)/g. Increases in the supersaturation and dissolution rate for dutasteride were dependent on the type of additive; increases in maximum solubility and extended supersaturation were observed in dutasteride-loaded HP-β-CD nanostructures with hydroxypropylmethyl cellulose, whereas the dissolution rate was the highest for nanostructures containing d-α-tocopheryl polyethylene glycol 1000 succinate. In rats, the oral bioavailability of dutasteride increased with the supersaturation induced by the HP-β-CD nanostructures. In addition, compared with the in vitro drug release rate, the in vivo pharmacokinetic parameters were more closely correlated with in vitro parameters related to supersaturation (solubility). Further, the bioavailability of the dutasteride-loaded HP-β-CD nanostructures with hydroxypropylmethyl cellulose was similar to that of the commercially available soft gelatin capsule (Avodart®). In conclusion, preparation of dutasteride-loaded HP-β-CD nanostructures using the supercritical antisolvent process affords a viable alternative solid dosage form for dutasteride.

Purpose: Co-administration of the 5α-reductase inhibitor dutasteride increases the oral testosterone bioavailability in men with experimentally induced hypogonadism. We examined oral testosterone with and without dutasteride administration in hypogonadal men for 28 days., Materials and Methods: We randomly assigned 43 hypogonadal men to twice daily oral doses of 150, 250 or 400 mg testosterone with 0.25 mg dutasteride, 400 mg testosterone alone or 0.25 mg dutasteride alone for 28 days in a multicenter study. Subjects underwent pharmacokinetic profiling of serum hormones on days 1 and 28. A total of 32 men completed all study procedures., Results: Serum testosterone increased in all groups on testosterone compared with that in the dutasteride only group. At the 400 mg dose the combination of testosterone and dutasteride resulted in average testosterone concentrations that were 2.7 and 4.6 times higher than in the testosterone only group on days 1 and 28, respectively (p <0.01). On day 28 average testosterone was 20% to 30% lower in all groups on testosterone and dutasteride, and 50% lower in the testosterone only group compared with day 1. Serum dihydrotestosterone was suppressed in all groups on dutasteride and increased in the testosterone only group., Conclusions: Oral testosterone administration resulted in a therapeutic serum testosterone concentration in hypogonadal men. Dutasteride improved the oral bioavailability of testosterone while suppressing dihydrotestosterone. Compared with day 1, testosterone was decreased after 28 days of administration. Additional study is warranted of oral testosterone with dutasteride for testosterone deficiency., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Studies to establish bioequivalence (BE) of a drug are important elements in support of drug applications. A typical BE study is conducted as a single dose, randomized, 2-period crossover design. For drugs with long half lives (≥ 48 hours) and evaluation of multiple BE objectives in 1 trial, this design may not be adequate. A parallel design may then be a more appropriate choice. However, parallel designs require increased sample size, which can become substantial. One option that is a compromise between the complete randomized block design and the parallel design is a partial-block crossover design. This approach came about during the development of a combination of dutasteride and tamsulosin. Previous experience with performing single-dose dutasteride studies suggested that 28 days of washout is needed between treatments because of its half-life of 7-9 days. Simulations were performed to assess the operating characteristics of this design using a previously developed PK model. Four scenarios were developed, and each scenario was simulated 500 times. The results showed that this design demonstrated acceptable consumer and producer risk. Partial-block crossover designs should be considered for studies when the half-life of the drug is long and there are more than 2 periods.

Importance of the Field: Benign prostatic hyperplasia (BPH) is the fourth most commonly diagnosed medical condition in the elderly. Selective α-blockers (tamsulosin) and dual 5α-reductase inhibitors (dutasteride) have an important role in the medical treatment of symptomatic BPH. Safety and efficacy of combination therapy with dutasteride and tamsulosin as well as long-term benefit on prevention of disease progression have been widely studied in recent trials., Areas Covered in This Review: The present article summarizes the pharmacologic properties of both dutasteride and tamsulosin. Clinical efficacy of combination therapy in different trials has also been reported. Major randomized trials on this concept published between 2000 and 2010 have been covered in this article., What the Reader Will Gain: Long-term efficacy and safety of combination therapy and its beneficial effect on quality of life and risk reduction of need for BPH-related surgeries have been discussed., Take Home Message: Combination therapy with dutasteride and tamsulosin is a highly efficacious medical treatment in patients with moderate-to-severe lower urinary tract symptoms due to benign prostatic enlargement, which could be safely tolerated and administrated for ≥ 4 years.

