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Effects of a novel finasteride 0.25% topical solution on scalp and serum

dihydrotestosterone in healthy men with androgenetic alopecia

Article  in  International journal of clinical pharmacology and therapeutics · December 2015

DOI: 10.5414/CP202467

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 www.clinpharmacol.com International
Journal of

Effects of a novel finasteride 0.25% topical solution

on scalp and serum dihydrotestosterone in healthy
men with androgenetic alopecia

Maurizio Caserini1, Milko Radicioni2, Chiara Leuratti2, Emanuela Terragni2,

Matilde Iorizzo3, and Renata Palmieri1

1Polichem S.A., Lugano-Pazzallo, 2CROSS Research S.A., Phase I Unit,

Arzo, and 3Private Practice in Dermatology, Bellinzona, Switzerland

54/1
January
2016
(19-27)

Dustri-Verlag
Dr. Karl Feistle
www.dustri.com Reprint
 International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 1/2016 (19-27)

Effects of a novel finasteride 0.25% topical

solution on scalp and serum
dihydrotestosterone in healthy men with
androgenetic alopecia
Original
©2016 Dustri-Verlag Dr. K. Feistle
ISSN 0946-1965
Maurizio Caserini1, Milko Radicioni2, Chiara Leuratti2, Emanuela Terragni2,
Matilde Iorizzo3, and Renata Palmieri1
DOI 10.5414/CP202467
e-pub: December 4, 2015
1Polichem S.A., Lugano-Pazzallo, 2CROSS Research S.A., Phase I Unit, Arzo, and
3Private Practice in Dermatology, Bellinzona, Switzerland

Key words Abstract. Objective: The effects on androgen insensitivity syndromes [1] and
androgenetic alopecia scalp and serum dihydrotestosterone (DHT) type 2 5α-reductase deficiencies [4] do not
– finasteride – topical of different doses of a novel topical solu-
treatment – type 2 5-α experience androgenetic alopecia: these find-
tion of 0.25% finasteride (P-3074), a type 2
reductase – dihydrotes- ings suggested that androgenetic alopecia is
5α-reductase, were investigated in men with
tosterone
androgenetic alopecia. Methods: Two ran- induced by activation of follicular androgen
domized, parallel-group studies were con- receptors by DHT [5].
ducted. Study I: 18 men received 1 mL (2.275 Finasteride is an effective drug for the
mg) P-3074, applied to the scalp once a day treatment of mild to moderate male andro-
(o.d.) or twice a day (b.i.d), or 1 mg oral tab-
let o.d. for 1 week. Study II: 32 men received genetic alopecia and is presently authorized
P-3074 at the dose of 100 (0.2275  mg), and marketed as a 1-mg oral tablet in the
200 (0.455  mg), 300 (0.6285  mg), or 400 USA and Europe [6, 7]. Finasteride selec-
(0.91 mg) µL or the vehicle o.d. for 1 week. tively inhibits the type 2 5α-reductase isoen-
Scalp and serum DHT and serum testoster- zyme, blocking the conversion of testoster-
one were evaluated at baseline and treat- one to DHT, and, administered at the daily
ment end. Results: Change from baseline in
scalp DHT was –70% for P-3074 o.d. and oral doses of 0.05 – 5 mg for 42 days, results
approx. –50% for P-3074 b.i.d. and the tab- in a 60  –  70% reduction in serum/plasma,
let. Serum DHT decreased by 60 – 70%. The prostate, and scalp DHT levels [8].
doses of 100 and 200 µL P-3074 resulted in Finasteride was proven to be effective
a –47/–52% scalp DHT reduction, similar to in the treatment of male pattern baldness in
the 300 and 400 µL doses (i.e., –37/–54%).
A –5.6% inhibition was observed for the terms of stabilization of hair loss and promo-
vehicle. Serum DHT was reduced by only tion of the conversion of hair follicles into
–24/–26% with 100 and 200 µL P-3074 and the actively growing phase [9, 10, 11]. A sys-
by –44/–48% with 300 and 400 µL P-3074. temic review by Mella et al. [12] concluded
No relevant changes occurred for serum tes- that daily use of oral finasteride (1-mg tablet)
tosterone. Conclusions: The novel finaste-
increases hair count and improves patient
ride 0.25% solution applied o.d. at the doses
of 100 and 200 µL results in an appropriate and investigator assessment of hair appear-
inhibition of scalp DHT potentially minimiz- ance.
ing the untoward sexual side-effects linked Generally, 1-mg oral finasteride is well
to a systemic DHT reduction. tolerated with long-term use, although evi-
Received
July 9, 2015; dence from preclinical and clinical stud-
accepted ies points to significant adverse effects of
August 26, 2015
Introduction 5α-reductase inhibitors on health and overall
quality of life. Adverse sexual effects have
Correspondence to
Renata Palmieri Androgenetic alopecia, or male pattern consistently been reported [1, 13, 14]. In
Polichem S.A., Via baldness, depends on genetic predisposition multiple double-blind randomized controlled
Senago 42D, CH-6912, [1, 2] and on the local presence of the andro- trials, 1-mg oral finasteride has been associ-
Lugano-Pazzallo,
gen dihydrotestosterone (DHT) [3], which ated with a significant number of sexual dys-
Switzerland
renata.palmieri@ is formed by testosterone reduction through functions, including decreased libido (1.8%),
polichem.com the action of 5α-reductases. Patients with erectile dysfunction (1.3%), ejaculation dis-
Caserini, Radicioni, Leuratti, et al. 20

