Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: testosterone-5-alpha-reductase inhibitors, ATC code: G04C B02.

Dutasteride reduces circulating levels of dihydrotestosterone (DHT) by inhibiting both type 1 and type 2, 5- reductase isoenzymes which are responsible for the conversion of testosterone to -DHT.

AVODART AS MONOTHERAPY

Effects on DHT/Testosterone:
Effect of daily doses of Avodart on the reduction on DHT is dose dependant and is observed within 1-2 weeks (85% and 90% reduction, respectively).
In patients with BPH treated with dutasteride 0.5 mg/day, the median decrease in serum DHT was 94% at 1 year and 93% at 2 years and the median increase in serum testosterone was 19% at both 1 and 2 years.

Effect on Prostate Volume:

Significant reductions in prostate volume have been detected as early as one month after initiation of treatment and reductions continued through Month 24 (p<0.001). Avodart led to a mean reduction of total prostate volume of 23.6% (from 54.9 ml at baseline to 42.1 ml) at Month 12 compared with a mean reduction of 0.5% (from 54.0 ml to 53.7 ml) in the placebo group. Significant (p<0.001) reductions also occurred in prostate transitional zone volume as early as one month continuing through Month 24, with a mean reduction in prostate transitional zone volume of 17.8% (from 26.8 ml at baseline to 21.4 ml) in the Avodart group compared to a mean increase of 7.9% (from 26.8ml to 27.5 ml) in the placebo group at Month 12. The reduction of the prostate volume seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies. Reduction of the size of the prostate leads to improvement of symptoms and a decreased risk for AUR and BPH-related surgery.


Clinical efficacy and safety

Avodart 0.5 mg/day or placebo was evaluated in 4325 male subjects with moderate to severe symptoms of BPH who had prostates  30ml and a PSA value within the range 1.5 - 10 ng/mL in three primary efficacy 2- year multicenter, multinational, placebo-controlled, double-blind studies. The studies then continued with an open-label extension to 4 years with all patients remaining in the study receiving dutasteride at the same 0.5 mg dose. 37% of initially placebo-randomized patients and 40% of dutasteride-randomized patients remained in the study at 4 years. The majority (71%) of the 2,340 subjects in the open-label extensions completed the 2 additional years of open-label treatment.

The most important clinical efficacy parameters were American Urological Association Symptom Index (AUA-SI), maximum urinary flow (Qmax) and the incidence of acute urinary retention and BPH-related surgery.

AUA-SI is a seven-item questionnaire about BPH-related symptoms with a maximum score of 35. At baseline the average score was approx. 17. After six months, one and two years treatment the placebo group had an average improvement of 2.5, 2.5 and 2.3 points respectively while the Avodart group improved 3.2, 3.8 and 4.5 points respectively. The differences between the groups were statistically significant. The improvement in AUA-SI seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies.

Qmax (maximum urine flow)

Mean baseline Qmax for the studies was approx 10 ml/sec (normal Qmax 15 ml/sec). After one and two years treatment the flow in the placebo group had improved by 0.8 and 0.9 ml/sec respectively and 1.7 and 2.0 ml/sec respectively in the Avodart group. The difference between the groups was statistically significant from Month 1 to Month 24. The increase in maximum urinary flow rate seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies.

Acute Urinary Retention and Surgical Intervention

After two years of treatment, the incidence of AUR was 4.2% in the placebo group against 1.8% in the Avodart group (57% risk reduction). This difference is statistically significant and means that 42 patients (95% CI 30-73) need to be treated for two years to avoid one case of AUR.

The incidence of BPH-related surgery after two years was 4.1% in the placebo group and 2.2% in the Avodart group (48% risk reduction). This difference is statistically significant and means that 51 patients (95% CI 33-109) need to be treated for two years to avoid one surgical intervention.

Hair distribution

The effect of dutasteride on hair distribution was not formally studied during the phase III programme, however, 5 alpha-reductase inhibitors could reduce hair loss and may induce hair growth in subjects with male pattern hair loss (male androgenetic alopecia).

Thyroid function

Thyroid function was evaluated in a one year study in healthy men. Free thyroxine levels were stable on dutasteride treatment but TSH levels were mildly increased (by 0.4 MCIU/mL) compared to placebo at the end of one year's treatment. However, as TSH levels were variable, median TSH ranges (1.4-1.9 MCIU/mL) remained within normal limits (0.5 - 5/6 MCIU/mL), free thyroxine levels were stable within the normal range and similar for both placebo and dutasteride treatment, the changes in TSH were not considered 
clinically significant. In all the clinical studies, there has been no evidence that dutasteride adversely affects thyroid function.

