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Dutasteride (Avodart®), an oral synthetic 4-azasteroid, is a potent, selective, irreversible inhibitor of type 1 and type 2 5α-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 preplanned, 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.
Dutasteride is a more potent inhibitor of type 1 (45-fold) and type 2 5AR (2.5-fold) than finasteride (a type 2 5AR inhibitor) in vitro. In patients with symptomatic BPH, oral dutasteride 0.5 mg once daily for 2 years was associated with a median 93.7% decrease in serum DHT levels from baseline compared with placebo (p < 0.001 vs baseline and placebo) in the phase III dutasteride trials, and this was maintained during the 2-year open-label extension studies. In phase II trials, mean intraprostatic DHT levels were reduced from baseline by 94% with dutasteride compared with placebo in men with BPH, and by 90–97% in men with prostate cancer receiving dutasteride 0.5–5 mg once daily. After 24 weeks’ treatment, dutasteride 0.5 mg once daily reduced serum DHT levels from baseline to a greater extent and with less variability than finasteride 5 mg once daily in a dose-ranging study (adjusted mean reductions of 95% vs 71%; p < 0.001).
Mean levels of serum prostate-specific antigen (PSA), a powerful predictor of prostate size, were halved after 2 years of dutasteride therapy in the phase III dutasteride trials (p < 0.001 vs baseline and placebo), whereas those in placebo recipients were increased. Reductions in mean serum PSA levels seen at 2 years were maintained for up to 4 years in the open-label extension studies. Dutasteride had no clinically significant effects on serum testosterone or luteinizing hormone levels, bone density, markers of bone metabolism or serum lipid levels, and had modest, reversible effects on semen parameters.
Mean peak serum concentrations of dutasteride were achieved 1–3 hours after oral administration of a single 0.5 mg dose, with steady-state concentrations achieved after 24 weeks’ administration of a once-daily 0.5 mg dose. The absolute bioavailability of dutasteride is ≈60% and the drug is highly bound to plasma proteins. It is extensively distributed throughout central and peripheral compartments, including semen, with a large volume of distribution (300–500 L). Steady-state concentrations of the drug are seen in semen after 6 months. Dutasteride is extensively metabolized in the liver via the cytochrome P450 (CYP) isoenzymes CYP3A4 and CYP3A5, and is mainly excreted via the faeces. The terminal elimination half-life at steady state is 5 weeks. Dutasteride has no pharmacokinetic interactions with α1-adrenergic antagonists, warfarin, digoxin or cholestyramine. Because of the potential for increased systemic exposure, caution is required when dutasteride is coadministered with potent, chronic CYP3A4 inhibitors, such as ritonavir.
Dutasteride was superior to placebo in the treatment of symptomatic BPH in the phase III dutasteride trials. The co-primary endpoints in these trials, which were evaluated using pre-planned pooled analyses in ≥4000 patients, were changes in the American Urological Association Symptom Index (AUA-SI) from baseline at 1 year and in the risk of AUR at 2 years. Dutasteride 0.5 mg once daily for 2 years was associated with a clinically significant improvement in the mean AUA-SI score from baseline (mean reduction of 4.5 points; p < 0.001 vs baseline and placebo). Clinically relevant improvements from baseline were seen after 6 months’ therapy with dutasteride and between-group differences evident at 1 year were maintained throughout the treatment period. The relative risks of AUR and BPH-related surgical interventions in dutasteride recipients were reduced by 57% and 48%, respectively, versus placebo at 2 years (both p < 0.001). Dutasteride reduced TPV (by a mean of ≈26%), improved urinary flow (Qmax) from baseline and was associated with clinically relevant improvements in health-related quality of life. The beneficial effects of dutasteride on AUA-SI scores, urinary flow, AUR, BPH-related surgery and TPV were maintained for up to 4 years in extension studies.
The efficacy of dutasteride and tamsulosin, alone and in combination, is under investigation in the 4-year CombAT trial, which has enrolled 4844 men with moderate to severe symptoms of BPH and prostate enlargement. Combination therapy with dutasteride and tamsulosin was superior (p < 0.001) to each drug as monotherapy with regard to symptom improvements in the 2-year interim analysis. Improvements in symptoms from baseline were significantly greater with combination therapy from month 3 versus dutasteride, and from month 9 versus tamsulosin (both p < 0.001). Improvements in Qmax from baseline were significantly (p ≤ 0.006) greater with combination therapy versus each monotherapy at each post-baseline visit from month 6 through to year 2.
Dutasteride was generally well tolerated, with similar proportions of dutasteride or placebo recipients reporting an adverse event in the phase III dutasteride trials. Although the incidence of treatment-related sexual adverse events (impotence, decreased libido, ejaculation disorder and gynaecomastia) was increased with dutasteride versus placebo, this was generally transient and the incidence of each event was low (1.8–6.0% vs 0.5–3.0% in year 1, reducing to 0.5–1.7% vs 0.1–1.2% in year 2). Only gynaecomastia occurred significantly more frequently with dutasteride than with placebo after the first 6 months of treatment. The tolerability profile of dutasteride after 4 years of treatment in the extension studies was consistent with that at 2 years. In the CombAT trial, the profile of adverse events at the 2-year interim analysis with the combination of dutasteride and tamsulosin was consistent with those of the respective monotherapies. Although the incidence of drug-related adverse events was significantly higher in the combination therapy group compared with each monotherapy group (both p < 0.001) in the CombAT trial, withdrawal rates were low, with no substantial differences between treatment groups.
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