orders (0.8  –  1.2%), and orgasm disorders scalp DHT levels, minimizing at the same
(0.4%) [12, 14, 15, 16]. It is likely that a lack time the systemic effects on serum DHT.
of plasmatic DHT or another 5α-reduced hor- Four doses of P-3074, as 4 different volumes
mone is responsible for the reported decrease (i.e., 100  µL (0.2275 mg), 200 µL (0.455
in libido and/or orgasm [17]. Recently, the mg), 300 µL (0.6825 mg), and 400 µL (0.91
use of 1 mg oral finasteride for the treatment mg)) were thus investigated in terms of their
of male pattern hair loss has been the focus effects on scalp DHT levels. In both studies,
of media and internet attention for potential serum testosterone was also evaluated. The
irreversible sexual dysfunction and severe final aim was to optimize finasteride delivery
depression, which raises concerns about the from the new topical formulation, reducing
safety of 1-mg oral finasteride [18]. finasteride systemic absorption and minimiz-
Given the efficacy and a concerning side- ing its systemic effects.
effect profile of oral finasteride, there is po-
tential for the development of a better-toler-
ated formulation for male pattern baldness. Subjects and methods
A topical formulation of finasteride
0.25% solution (namely P-3074), in hy- Subjects
droxypropyl chitosan (HPCH) film-forming
technology, allows finasteride to act on the In study I and II, 18 – 65 year-old healthy
scalp skin follicular portion of the bulb [19] men with recession of the frontal hairline and
and to promote a cutaneous depot of finaste- hair loss over the frontal and vertex scalp
ride in the region of hair bulbs, thus minimiz- regions (at least stage II of the Hamilton-
ing systemic absorption even after repeated Norwood classification scale [22]) were en-
treatments [20]. A recent study in 24 healthy rolled. All men were in good physical health,
men with androgenetic alopecia [21] showed as assessed at study entry by medical history
that 1-week treatment with 1  mL P-3074 and physical examination, including elec-
applied twice daily (b.i.d.) to the scalp and trocardiogram (ECG) recording, vital signs
with finasteride 1-mg tablet orally adminis- measurement, and routine laboratory blood
tered once daily (o.d.) resulted in a similar and urine assays. Men with damaged scalp
plasma DHT reduction: plasma DHT was in skin, such as abrasions, hyperkeratosis, or
fact reduced by 68 – 75% with P-3074 and by inflammatory disorders, were excluded. Sub-
62 – 72% with the reference tablet. As expect- jects were not enrolled if they had participat-
ed, no relevant changes in plasma testoster- ed in other clinical trials or donated blood in
one occurred with either treatment. Notably, the previous 2 months, or if they had been on
plasma finasteride rate and extent of systemic any medications in the 2 weeks preceding the
absorption were ~ 10 – 15 times lower for the study. All the subjects were given a detailed
topical solution than for the tablet. description of the study, and all of them gave
On the basis of the results of the previ- their written informed consent before enrol-
ous study, the present set of studies aimed at ment. The studies were approved by an in-
further investigating the systemic and local dependent Ethics Committee, Canton Ticino,
(scalp) DHT suppressive effects of P-3074, Switzerland, and were performed at CROSS
topically applied at different dose regimens Research S.A., Switzerland, in accordance
(1 mL o.d. or b.i.d., study I) and at different with the Declaration of Helsinki and the har-
o.d. doses (study II) in men with adrogenetic monized European standards of Good Clini-
alopecia. cal Practice (ICH E6 1.24).
Primary objective of study I was to inves-
tigate whether multiple applications of 1 mL
P-3074 o.d. resulted in an inhibition of scalp Study design and dose regimens
and serum DHT similar to that obtained
with b.i.d. applications and with the 1-mg Test product was finasteride 0.25% topi-
oral tablet. Study II was designed to evalu- cal solution (P-3074; 2.275  mg/mL, Poli-
ate whether lower doses of P-3074 applied to chem, S.A., Switzerland). The study design
the scalp of men with androgenetic alopecia was consistent across the two trials: both
could achieve the same inhibitory effect on studies were single center, randomized,
Effects of finasteride on scalp and serum dihydrotestosterone in androgenetic alopecia 21

