Propecia Mechanism of Action

PROPECIA (finasteride, MSD) is a synthetic 4-azasteroid compound that is a specific inhibitor of Type II 5α-reductase, an intracellular enzyme that metabolizes the androgen testosterone into dihydrotestosterone (DHT).
Pharmacology: Pharmacodynamics: Finasteride is a competitive and specific inhibitor of Type II 5α-reductase. Finasteride has no affinity for the androgen receptor and has no androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects. Inhibition of this enzyme blocks the peripheral conversion of testosterone to the androgen dihydrotestosterone (DHT), resulting in significant decreases in serum and tissue DHT concentrations. Circulating levels of testosterone were increased by approximately 10-15% compared with placebo, yet remained within the physiologic range.
Finasteride produces a rapid reduction in serum DHT concentration, reaching significant suppression within 24 hours of dosing.
Hair follicles contain Type II 5α-reductase. In men with male pattern hair loss, the balding scalp contains miniaturized hair follicles and increased amounts of DHT. Administration of finasteride decreases scalp and serum DHT concentrations in these men. Men with a genetic deficiency of Type II 5α-reductase do not suffer from male pattern hair loss. These data and the results of the clinical studies confirm that finasteride inhibits the process responsible for miniaturization of the scalp hair follicles, leading to reversal of the balding process.
The efficacy of PROPECIA was demonstrated in three studies in 1879 men 18 to 41 years of age with mild to moderate, but not complete, vertex and frontal/mid-area hair loss. In these studies, hair growth was assessed using four separate measures including hair count, rating of photographs of the head by an expert panel of dermatologists, investigator assessment, and patient self-assessment.
In the two studies in men with vertex hair loss, treatment with PROPECIA was continued for 5 years, during which time patients improved compared to both baseline and placebo beginning as early as 3 months. Treatment with PROPECIA for 5 years resulted in stabilization of hair loss in 90% of men based on photographic assessment and in 93% based on investigator assessment. In addition, increased hair growth was reported in 65% of men treated with PROPECIA based on hair counts (vs 0% of the placebo group), in 48% based on photographic assessment (vs 6% of the placebo group), and in 77% based on investigator assessment (vs 15% of the placebo group). In contrast, in the placebo group, gradual hair loss over time was observed in 100% of men based on hair counts (vs 35% of men treated with PROPECIA), in 75% based on photographic assessment (vs 10% of men treated with PROPECIA), and in 38% based on investigator assessment (vs 7% of men treated with PROPECIA). In addition, patient self-assessment demonstrated significant increases in hair density, decreases in hair loss, and improvement in appearance of hair over 5 years of treatment with PROPECIA. While hair improvement measures compared to baseline were greatest in men treated with PROPECIA at 2 years and gradually declined thereafter (e.g., increase of 88 hairs in a representative 5.1 cm² area at 2 years and increase of 38 hairs at 5 years), hair loss in the placebo group progressively worsened compared to baseline (decrease of 50 hairs at 2 years and 239 hairs at 5 years). Thus, based on all four measures, the difference between treatment groups continued to increase throughout the 5 years of the studies.
The 12-month study in men with frontal/mid-area hair loss also demonstrated significant improvements in scalp hair growth and appearance as evaluated by the same measures as those described previously.
A 48-week, placebo-controlled study designed to assess the effect of PROPECIA on the phases of the hair-growth cycle (growing phase [anagen] and resting phase [telogen]) in vertex baldness enrolled 212 men with androgenetic alopecia. At baseline and 48 weeks, total, telogen, and anagen hair counts were obtained in a 1-cm² target area of the scalp. Treatment with PROPECIA led to improvements in anagen hair counts, while men in the placebo group lost anagen hair. At 48 weeks, men treated with PROPECIA showed net increases in total and anagen hair counts of 17 hairs and 27 hairs, respectively, compared to placebo. This increase in anagen hair count, compared to total hair count, led to a net improvement in the anagen-to-telogen ratio of 47% at 48 weeks for men treated with PROPECIA, compared to placebo. These data provide direct evidence that treatment with PROPECIA promotes the conversion of hair follicles into the actively growing phase.
In summary, these studies demonstrated that treatment with PROPECIA increases hair growth and prevents further hair loss in men with androgenetic alopecia.
Pharmacokinetics: Absorption: Relative to an intravenous reference dose, the oral bioavailability of finasteride is approximately 80%. The bioavailability is not affected by food. Maximum finasteride plasma concentrations are reached approximately 2 hours after dosing and the absorption is complete after 6-8 hours.
