Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: other dermatologicals, ATC code: D11AX 
The effect of minoxidil 5% has been assessed in a phase III clinical trial conducted over a 48 week treatment period.

In this study minoxidil (5% minoxidil cutaneous solution) was compared to the product vehicle without the minoxidil active ingredient and also to           2% minoxidil cutaneous solution.

The primary efficacy criterion was non-vellus hair count in a 1.0cm2 reference area of affected scalp. The mean changes observed in this parameter in these studies were significantly in favour of active treatment. A significant dose effect was also demonstrated. The results are summarized in the following table:


Mean change in non-vellus hair count in reference 1cm2 area of scalp compared with baseline
Pairwise comparison
(n=139)                (n=142)           (n=71)
Minoxidil 5%          Minoxidil 2%          Vehicle
Baseline           151.1                  143.6             152.4 Mean change from        Mean change       Mean change baseline           from baseline     from baseline
8 weeks           +29.7                  +24.9             +14.3        5%>2%>vehicle 16 weeks           +35.3                  +29.8             +15.3        5%>2%>vehicle 32 weeks           +29.0                  +22.2             +7.7         5%>2%>vehicle 48 weeks           +18.6                  +12.7             +3.9         5%>2%>vehicle
Efficacy was further assessed by comparing photographs taken at various timepoints with baseline.

Assessment was undertaken by patients using a 100 mm visual analogue scale and assessing scalp coverage where point 0 represented much less scalp coverage, 50 mm no difference and
100 mm much more scalp coverage. In addition, an assessment was undertaken by 2 blinded reviewers who compared photographs taken at baseline and after 48 weeks. Differences were assessed using a 7 point categorical scale viz:
Dense growth
Moderate growth
Minimal growth
No change
Minimal loss
Moderate loss
Dense loss

The results of these analyses were as follows:
Patient evaluation of change in scalp coverage
(n=139)           (n=142)          (n=71)           Pairwise
Minoxidil 5%    Minoxidil 2%         Vehicle         comparison mm                mm               mm
16 weeks           63.5              58.2            51.4         5%>2%>vehicle 32 weeks           63.4              58.0            52.0         5%>2%>vehicle    48 weeks            62               56.9            51.0         5%>2%>vehicle


Photographic Evaluation of Clinical Response (Reviewer 1)
Dense    Moderate Minimal             No      Hair Loss     Unable Growth     Growth      Growth        change        %         to rate %           %           %            %
Minoxidil
5%                2.2          37.4         22.3         31.7         5.0     1.4 Minoxidil
2%                2.8          19.7         21.1         50.0         2.8     3.5

Vehicle            0           7.0          22.5         60.0         9.9      0 

Photographic Evaluation of Clinical Response (Reviewer 2)
Dense    Moderate Minimal            No      Hair Loss Unable to
Growth     Growth      Growth       change       %        rate
%          %           %           %
Minoxidi l 5%             10.1         20.1         23.7         28.8         6.5    10.8 Minoxidi l 2%              3.5         12.0         22.5         47.2       1.4      13.4 Vehicle            0           7.0          9.9         60.6      14.1       8.5 Based upon these photographic data, around 60% of the patients experienced an increased scalp coverage after 48 weeks treatment with minoxidil 5|% as defined by re-growth of hair; compared with around         23% as an average for those who received vehicle alone. Of these,
around 35% treated with minoxidil 5% experienced dense or moderate re-growth compared with around 7% who received vehicle alone. In addition 30% of patients who received minoxidil 5% were adjudged to have no change between the photographic assessments of hair growth compared with 60% who received vehicle alone. Stabilisation of hair loss (expressed both as re-growth of hair and no continuation of hair loss) can therefore be expected in about 4 out of 5 of patients using minoxidil 5% compared with 3 out of 4 patients using vehicle alone.
 minoxidil 5% may therefore be considered by men who wish to achieve a faster onset and greater degree of hair re-growth than would be expected through the use of minoxidil 2%

The mechanism by which minoxidil stimulates hair growth is not fully understood, but minoxidil can reverse the hair loss process of androgenetic alopecia by the following means:
− increasing the diameter of the hair shaft
− stimulating anagen growth
− prolonging the anagen phase
− stimulating anagen recovery from the telegon phase

As a peripheral vasodilator minoxidil enhances microcirculation to hair follicles. The Vascular Endothelial Growth Factor (VEGF) is stimulated by minoxidil and VEGF is presumably responsible for the increased capillary fenestration, indicative of a high metabolic activity, observed during the anagen phase.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
The failure to detect evidence of systemic effects during treatment with minoxidil solution reflects the poor absorption of topically applied minoxidil from normal intact skin. Systemic absorption of minoxidil from topically applied solution ranges between 1% and 2% of the total applied dose.

The systemic absorption of minoxidil from a 5% solution formulation has been estimated in a pharmacokinetic study in subjects with androgenetic alopecia, which included 5% topical foam as a comparator. This demonstrated that in men, the systemic absorption of minoxidil from twice daily application of 5% minoxidil solution was about twice that, as observed with 5% minoxidil foam.
The mean steady state AUC(0-12 h) and Cmax for 5% minoxidil foam, 8.81 ng·h/ml and 1.11 ng/ml, respectively, were both approximately 50% of AUC(0-12 h) and Cmax of the 5% solution, 18.71 ng·h/ml and 2.13 ng/ml, respectively. The time to maximum minoxidil concentration (Tmax) for the 5% solution, 5.79 hours, was similar to Tmax for the 5% foam, 5.42 hours.
There is some evidence from in vitro studies that minoxidil reversibly binds to human plasma proteins. However, since only 1 – 2% of topically applied minoxidil is absorbed, the extent of plasma protein binding occurring in vivo after topical application would be clinically insignificant. The volume of distribution of minoxidil after intravenous administration has been estimated at 70 litres.

Approximately 60% minoxidil absorbed after topical application is metabolised to minoxidil glucuronide, primarily in the liver. Minoxidil and its metabolites are excreted almost entirely in the urine, with a very minor degree of elimination via the faeces. Following cessation of dosing, approximately 95% of topically applied minoxidil will be eliminated within four days.