parallel-group, pharmacodynamic studies. puffs, in order to homogeneously cover the

The randomization lists for the two studies scalp skin area. Scalp and serum concentra-
were computer generated by CROSS Metrics tions of DHT and serum testosterone were
S.A., Switzerland, using the PLAN proce- determined at baseline and 6  ±  2  hours af-
dure of the validated SAS for Windows Ver- ter the last application of P-3074 or vehicle
sion 9.1.3, Service Pack 4. topical solution. Punch scalp biopsies were
In study I, which was conducted from collected as described for study I. Plasma fi-
August 3 to September 7, 2012, 18 men nasteride was analyzed at baseline and 6 ± 2
with androgenetic alopecia were randomly hours after the last dose of P-3074.
allocated to 3 treatment groups in a 1 : 1 : 1 The subjects were confined to the clinical
ratio to receive, in open–label fashion, 1 mL center from the day of the first application
topical solution twice daily (P-3074 b.i.d.) or the day of the last administration (refer-
or once daily (P-3074 o.d.), or finasteride ence tablet group only, study I) up to at least
1-mg oral tablet o.d. (Propecia®, MSD S.A., 12 hours after the last dose. Final assessment
Switzerland) for 1 week. Before the first ap- was performed after completion of all study
plication of P-3074, subjects had their scalp procedures.
completely shaven. For each application, 1
mL (i.e., 2.275 mg finasteride) of the solu-
tion was homogeneously sprayed by the in- Analytical methods
vestigator on the whole scalp, for a total of
either 7 applications (P-3074 o.d. group) or DHT concentrations in scalp/serum, tes-
14 applications (P-3074 b.i.d. group). The tosterone concentrations in serum, and fin-
reference tablet was orally administered with asteride concentrations in plasma (study II
150 mL of still mineral water. 4-mm punch only) were determined at ABL, Analytisch
scalp biopsies for DHT and testosterone Biochemisch Laboratorium, Assen, The
analysis were performed at baseline (day Netherlands, using fully validated LC-MS/
–17) and 6 ± 2 hours after the last multiple MS methods [21, 23]. Lower quantification
dose. Before each biopsy, the scalp skin was limits (LQL) were 0.05  ng/mL for serum
cleansed with betadine solution, and the DHT and testosterone, 0.25 ng/g for scalp
scalp area was anaesthetized by injection of DHT, and 0.10 ng/mL for plasma finasteride.
lidocaine 1%/epinephrine 10 µg/mL and so- All the analyses were conducted under blind
dium bicarbonate 8.4%. Punch-biopsied sites conditions.
were disinfected with betadine and sutured.
Blood samples for serum DHT and testoster-
one determinations were collected before the Pharmacodynamic and
first application (baseline) and after 1-week
pharmacokinetic analyses
treatment just before (predose, 0 hour) and at
6 and 12 hours after the last dose. DHT concentrations in scalp and se-
In study II (13 March – 22 April, 2014), rum, testosterone concentrations in serum,
4 active doses of P-3074, i.e. 100 µL (0.2275 and finasteride concentrations in plasma
mg), 200  µL (0.455 mg), 300  µL (0.6825 were summarized by descriptive statistics.
mg), or 400 µL (0.91 mg), or the vehicle solu- Changes from baseline in DHT scalp levels
tion, were administered to 4 subject cohorts. and in DHT and testosterone serum levels
Each cohort was composed of 8 subjects for after multiple doses were calculated and pre-
a total of 32 subjects enrolled in the study. sented as percentage of inhibition. Individual
According to a computer-generated random- and mean DHT scalp/serum ratios of the per-
ization list, within each cohort 6 subjects centage of change were calculated for all ac-
received 1 of the 4 P-3074 dose regimens, tive treatment groups (both studies). Ratios
and 2 subjects received the vehicle in double equal (or very close) to 1.0 indicate that DHT
blind fashion. The topical solution (P-3074 changed equally in scalp and serum, ratios
or the vehicle) was applied to the subjects’ above 1.0 indicate that DHT was inhibited
shaven scalp o.d., in the morning, for 7 days. more in scalp than in serum, and ratios be-
The solution was sprayed from a distance of low 1 indicate that DHT was inhibited less in
8  –  10 cm, without overlapping subsequent scalp than in serum.
 Caserini, Radicioni, Leuratti, et al. 22