Distribution: Protein binding is approximately 93%. The volume of distribution of finasteride is approximately 76 liters.
At steady state following dosing with 1 mg/day, maximum finasteride plasma concentration averaged 9.2 ng/mL and was reached 1-2 hours postdose; AUC _{(0-24 hr)} was 53 ng·hr/mL.
Finasteride has been recovered in the cerebrospinal fluid (CSF) but the drug does not appear to concentrate preferentially to the CSF. A very small amount of finasteride has also been detected in the seminal fluid of subjects receiving finasteride.
Biotransformation: Finasteride is metabolized primarily via the cytochrome P450 3A4 enzyme subfamily. Following an oral dose of ¹⁴C-finasteride in man, two metabolites of finasteride were identified that possess only a small fraction of the 5α-reductase inhibitory activity of finasteride.
Elimination: Following an oral dose of ¹⁴C-finasteride in man, 39% of the dose was excreted in the urine in the form of metabolites (virtually no unchanged drug was excreted in the urine) and 57% of total dose was excreted in the feces.
Plasma clearance is approximately 165 mL/min.
The elimination rate of finasteride decreases somewhat with age. Mean terminal half-life is approximately 5-6 hours in men 18-60 years of age and 8 hours in men older than 70 years of age. These findings are of no clinical significance and hence, a reduction in dosage in the elderly is not warranted.
Characteristics in Patients: No adjustment in dosage is necessary in nondialyzed patients with renal impairment.
Toxicology: Animal Toxicology: Acute Toxicity: The oral LD₅₀ of finasteride in male and female mice is approximately 500 mg/kg. The oral LD₅₀ of finasteride in female and male rats is approximately 400 and 1,000 mg/kg, respectively.
Chronic Toxicity: Repeated oral toxicity studies up to 1 year were done in rats and dogs given high doses of finasteride up to 80 mg/kg/day (4,000 times the recommended human dose of 1 mg/day). In rats, increased incidence of testicular Leydig cell hyperplasia at doses ≥40 mg/kg/day (≥2,000 times the recommended human dose of 1 mg/day) was observed in the 1-year study (see Carcinogenicity as follows). There were no findings in the chronic toxicity studies that would preclude use of finasteride for the treatment of men with male pattern hair loss.
Carcinogenicity: No evidence of a tumorigenic effect was observed in a 24-month study in rats receiving doses of finasteride up to 320 mg/kg/day (16,000 times the recommended human dose of 1 mg/day).
In a 19-month carcinogenicity study in mice, a statistically significant (p≤0.05) increase in the incidence of testicular Leydig cell adenoma was observed at a dose of 250 mg/kg/day (12,500 times the recommended human dose of 1 mg/day); no adenomas were seen in mice given 2.5 or 25 mg/kg/day (125 and 1,250 times the recommended human dose of 1 mg/day, respectively).
In mice at a dose of 25 mg/kg/day and in rats at a dose of ≥40 mg/kg/day (1,250 and ≥2,000 times the recommended human dose of 1 mg/day, respectively), an increase in the incidence of Leydig cell hyperplasia was observed.
A positive correlation between the proliferative changes of the Leydig cells and the increase in serum LH levels (2-3 fold above control) has been demonstrated in both rodent species treated with high doses of finasteride. This suggests the Leydig cell changes are secondary to elevated serum LH levels and not due to a direct effect of finasteride.
No drug-related Leydig cell changes were seen in either rats or dogs treated with finasteride for one year at doses of 20 mg/kg/day and 45 mg/kg/day (1,000 and 2,250 times the recommended human dose of 1 mg/day, respectively) or in mice treated for 19 months at a dose of 2.5 mg/kg/day (125 times the recommended human dose of 1 mg/day).
Mutagenesis: No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration assay, when Chinese hamster ovary cells were treated with high concentrations (450-550 μmol) of finasteride, there was a slight increase in chromosome aberrations. These concentrations correspond to 18,000-22,000 times the peak plasma levels in man given a total dose of 1 mg. Further, the concentrations (450-550 μmol) used in the in vitro studies are not achievable in a biological system. In an in vivo chromosome aberration assay in mice, no treatment-related increases in chromosome aberration were observed with finasteride at the maximum tolerated dose (250 mg/kg/day; 12,500 times the recommended human dose of 1 mg/day).