Background: Ketoconazole is a commonly used secondary hormonal therapy in castration-refractory prostate cancer (CRPC), but disease progression inevitably occurs. Both prostatic and metastatic lesions in patients with CRPC overexpress 5-alpha reductase (SRDA5) type I. We hypothesized that SRDA5 inhibition in combination with ketoconazole would mitigate progression after treatment with ketoconazole alone., Patients and Methods: A total of 10 patients with CRPC with progression after ketoconazole treatment were treated with a combination of ketoconazole plus dutasteride 0.5 mg/day, a dual SRDA5 inhibitor., Results: After dutasteride addition, 8 (80%) of the 10 patients had varying degrees of prostate-specific antigen (PSA) decline relative to baseline. Median progression-free survival after dutasteride addition was 4.9 months (range, 2.7+ to 9.8 months); no patient had a >OR= 50% PSA decline., Conclusion: We conclude that dutasteride added to ketoconazole at the time progression might prolong time to PSA progression in patients with CRPC.

Benign prostatic hyperplasia (BPH) is a frequent cause of lower urinary symptoms, with a prevalence of 50% by the sixth decade of life. Hyperplasia of stromal and epithelial prostatic elements that surround the urethra cause lower urinary tract symptoms (LUTS), urinary tract infection and acute urinary retention. Medical treatments of symptomatic BPH include; 1) the 5alpha-reductase inhibitors, 2) the alpha1-adrenergic antagonists, and 3) the combination of a 5alpha-reductase inhibitor and a alpha1-adrenergic antagonist. Selective alpha1-adrenergic antagonists relax the smooth muscle of the prostate and bladder neck without affecting the detrussor muscle of the bladder wall, thus decreasing the resistance to urine flow without compromising bladder contractility. Clinical trials have shown that alpha1-adrenergic antagonists decrease LUTS and increase urinary flow rates in men with symptomatic BPH, but do not reduce the long-term risk of urinary retention or need for surgical intervention. Inhibitors of 5alpha-reductase decrease production of dihydrotestosterone within the prostate resulting in decreased prostate volumes, increased peak urinary flow rates, improvement of symptoms, and decreased risk of acute urinary retention and need for surgical intervention. Interim results of the ongoing Combination of Avodart and Tamsulosin (CombAt) study have shown combination therapy with the 5alpha-reductase inhibitor dutasteride and the alpha1-adrenergic antagonist tamsulosin offer significant improvements from baseline compared with either drug alone.

Oral administration of testosterone enanthate (TE) and dutasteride increases serum testosterone and might be useful for male hormonal contraception. To ascertain the contraceptive potential of oral TE and dutasteride by determining the degree of gonadotropin suppression mediated by 4 weeks of oral TE plus dutasteride, 20 healthy young men were randomly assigned to 4 weeks of either 400 mg oral TE twice daily or 800 mg oral TE once daily in a double-blinded, controlled fashion at a single site. All men received 0.5 mg dutasteride daily. Blood for measurement of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, dihydrotesterone (DHT), and estradiol was obtained prior to treatment, weekly during treatment, and 1, 2, 4, 8, 12, 13, 14, 16, 20, and 24 hours after the morning dose on the last day of treatment. FSH was significantly suppressed throughout treatment with 800 mg TE once daily and after 4 weeks of treatment with 400 mg TE twice daily. LH was significantly suppressed after 2 weeks of treatment with 800 mg TE, but not with 400 mg TE. Serum DHT was suppressed and serum estradiol increased during treatment in both groups. High-density lipoprotein cholesterol was suppresed during treatment, but liver function tests, hematocrit, creatinine, mood, and sexual function were unaffected. The administration of 800 mg oral TE daily combined with dutasteride for 28 days significantly suppresses gonadotropins without untoward side effects and might have utility as part of a male hormonal contraceptive regimen.