Table 1.  Serum DHT concentrations (mean ± SD) and changes from baseline (%) after 1 week of treatment.

Study Treatment group Baseline 1 week – last dose

ng/g Predose 6 h postdose 12 h postdose
ng/g % ng/g % ng/g %
Study I Tablet, 1 mg o.d. 0.40 ± 0.11 0.12 ± 0.05 – 69.7 0.10 ± 0.06 – 75.9 0.10 ± 0.03 – 76.1
P-3074, 1 mL b.i.d. 0.53 ± 0.34 0.16 ± 0.02 – 69.3 0.14 ± 0.03 – 74.0 0.14 ± 0.02 – 73.8
P-3074, 1 mL o.d. 0.32 ± 0.09 0.10 ± 0.02 – 67.6 0.07 ± 0.01 – 76.4 0.06 ± 0.03 – 80.4
Study II P-3074, 400 µL o.d. 0.52 ± 0.14 NA 0.27 ± 0.09 – 47.7 NA
P-3074, 300 µL o.d. 0.50 ± 0.19 NA 0.28 ± 0.08 – 44.1 NA
P-3074, 200 µL o.d. 0.39 ± 0.07 NA 0.29 ± 0.04 – 26.2 NA
P-3074, 100 µL o.d. 0.65 ± 0.27 NA 0.49 ± 0.16 – 24.4 NA
Vehicle o.d. 0.49 ± 0.12 NA 0.46 ± 0.14 – 7.1 NA

P-3074: finasteride 0.25% topical solution; P-3074 1 mL = 2.275 mg; P-3074 400 µL = 0.91 mg; P-3074 300 µL = 0.6825 mg; P-3074
200 µL = 0.455 mg; P-3074 100 µL = 0.2275 mg. Tablet, 1 mg: Reference tablet, Propecia®, MSD S.A. DHT

ment group) for study I and the number of

32 volunteers (N  =  8 (6 active product + 2
vehicle)/cohort) for study II were regarded
as being sufficient for the purposes of the
studies. Baseline-corrected (i.e., changes
from baseline) DHT and testosterone serum
and DHT scalp concentrations at 6 ± 2 hours
after the last dose were compared between
dose groups using an independent sample t-
test. Individual DHT scalp/serum percentage
of change ratios were compared between the
active treatment groups, both within and be-
tween the two studies, using the nonparamet-
ric Wilcoxon Mann Whitney test.