Breast neoplasia

In the 2 year clinical trials, providing 3374 patient years of exposure to dutasteride, and at the time of registration in the 2 year open label extension, there were 2 cases of male breast cancer reported in dutasteride-treated patients and 1 case in a patient who received placebo. In the 4 year CombAT and REDUCE clinical trials providing 17489 patient years exposure to dutasteride and 5027 patient years exposure to dutasteride and tamsulosin combination, there were no cases of breast cancer reported in any treatment groups.

Two case control, epidemiological studies, one conducted in a US (n=339 breast cancer cases and n=6,780 controls) and the other in a UK (n=398 breast cancer cases and n=3,930 controls) healthcare database, showed no increase in the risk of developing male breast cancer with the use of 5-alpha reductase inhibitors (see section 4.4). Results from the first study did not identify a positive association for male breast cancer (relative risk for  1-year of use before breast cancer diagnosis compared with < 1-year of use: 0.70: 95% CI 0.34, 1.45). In the second study, the estimated odds ratio for breast cancer associated with the use of 5-alpha reductase inhibitors compared with non-use was 1.08: 95% CI 0.62, 1.87).

A causal relationship between the occurrence of male breast cancer and long term use of dutasteride has not been established.

Effects on male fertility

The effects of dutasteride 0.5mg/day on semen characteristics were evaluated in healthy volunteers aged 18 to 52 (n=27 dutasteride, n=23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reduction from baseline in total sperm count, semen volume and sperm motility were 23%, 26% and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all parameters at all time points remained within the normal ranges and did not meet the predefined criteria for a clinically significant change (30%), two subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24 week follow-up. The possibility of reduced male fertility cannot be excluded.


AVODART IN COMBINATION WITH THE ALPHA-BLOCKER TAMSULOSIN
Avodart 0.5 mg/day (n = 1,623), tamsulosin 0.4 mg/day (n = 1,611) or the combination of Avodart 0.5 mg plus tamsulosin 0.4 mg (n = 1,610) were evaluated in male subjects with moderate to severe symptoms of BPH who had prostates 30 ml and a PSA value within the range 1.5 - 10 ng/mL in a multicentre, multinational, randomized double-blind, parallel group study (the CombAT study). Approximately 53% of subjects had previous exposure to 5-alpha reductase inhibitor or alpha-blocker treatment. The primary efficacy endpoint during the first 2 years of treatment was change in International Prostate Symptom Score (IPSS), an 8-item instrument based on AUA-SI with an additional question on quality of life. Secondary efficacy endpoints at 2 years included maximum urine flow rate (Qmax) and prostate volume. The combination achieved significance for IPSS from Month 3 compared to Avodart and from Month 9 compared to tamsulosin. For Qmax combination achieved significance from Month 6 compared to both Avodart and tamsulosin.

The primary efficacy endpoint at 4 years of treatment was time to first event of AUR or BPH-related surgery.
After 4 years of treatment, combination therapy statistically significantly reduced the risk of AUR or BPH- related surgery (65.8% reduction in risk p<0.001 [95% CI 54.7% to 74.1%]) compared to tamsulosin monotherapy. The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 11.9% for tamsulosin (p<0.001). Compared to Avodart monotherapy, combination therapy reduced the risk of AUR or BPH-related surgery by 19.6% (p=0.18 [95% CI -10.9% to 41.7%]). The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 5.2% for Avodart.
Secondary efficacy endpoints after 4 years of treatment included time to clinical progression (defined as a composite of: IPSS deterioration by 4 points, BPH-related events of AUR, incontinence, urinary tract infection (UTI), and renal insufficiency) change in International Prostate Symptom Score (IPSS), maximum urine flow rate (Qmax) and prostate volume. Results following 4 years of treatment are presented below: 
Parameter               Time-point                              Combination        Avodart       Tamsulosin 
AUR or BPH related Incidence at Month 48                             4.2             5.2            11.9a surgery (%)
Clinical progression* Month 48                                       12.6           17.8b           21.5a (%)
IPSS (units)          [Baseline]                                    [16.6]          [16.4]          [16.4] Month 48 (Change from Baseline)                 -6.3          -5.3b            -3.8a Qmax (mL/sec)         [Baseline]                                    [10.9]          [10.6]          [10.7] Month 48 (Change from Baseline)                 2.4             2.0            0.7a Prostate Volume (ml) [Baseline]                                     [54.7]          [54.6]          [55.8] Month 48 (% Change from Baseline)             -27.3           -28.0           +4.6a Prostate Transition   [Baseline]                                    [27.7]          [30.3]          [30.5] Zone Volume (ml)# Month 48 (% Change from Baseline)                 -17.9           -26.5           18.2a BPH Impact Index      [Baseline]                                     [5.3]           [5.3]           [5.3] (BII) (units)         Month 48 (Change from Baseline)                 -2.2          -1.8b            -1.2a IPSS Question 8       [Baseline]                                     [3.6]           [3.6]           [3.6] (BPH-related Health Month 48 (Change from Baseline)                   -1.5          -1.3b            -1.1a Status) (units)