Dutasteride (Avodart), an oral synthetic 4-azasteroid, is a potent, selective, irreversible inhibitor of type 1 and type 2 5alpha-reductase (5AR), the enzyme that converts testosterone to dihydrotestosterone (DHT) intracellularly. Although type 2 5AR predominates, both isoenzymes are overexpressed in prostate tissue in benign prostatic hyperplasia (BPH) and at all stages in some prostate cancers. Oral dutasteride 0.5 mg once daily is approved for the treatment of moderate to severe symptomatic BPH in men with an enlarged prostate to improve symptoms, and to reduce the risk of acute urinary retention (AUR) and the need for BPH-related surgery.In pivotal 2-year phase III trials, oral dutasteride 0.5 mg once daily improved urinary symptoms, decreased total prostate volume (TPV), and reduced the risk of AUR and BPH-related surgery in men with moderate to severe symptoms of BPH and prostate enlargement. The good efficacy and tolerability of dutasteride was maintained for up to 4 years in open-label extension studies. Results of the pre-planned, 2-year interim analysis of the CombAT trial showed that the combination of dutasteride and tamsulosin was superior to either drug as monotherapy in improving BPH-related symptoms, peak urinary flow and BPH-related health status. The overall adverse event profile for combination therapy was consistent with those reported for both monotherapies. Although drug-related adverse events were more frequent with combination therapy versus both monotherapies, most did not result in treatment cessation. Dutasteride is being investigated for its efficacy in reducing the risk of prostate cancer in at-risk men in the 4-year REDUCE study and as treatment to extend the time to progression in men with low-risk localized prostate cancer who would otherwise undergo watchful waiting in the 3-year REDEEM study. Thus, dutasteride is an effective treatment option in patients with moderate to severe symptomatic BPH and demonstrable prostatic enlargement, and may have potential to reduce the risk of developing biopsy-detectable prostate cancer in at-risk individuals or extending the time to progression in low-risk localized prostate cancer.

The dual 5alpha-reductase inhibitor, dutasteride has been shown to suppress serum dihydrotestosterone (DHT) by >90%. In the present study, the effect of dutasteride 0.5 mg/day on intraprostatic DHT levels was investigated. In this multicenter, double-blind trial, 43 men with benign prostatic hyperplasia (BPH) scheduled to undergo transurethral resection of the prostate (TURP) were randomized to receive dutasteride, 0.5 mg/day or placebo for 3 months before surgery. Intraprostatic DHT, testosterone and dutasteride levels were determined at the time of TURP. Changes in serum DHT and testosterone from baseline, and both serum and intraprostatic dutasteride levels at the time of TURP were also assessed. Dutasteride reduced intraprostatic DHT by 94% relative to placebo (P<0.001); the adjusted mean intraprostatic DHT concentration was 3.23 and 0.209 ng/g in the placebo and dutasteride groups, respectively. In the dutasteride group, serum DHT was reduced from baseline by 93% at month 3, a significantly greater reduction (P<0.001) than the 15% decrease observed in the placebo group. There was a reciprocal increase in intraprostatic testosterone but the level of intraprostatic testosterone in the dutasteride group tended to be lower than the intraprostatic DHT level in the placebo group (P=0.06). Significant intraprostatic DHT suppression was achieved in all subjects who received dutasteride, regardless of the level of intraprostatic dutasteride. There was a strong positive correlation between serum and intraprostatic dutasteride concentrations (R(2)=0.73). After 3 months of treatment, dutasteride 0.5 mg/day provided near-complete suppression of both intraprostatic and serum DHT in men with BPH.

Benign prostatic hyperplasia (BPH) is a frequent cause of lower urinary symptoms, with a prevalence of 50% by the sixth decade of life. Hyperplasia of stromal and epithelial prostatic elements that surround the urethra cause lower urinary tract symptoms (LUTS), urinary tract infection, and acute urinary retention. Medical treatments of symptomatic BPH include; 1) the 5alpha-reductase inhibitors, 2) the alpha1-adrenergic antagonists, and 3) the combination of a 5alpha-reductase inhibitor and a alpha1-adrenergic antagonist. Selective alpha1-adrenergic antagonists relax the smooth muscle of the prostate and bladder neck without affecting the detrussor muscle of the bladder wall, thus decreasing the resistance to urine flow without compromising bladder contractility. Clinical trials have shown that alpha1-adrenergic antagonists decrease LUTS and increase urinary flow rates in men with symptomatic BPH, but do not reduce the long-term risk of urinary retention or need for surgical intervention. Inhibitors of 5alpha-reductase decrease production of dihydrotestosterone within the prostate resulting in decreased prostate volumes, increased peak urinary flow rates, improvement of symptoms, and decreased risk of acute urinary retention and need for surgical intervention. The combination of a 5alpha-reductase inhibitor and a alpha1-adrenergic antagonist reduces the clinical progression of BPH over either class of drug alone.