Figure 1.  Mean changes from baseline (%) in

scalp and serum DHT concentrations after 1 week
of treatment with 1 mL P-3074 b.i.d., 1 mL P-3074 Results
o.d., and 1-mg oral tablet o.d. – study I.
All the randomized subjects, i.e., 18 in
study I (N  =  6/treatment group) and 32 in
Safety profile study II (N  =  6/active dose group; N  =  8/
vehicle group), completed the study per pro-
Safety and tolerability were assessed tocol and were included in the pharmacody-
by physical examinations, ECG, vital signs namic, pharmacokinetic (study II only), and
check, routine laboratory tests, and adverse safety analyses.
events monitoring throughout the study. Ad-
verse events were coded by system organ
class and preferred term using the medical
dictionary for regulatory activities version Pharmacodynamics and
15.1 (study I) or 17.0 (study II). pharmacokinetics
Study I

Sample size and statistical After multiple-dose treatment for 1 week,

methods a clear and similar suppressive effect of the
3 finasteride treatments on serum DHT lev-
For the two studies, no formal sample els was evident at all postdose assessment
size power calculation was performed. times: serum DHT was, in fact, reduced by
The number of 18 volunteers (N  =  6/treat- ~  69  –  74% with P-3074 b.i.d., 68  –  80%
 Effects of finasteride on scalp and serum dihydrotestosterone in androgenetic alopecia 23

Table 2.  Scalp DHT concentrations (mean ± SD; range) and changes from
tablet, scalp DHT concentrations at the end
baseline (%) after 1 week of treatment. of the study ranged from 0.41 to 1.29 ng/g
(CV: 50.6%).
Study Treatment group Scalp DHT
Baseline 1 week Change from
No clinically relevant changes occurred
ng/g ng/g baseline (%) for serum testosterone during the study.
Study I Tablet, 1 mg o.d. 1.39 ± 0.25 0.68 ± 0.34 –51.1
P-3074, 1 mL b.i.d. 1.91 ± 0.54 1.01 ± 0.39 –47.2
P-3074, 1 mL o.d. 1.52 ± 0.41 0.44 ± 0.08 –71.2 Study II
Study II P-3074, 400 µL o.d. 1.03 ± 0.28 0.47 ± 0.10 –54.3
P-3074, 300 µL o.d. 1.03 ± 0.14 0.65 ± 0.32 –37.2 After multiple-dose treatment for 1 week,
P-3074, 200 µL o.d. 1.22 ± 0.52 0.65 ± 0.31 –46.8 serum DHT was reduced by –24.4, –26.2,
P-3074, 100 µL o.d. 1.24 ± 0.14 0.59 ± 0.10 –52.3 –44.1, and –47.7% with 100, 200, 300, and
Vehicle o.d. 1.03 ± 0.19 0.97 ± 0.27 –5.6 400 µL P-3074 o.d., respectively (Table 1)
(Figure 2). Change from baseline with the
P-3074: finasteride 0.25% topical solution; P-3074 1 mL=2.275 mg; P-3074 400
µL=0.91 mg; P-3074 300 µL=0.6825 mg; P-3074 200 µL=0.455 mg; P-3074 100 vehicle solution was –7.1%.
µL=0.2275 mg. Tablet, 1 mg: Reference tablet, Propecia®, MSD S.A. DHT = di- Percentage of scalp DHT inhibition was
hydrotestosterone. similar in the 4 finasteride dose groups, with
values ranging from –37 to –54%. In com-
parison, a reduction of –5.6% was observed
in the vehicle group (Table 2) (Figure  2).
Differences in scalp DHT were statistically
significant between each dose group and the
vehicle (p ≤ 0.0249), whereas no significant
differences between P-3074 dose groups
were observed.
No clinically relevant changes occurred
for serum testosterone during study II.
After 1-week treatment with P-3074 at
the 4 investigational doses, plasma finaste-
ride was below the lower quantification limit
for all subjects, with the exception of 1 sub-
ject in the 300 µL dose group, who showed
a low but detectable concentration (i.e.,
0.13 ng/mL) at 6 hours postdose.
Figure 2.  Mean changes from baseline (%)
in scalp and serum DHT concentrations after 1
week of treatment with 100 µL (0.2275 mg), 200
µL (0.455 mg), 300 µL (0.6825 mg), and 400 µL Studies I and II – DHT scalp/serum
(0.2275 mg) P-3074 o.d. and vehicle o.d. – study II. percentage of change ratios
Figure 3 reports the mean scalp DHT/
with P-3074 o.d., and 70 – 76% with the ref- serum DHT percentage of change from base-
erence tablet (Table 1) (Figure 1). line ratios: The higher the reported ratio val-
Reduction from baseline in scalp DHT ue, the better the expected safety profile due
was similar for P-3074 b.i.d and the oral to a lower serum DHT inhibition.
tablet, corresponding to –47% and –51%, Mean scalp/serum DHT reduction per-
respectively, and more marked for P-3074 centage ratios were 2.3 and 1.7 for 100 and
o.d. (i.e., –71%) (Table 2) (Figure 1). Nota- 200 µL P-3074, and 0.6 – 1.1 for the oral and
bly, at the end of the 1-week treatment, scalp higher topical P-3074 dose groups.
DHT concentrations were similar for all the In particular, scalp DHT reduction was
subjects in the P-3074 o.d. treatment group similar in all tested oral and topical P-3074
(range 0.36 to 0.57 ng/g, coefficient of varia- formulations, indicating a potentially similar
tion (CV): 18.4%) despite the quite different efficacy profile. On the contrary, the inhibi-
baseline levels (range 1.03 – 2.20 ng/g, CV: tion of serum DHT differed between the low-
26.8%), and ranged from 0.44 to 1.56 ng/g er topical (i.e., 100 and 200 µL P-3074 o.d.)
(CV: 39.1%) for P-3074 b.i.d. For the oral and the oral and higher topical tested doses
 Caserini, Radicioni, Leuratti, et al. 24