Baseline values are mean values and changes from baseline are adjusted mean changes.
* Clinical progression was defined as a composite of: IPSS deterioration by 4 points, BPH-related events of AUR, incontinence, UTI, and renal insufficiency.
# Measured at selected sites (13% of randomized patients) a. Combination achieved significance (p<0.001) vs. tamsulosin at Month 48 b. Combination achieved significance (p<0.001) vs. Avodart at Month 48 
CARDIOVASCULAR ADVERSE EVENTS

In a 4 year BPH study of Avodart in combination with tamsulosin in 4844 men (the CombAT study) the incidence of the composite term cardiac failure in the combination group (14/1610, 0.9%) was higher than in either monotherapy group: Avodart, (4/1623, 0.2%) and tamsulosin, (10/1611, 0.6%).

In a separate 4-year study in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years of age, or 3 ng/mL and 10.0 ng/mL in the case of men older than 60 years of age) (the REDUCE study), there was a higher incidence of the composite term cardiac failure in subjects taking Avodart 0.5 mg once daily (30/4105, 0.7%) compared to subjects taking placebo (16/4126, 0.4%). A post-hoc analysis of this study showed a higher incidence of the composite term cardiac failure in subjects taking Avodart and an alpha blocker concomitantly (12/1152, 1.0%), compared to subjects taking Avodart and no alpha blocker (18/2953, 0.6%), placebo and an alpha blocker (1/1399, <0.1%), or placebo and no alpha blocker (15/2727, 0.6 %). (see section 4.4).

In a meta-analysis of 12-randomised, placebo- or comparator-controlled clinical studies (n=18,802) that evaluated the risks of developing cardiovascular adverse events from the use of Avodart (by comparison with controls), no consistent statistically significant increase in the risk of heart failure (RR 1.05; 95% CI 0.71, 1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77, 1.30) or stroke (RR 1.20; 95% CI 0.88, 1.64) were found.

PROSTATE CANCER AND HIGH GRADE TUMOURS
In a 4-year comparison of placebo and Avodart in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years of age, or 3 ng/mL and 10.0 ng/mL in the case of men older than 60 years of age) (the REDUCE study), 6,706 subjects had prostate needle biopsy (primarily protocol mandated) data available for analysis to determine Gleason Scores. There were 1517 subjects diagnosed with prostate cancer in the study. The majority of biopsy-detectable prostate cancers in both treatment groups were diagnosed as low grade (Gleason 5-6, 70%).

There was a higher incidence of Gleason 8-10 prostate cancers in the Avodart group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%) (p=0.15). In Years 1-2, the number of subjects with Gleason 8-10 cancers was similar in the Avodart group (n=17, 0.5%) and the placebo group (n=18, 0.5%). In Years 3-4, more Gleason 8-10 cancers were diagnosed in the Avodart group (n=12, 0.5%) compared with the placebo group (n=1, <0.1%) (p=0.0035). There are no data available on the effect of Avodart beyond 4 years in men at risk of prostate cancer. The percentage of subjects diagnosed with Gleason 8-10 cancers was consistent across study time periods (Years 1-2 and Years 3-4) in the Avodart group (0.5% in each time period), while in the placebo group, the percentage of subjects diagnosed with Gleason 8-10 cancers was lower during Years 3-4 than in Years 1-2 (<0.1% versus 0.5%, respectively) (see section 4.4). There was no difference in the incidence of Gleason 7-10 cancers (p=0.81).