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, drug interactions, and dosing recommendations of dutasteride, a 5-alpha reductase inhibitor for benign prostatic hyperplasia (BPH)., Data Sources: A MEDLINE search (1966-February 2006) was conducted to extract human research data in the English language on dutasteride. Search terms included benign prostatic hyperplasia, dutasteride, and finasteride. The reference lists of articles identified through this search process, the manufacturer's Web site, and dutasteride prescribing information were also examined., Study Selection and Data Extraction: All published studies and clinical data from the manufacturer were included, with emphasis placed on randomized, controlled trials., Data Synthesis: Dutasteride is approved for the treatment of symptomatic BPH in men with an enlarged prostate to improve urinary symptoms, reduce the risk of acute urinary retention, and reduce the need for BPH-related surgical interventions. Compared with placebo, dutasteride has been shown to significantly improve BPH symptoms, reduce the incidence of acute urinary retention and BPH-related surgery, and improve BPH-related quality of life. Few published data exist comparing dutasteride with finasteride. The most common adverse effects of dutasteride include ear, nose, and throat infection; malaise; headache; dizziness; and musculoskeletal pain., Conclusions: Clinical trials, sponsored primarily by the manufacturer, have shown dutasteride to be an effective treatment of BPH compared with placebo and to likely possess efficacy similar to that of finasteride. Further studies are needed to gain a more clear understanding of any clinically significant differences between dutasteride and finasteride.

Dutasteride is a new 5-alpha reductase inhibitor for the treatment of men with moderate to severe lower urinary tract symptoms secondary to benign prostatic hyperplasia. It has been available in the UK since March 2003. It is a competitive inhibitor of both type I and type II isoforms of the 5-alpha reductase enzyme that converts testosterone to the more potent androgen, dihydrotestosterone. Randomised controlled studies have shown dutasteride to be statistically more effective than placebo in reducing lower urinary tract symptoms and increasing maximum urinary flow rates. This is a consequence of a reduction in serum dihydrotestosterone and hormone dependent prostate volume. Dutasteride has also been shown to decrease the absolute risk of urinary retention and the need for prostate-related surgery when compared to placebo taken over a 24-month period. In this review article we discuss the pharmacology and clinical effects of dutasteride, a new dual-acting 5-alpha reductase inhibitor.

Dutasteride, a potent inhibitor of type 1 and 2 5alpha-reductase, reduced dihydrotestosterone levels by >90% in 85% of patients following 1 years' administration of oral dutasteride 0.5 mg/day. A combined analysis of three placebo-controlled clinical studies conducted in patients with benign prostatic hyperplasia (BPH) found sustained improvements in American Urological Association- Symptom Index scores and urinary flow rate and a 57% decrease in the risk of acute urinary retention throughout the 2-year treatment period (all p < 0.001 vs placebo). Total prostate and transition zone volume were also reduced (both p < 0.001), as was the risk of BPH-related surgery (by 48%). A nonblind extension study found that dutasteride maintains efficacy for up to 4 years. Dutasteride monotherapy maintained symptom relief following combination treatment with dutasteride and tamsulosin in all patients but those with severe symptoms. Dutasteride was generally well tolerated. Impotence, reduced libido, gynaecomastia and ejaculation disorder occurred significantly more often in dutasteride than placebo recipients, but incidence was generally low. With the exception of gynaecomastia, incidence consistently decreased over time.

