Source: Web Search Revision Year: 2019
The development and enlargement of the prostate gland is dependent on the potent androgen, 5αdihydrotestosterone (DHT). Type II 5 α-reductase metabolizes testosterone to DHT in the prostate gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs.
Finasteride is a synthetic 4-azasteroid compound. Finasteride is a competitive and specific inhibitor of Type II 5 alpha-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t½ ~30 days). This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride.
In man, a single 5 mg oral dose of finasteride produces a rapid reduction in serum DHT concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of finasteride at 5 mg/day for up to 4 years has been shown to reduce the serum DHT concentration by approximately 70%. The median circulating level of testosterone increased by approximately 10–20%,but remained within the physiologic range. In a separate study in healthy men treated with finasteride 1 mg per day (n=82) or placebo (n=69), mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline, but these remained within the physiologic range.
In patients receiving finasteride 5 mg/day, increases of about 10% were observed in luteinizing hormone (LH) and follicle-stimulating hormone (FSH), but levels remained within the normal range. In healthy volunteers, treatment with finasteride did not alter the response of LH and FSH to gonadotropin-releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected.
In patients with BPH, finasteride has no effect on circulating levels of cortisol, prolactin, thyroidstimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral density.
Adult males with genetically inherited Type II 5 alpha-reductase deficiency also have decreased levels of DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to Type II 5 alpha-reductase deficiency have been observed in these individuals. These individuals have a small prostate gland throughout life and do not develop BPH.
In patients with benign prostatic hyperplasia (BPH) treated with finasteride (1–100 mg/day) for 7–10 days prior to prostatectomy, an approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to placebo; testosterone tissue concentration was increased up to 10 times over pre-treatment levels, relative to placebo. Intraprostatic content of the prostatespecific antigen (PSA) was also decreased.
In healthy male volunteers treated with finasteride for 14 days, discontinuation of therapy resulted in a return of DHT levels to pre-treatment levels in approximately 2 weeks. In patients treated for 3 months, prostate volume, which declined by approximately 20%, returned to close to baseline value after approximately 3 months of discontinuation of therapy.
In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5 mg tablets was 63% (range: 34% to 108%), based on the ratio of area under the curve (AUC) relative to an intravenous (I.V.) reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range: 27 to 49 ng/mL) and was reached 1–2 hours postdose. Bioavailability of finasteride was not affected by food.
Mean steady-state volume of distribution was 76 litres (range: 44 to 96 litres). Approximately 90% of circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of finasteride were 47% and 54% higher than after the first dose in males aged 45 to 60 years (n=12) and 70 years and older (n=12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range: 2.4 to 9.8 ng/mL) and 8.1 ng/mL (range: 1.8 to 19.7 ng/mL), respectively, in the two age groups. Although the steady state was not reached in this study, mean trough plasma concentration in another study in patients with BPH (mean age: 65 years) receiving 5 mg/day was 9.4 ng/mL (range: 7.1 to 13.3 ng/mL; n=22) after over a year of dosing.
Finasteride has been shown to cross the blood–brain barrier but does not appear to distribute preferentially to the cerebrospinal fluid (CSF).
In two studies of healthy subjects (n=69) receiving finasteride 5 mg/day for 6–24 weeks, finasteride concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving finasteride 5 mg/day ranged from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5 mL ejaculate volume, the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride (5 µg) that had no effect on circulating DHT levels in men.
Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites, have been identified that possess no more than 20% of the 5 -reductase inhibitory activity of finasteride.
In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range: 70 to 279 mL/min) and mean elimination half-life in plasma was 6 hours (range: 3 to 16 hours). Following an oral dose of 14C-finasteride in man (n=6), a mean of 39% (range: 32% to 46%) of the dose was excreted in the urine in the form of metabolites; 57% (range: 51% to 64%) was excreted in the faeces.
The mean terminal half-life of finasteride in subjects >70 years of age was approximately 8 hours (range: 6 to 15 hours; n=12), compared with 6 hours (range: 4 to 12 hours; n=12) in subjects 45 to 60 years of age. As a result, the mean AUC after 17 days of dosing was 15% higher in subjects >70 years of age than in subjects 45 to 60 years of age (p=0.02).
Table 1. Mean (SD) Pharmacokinetic Parameters in Healthy Young Subjects (n=15):
| Mean (SD) | |
|---|---|
| Bioavailability | 63% (34-108%)* |
| Clearance (mL/min) | 165 (55) |
| Volume of Distribution (L) | 76 (14) |
| Half-Life (hours) | 6.2 (2.1) |
* Range
Finasteride pharmacokinetics have not been investigated in patients <18 years of age. Finasteride is not indicated for use in pediatric patients
Finasteride is not indicated for use in women
No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is decreased in the elderly, these findings are of no clinical significance.
Table 2. Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5 mg/day in Older Men:
| Mean (± SD) | ||
|---|---|---|
| 45-60 years old (n=12) | >70 years old (n=12) | |
| AUC (ng hr/mL) | 389 (98) | 463 (186) |
| Peak Concentration (ng/mL) | 46.2 (8.7) | 48.4 (14.7) |
| Time to Peak (hours) | 1.8 (0.7) | 1.8 (0.6) |
| Half-Life (hours)* | 6.0 (1.5) | 8.2 (2.5) |
* First-dose values; all other parameters are last-dose values
The effect of race on finasteride pharmacokinetics has not been studied.
The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution should be exercised in the administration of finasteride in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.
No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to values obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60% increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these patients to metabolites would presumably be much greater.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