The additional 2-year follow-up study of the REDUCE trial did not identify any new cases of Gleason 8–10 prostate cancers.

In a 4 year BPH study (CombAT) where there were no protocol-mandated biopsies and all diagnoses of prostate cancer were based on for-cause biopsies, the rates of Gleason 8-10 cancer were (n=8, 0.5%) for Avodart, (n=11, 0.7%) for tamsulosin and (n=5, 0.3%) for combination therapy.

Four different epidemiological, population-based studies (two of which were based on a total population of 174,895, one on a population of 13,892, and one on a population of 38,058) showed that the use of 5-alpha reductase inhibitors is not associated with the occurrence of high grade prostate cancer, nor with prostate cancer, or overall mortality.

The relationship between Avodart and high grade prostate cancer is not clear.

Effects on sexual function:
The effects of dutasteride-tamsulosin fixed dose combination on sexual function were assessed in a double- blind, placebo-controlled study in sexually active men with BPH (n=243 dutasteride-tamsulosin combination, n=246 placebo). A statistically significant (p<0.001) greater reduction (worsening) in the Men’s Sexual Health Questionnaire (MSHQ) score was observed at 12 months in the combination group.
The reduction was mainly related to a worsening of the ejaculation and overall satisfaction domains rather than the erection domains. These effects did not affect study participants’ perception of the combination, which was rated with a statistically significant greater satisfaction throughout the duration of the study compared with placebo (p<0.05). In this study the sexual adverse events occurred during the 12 months of treatment and approximately half of these resolved within 6 months post-treatment.

Dutasteride-tamsulosin combination and dutasteride monotherapy are known to cause sexual function adverse effects (see section 4.8).

As observed in other clinical studies, including CombAT and REDUCE, the incidence of adverse events related to sexual function decreases over time with continued therapy.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Absorption

Following oral administration of a single 0.5 mg dutasteride dose, the time to peak serum concentrations of dutasteride is 1 to 3 hours. The absolute bioavailability is approximately 60%. The bioavailability of dutasteride is not affected by food.

Distribution

Dutasteride has a large volume of distribution (300 to 500 L) and is highly bound to plasma proteins (>99.5%). Following daily dosing, dutasteride serum concentrations achieve 65% of steady state concentration after 1 month and approximately 90% after 3 months.

Steady state serum concentrations (Css) of approximately 40 ng/mL are achieved after 6 months of dosing 0.5mg once a day. Dutasteride partitioning from serum into semen averaged 11.5%.

Biotransformation

Dutasteride is extensively metabolised in vivo. In vitro, dutasteride is metabolised by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite.

Following oral dosing of dutasteride 0.5 mg/day to steady state, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as unchanged dutasteride in the faeces. The remainder is excreted in the faeces as 4 major metabolites comprising 39%, 21%, 7%, and 7% each of drug-related material and 6 minor metabolites (less than 5% each). Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are detected in human urine.

Elimination

The elimination of dutasteride is dose dependent and the process appears to be described by two elimination pathways in parallel, one that is saturable at clinically relevant concentrations and one that is non saturable.
At low serum concentrations (less than 3ng/mL), dutasteride is cleared rapidly by both the concentration dependent and concentration independent elimination pathways. Single doses of 5 mg or less showed evidence of rapid clearance and a short half-life of 3 to 9 days.

At therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower, linear elimination pathway is dominating and the half-life is approx. 3-5 weeks.

Elderly

Dutasteride pharmacokinetics were evaluated in 36 healthy male subjects between the ages of 24 and 87 years following administration of a single 5mg dose of dutasteride. No significant influence of age was seen on the exposure of dutasteride but the half-life was shorter in men under 50 years of age. Half-life was not statistically different when comparing the 50-69 year old group to the greater than 70 years old.

Renal impairment

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5 mg dose of dutasteride is recovered in human urine, so no clinically significant increase of the dutasteride plasma concentrations is anticipated for patients with renal impairment (see section 4.2).

Hepatic impairment

The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied (see section 4.3). Because dutasteride is eliminated mainly through metabolism the plasma levels of dutasteride are expected to be elevated in these patients and the half-life of dutasteride be prolonged (see section 4.2 and section 4.4).