The interaction of baculovirus expressed rat steroid 5alpha-reductase types 1 and 2 (r5AR1 and r5AR2) with 17beta-N-(2,5-bis(trifluoromethyl)phenyl)carbamoyl-4-aza-5alpha-androst-1-en-3-one (GI198745) was investigated at pH 7 and 37 degrees. This 5alpha-reductase inhibitor was found previously to be a time-dependent inhibitor of the two human 5alpha-reductase isozymes. In contrast, we demonstrate in the present study that although GI198745 is a potent time-dependent inhibitor of r5AR2, it is a classical rapid-equilibrium inhibitor of r5AR1. This type of behavior with human and rat 5alpha-reductases has been shown for the inhibitor 17beta-(N-tert-butylcarbamoyl)-4-aza-5alpha-androst-1-en-3-one (finasteride), a current therapy for benign prostatic hyperplasia. Inhibition of r5AR1 by GI198745 was competitive with testosterone and followed Michaelis-Menten kinetics with a K(i) value of 0.3 +/- 0.02 nM. Data for the inhibition of r5AR2 by GI198745 were consistent with a two-step mechanism, where K(i) is the dissociation constant for an initial enzyme-inhibitor complex and k(3) is the rate constant for the second slow step. The pseudo-bimolecular rate constant (k(3)/K(i)) for the association of GI198745 with r5AR2 was (2.0 +/- 0.4) x 10(7) M(-1) sec(-1). The high affinity of this inhibitor for r5AR2 was further demonstrated by the inability of the enzyme-inhibitor complex to dissociate after approximately 7 days of dialysis at 4 degrees. Both GI198745 and finasteride appear to inactivate r5AR2 by apparent irreversible modification, but are classical, reversible inhibitors of r5AR1. Therefore, we hypothesize that because of its pharmacokinetic parameters and increased potency against r5AR1, GI198745 is more effective than finasteride in preventing the growth of the rat prostate.

A population pharmacokinetic/dynamic model describing the conversion of testosterone to dihydrotestosterone (DHT) by 5alpha-reductases and the irreversible inhibition of 5alpha-reductase(s) by finasteride and dutasteride was validated. The model had been developed using data from a single dose study in healthy volunteers and was validated against data from a 28-day repeat dose study in patients with benign prostatic hyperplasia. Validation was carried out by comparing results of Monte Carlo simulations to the observed data, fitting the model to the repeat dose data and comparing with previously derived parameter values, and examining individual predictions of the model for the individuals in the repeat dose study for any bias. Simulations closely predicted the outcome of the repeat dose study, estimated parameters of the pharmacodynamic modelling were generally close to within 88 to 116% of those from the original model and the individual predictions did not indicate any bias. Thus the model derived from single dose data from healthy volunteers was considered to be valid for the prediction of DHT levels in the patient population after repeated dosing of dutasteride and finasteride.

Selective inhibition of type 2 5alpha-reductase has been shown to be efficacious in the treatment of benign prostatic hyperplasia. Pharmacokinetic and pharmacodynamic results are reported of treatment with a potent inhibitor of both 5alpha-reductase isozymes, GG745, in rats, dogs and men. In the rat, GG745 has a similar effect on DHT-driven prostatic growth as finasteride, another dual 5alpha-reductase inhibitor in this species. However, GG745 appears to be more potent in the rat, a result that likely reflects the greater inherent potency and terminal half-life of GG745 (14 hr) compared with that of finasteride (1 hr). These pharmacokinetic differences are also maintained in the dog (65 and 4 hr for GG745 and finasteride, respectively). From these results, the literature, and in vitro studies, we estimated doses of GG745 likely to prove efficacious in reducing DHT levels in man. These estimated values were predictive of single-dose effects of GG745 in man. Results from single-dose evaluations in man indicate that GG745 has a terminal half-life of approximately 240 hr, and single doses of >10 mg decreased DHT levels significantly more than did single 5-mg doses of finasteride. These data support the hypothesis that a molecule (GG745) that effectively inhibits both 5alpha-reductases will lower serum DHT levels significantly more than a molecule that inhibits only a single 5alpha-reductase isozyme (e.g., finasteride, a selective inhibitor of the type 2 enzyme in man).

A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.

Finasteride is a synthetic 4-azasteroid that is a specific competitive inhibitor of 5 alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone (DHT). It has no binding affinity for androgen receptor sites and itself possesses no androgenic, antiandrogenic, or other steroid hormone-related properties. It is well absorbed after oral administration, with absolute bioavailability in humans of 63% (range 34-108%). The mean time to maximum concentration is 1-2 hours, and it is approximately 90% plasma protein bound. The elimination half-life averages 6-8 hours. The agent is metabolized to a series of five metabolites, of which two are active and possess less than 20% of the 5 alpha-reductase activity of finasteride. Little is known about potential drug interactions, although they appear to be minimal and not clinically relevant. The drug is indicated for the treatment of symptomatic benign prostatic hyperplasia. Its efficacy in regression of prostate gland enlargement is rapid and predictable, although correlation with subsequent improvement in urinary flow and symptoms is highly variable. Dosages of 0.5-100 mg/day regress prostate enlargement; the recommended dosage is 5 mg once/day. Finasteride may hold promise for other DHT-mediated disorders such as acne, facial hirsutism, frontal lobe alopecia, and prostate cancer, but its use in these conditions remains investigational. The frequency of adverse drug events is low, with the most common side effects being impotence, decreased libido, and decreased volume of ejaculate. No reports of intentional overdose have been reported, and dosages of up to 80 mg/day for 3 months have been taken without adverse effect.

The pharmacology and pharmacokinetics of finasteride are reviewed, and finasteride's clinical efficacy, adverse effects, and dosage in patients with benign prostatic hyperplasia (BPH) are described. Finasteride is a member of a new class of medications, the azasteroids, that have antiandrogenic activity limited to certain tissues, including the prostate gland. Finasteride inhibits the activity of 5 alpha-reductase, the enzyme necessary for converting testosterone to dihydrotestosterone in the prostate and other tissues. BPH is androgen dependent, and dihydrotestosterone is necessary for the hyperplasia to occur. Finasteride is well absorbed after oral administration; peak plasma concentration is reached in as little as one hour. Finasteride is approximately 90% bound to plasma proteins, is widely distributed, and is extensively metabolized by the liver. In clinical studies, finasteride has been effective in decreasing prostatic volume, increasing urinary flow rate, and decreasing the obstructive and irritative symptoms of BPH. Because of the heterogeneity of BPH, however, treatment is successful in only one third to one half of patients. Finasteride's adverse effects include decreased libido, ejaculatory disorders, and effects on prostate-specific antigen. The recommended dosage of finasteride is 5 mg/day orally. Therapy should be continued for at least six months before the clinical response is evaluated. Finasteride provides a pharmacologic alternative to surgery in patients with BPH.

The disposition of [14C]finasteride, a competitive inhibitor of steroid 5 alpha-reductase, was investigated after oral administration of 38.1 mg (18.4 microCi) of drug in six healthy volunteers. Plasma, urine, and feces were collected for 7 days and assayed for total radioactivity. Concentrations of finasteride and its neutral metabolite, omega-hydroxyfinasteride (monohydroxylated on the t-butyl side chain), in plasma and urine were determined by HPLC assay. Mean excretion of radioactivity equivalents in urine and feces equaled 39.1 +/- 4.7% and 56.8 +/- 5.0% of the dose, respectively. The mean peak plasma concentrations reached for total radioactivity (ng equivalents), finasteride, and omega-hydroxyfinasteride were 596.5 +/- 88.3, 313.8 +/- 99.4, and 73.7 +/- 11.8 ng/ml, respectively, at approximately 2 hr; the mean terminal half-life for drug and metabolite was 5.9 +/- 1.3 and 8.4 +/- 1.7 hr, respectively. Of the 24-hr plasma radioactivity, 40.9% was finasteride, 11.8% was the neutral metabolite, and 26.7% was characterized as an acidic fraction of radioactivity. Binding of [14C]finasteride to plasma protein was extensive (91.3 to 89.8%), with a trend suggesting concentration dependency (range 0.02 to 2 micrograms/ml). Little of the dose was excreted in urine as parent (0.04%) or omega-hydroxyfinasteride (0.4%). Urinary excretion of radioactivity was largely in the form of acidic metabolite(s)--18.4 +/- 1.7% of the dose was eliminated as the omega-monocarboxylic acid metabolite. Finasteride was scarcely excreted unchanged in feces. In humans, finasteride is extensively metabolized through oxidative pathways.(ABSTRACT TRUNCATED AT 250 WORDS)

The hormonal effects following the acute (single dose) administration of a 4-azasteroid inhibitor of 5 alpha-reductase (MK-906) were evaluated in 10 healthy male volunteers. Marked suppression of serum dihydrotestosterone (DHT) was observed after the administration of single doses as low as 12.5 mg. The mean percent decrease in DHT at 24 hours in the group treated with a single 25-mg dose was 56% +/- 10% compared with the baseline. The suppression of plasma DHT levels continued for up to 72 hours. This study demonstrates that administration of single oral doses (12.5 to 400 mg) of MK-906 results in a significant decrease in the conversion of testosterone to DHT.

A high-performance liquid chromatographic (HPLC) method with ultraviolet detection for the determination of a novel 4-aza-steroidal inhibitor of 5 alpha-reductase in human plasma has been developed. The assay is based on a single solid-phase extraction and an efficient HPLC separation on two analytical columns in series. The assay has been fully validated and used to support Phase II and III clinical pharmacokinetic studies. The lowest limit of quantification was found to be at 1 ng/ml and allowed pharmacokinetic evaluation of the drug at doses down to 5 mg.

The pharmacokinetics and biochemical efficacy of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) were evaluated in healthy male volunteers after single and multiple oral administration. The mean times to reach peak plasma concentrations (Tmax) of (I) at doses of 5, 10, 20, 50 and 100 mg ranged from 1.8 to 2.8 h, and the corresponding mean peak plasma concentrations (Cmax) were 38.1, 81.5, 147.1, 442.0 and 835.5 ng/ml, respectively. The drug disappeared from the systemic circulation with half-lives (t1/2) of 4.7-7.1 h. The mean values of the area under the curve (AUC0-24) and Cmax increased linearly in a dose-dependent manner. After multiple oral administration of (I) (10 mg/d) for 7 days, Cmax and AUC increased slightly during administration, however, there were no significant differences between day 4 and day 7. Although there were large intersubject differences in the 24 h plasma levels after each dosing, no accumulation of (I) occurred after 7 days dosing. Serum 5-alpha-dihydrotestosterone (DHT) was markedly reduced at all dose levels. The mean serum levels of DHT at 24 h post-dosing decreased to 27-42% of that before dosing. On the other hand, the serum testosterone (T) did not change significantly. After multiple administration of (I), serum DHT was significantly reduced and remained suppressed for up to 7 days after the final dosing.

The pharmacokinetic investigation and the study of metabolism of an immunostimulator of 8-azasteroid series were performed on a single-compartment model. The main pharmacokinetic parameters of the immunomodulator in mice were established using different routes of administration. The maximal accumulation of tritium-labeled 8-azasteroid was recorded in the kidneys, liver and lung. The character of distribution changes with time. The half-life period is in the range of from 0.69 to 1.4 hours at different routes of administration. The total clearance is 0.49 ml/min, the area under the pharmacokinetic curve--3.8-8.1 micrograms/h/ml. On the model of the monooxygenase cytochrome P-450-containing system of the liver microsomes there was confirmed the formation of two metabolites preliminarily isolated from the mouse urine. By the character of resorption, distribution, elimination this 8-azasteroid immunoactivator is close to the agents of glucocorticoid series.

A sensitive and selective high-performance liquid chromatographic method has been developed for the quantitative determination of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) in human plasma. I, a 5 alpha-reductase inhibitor and a potential therapeutic agent for benign prostatic hyperplasia, is a member of the family of compounds referred to as the 4-azasteroids. The 4-N-methyl analogue of the drug was used as the internal standard and calibration curves were developed at two levels of sensitivity to cover a large dynamic range of plasma concentrations. Drug was isolated from biological fluids with a solid-phase C18 extraction column; the analyte was further purified by adsorption and desorption from a second extraction column (CN cartridge). Evaluation of the isolation method revealed that it was reproducible and drug recoveries equalled ca. 90%. Chromatography was carried out on a C8 column (5 micron) with ultraviolet detection at 210 nm. The detection limit was ca. 10 ng/ml for I. Human plasma levels are reported for I following single-dose oral administration of 50,200 and 400 mg of drug; urinary excretion data are reported for a single volunteer given 400 mg of I.