Safety
Tolerability of the topical formulation
was excellent, with no signs or symptoms
detected at the scalp application site through-
out the studies. In study I, 3 adverse events
were reported by 2 (11.1%) subjects with
P-3074 (b.i.d. or o.d.), i.e., increased alanine
aminotransferase, pollakiuria, and testicular
pain. In study II, 5 (15.6%) subjects suffered
from adverse events, namely presyncope,
conjunctivitis, headache, and oropharyngeal
pain. All the reported TEAEs were of mild
Figure 3.  Mean DHT scalp/serum percentage of
change from baseline ratios – study I and study II. intensity, resolved by the end of the study,
and did not give rise to any safety concern.

(i.e., 1-mg tablet, 300 µL, 400 µL, 1 mL o.d.,

1 mL b.i.d. P-3074).
In order to evaluate which was the lead Discussion
P-3074 dosage, able to separate the effect
In men with androgenetic alopecia, af-
on scalp from the effect on serum, pair-wise
ter 1-week treatment (study I), the reduc-
comparisons among all P-3074 dose groups
tion in scalp DHT levels was more marked
and the oral tested dose were performed on
for P-3074 o.d. (approx. –70%) than for
the efficacy/safety ratio parameter using the
P-3074 b.i.d. and for the oral tablet (approx.
Wilcoxon Mann Whitney test (Table 3). The
–50% each). A marked decrease in serum
P-3074 dosages up to 200  µL were statisti-
DHT levels was found at all time-points in
cally different from the other P-3074 dose
the 3 treatment groups, in good agreement
groups and the oral finasteride. In contrast,
with the data of the previous study [21] and
all the other dose group comparisons were
with literature data [12, 24], which reported
not statistically different.
60 – 70% reduction in serum DHT levels fol-
These results confirm that low doses of lowing treatment with different finasteride
the topical solution (100 and 200 µL P-3074 oral doses.
o.d.) have a stronger inhibitory effect on Moreover, application of 1 mL P-3074
scalp than on serum DHT, as opposed to the o.d. for 1 week resulted in a more constant
higher doses of the same topical solution response in terms of scalp DHT inhibition,
(1 mL P-3074 b.i.d. and o.d.) and to the ref- than the 1-mg reference tablet administered
erence oral tablet (1 mg), which exhibited a o.d., taking into consideration the possible
stronger effect on serum DHT. intersubject variability derived from vari-
ous factors, such as the different grade of
baldness in treated subjects, differences in

Table 3.  Comparison between treatment groups - DHT scalp/serum percentage of change ratios.

Scalp/serum DHT 100 µL 200 µL 100 + 200 µL 300 µL 400 µL 1 mL b.i.d. 1 mL o.d. 1-mg tablet
100 µL NA n.s. n.s. < 0.05 < 0.05 < 0.05 < 0.05 < 0.05
200 µL n.s. NA n.s. n.s. n.s. < 0.05 < 0.05 < 0.05
100+200 µL n.s. n.s. NA < 0.05 < 0.05 < 0.05 < 0.05 < 0.05
300 µL < 0.05 n.s. < 0.05 NA n.s. n.s. n.s. n.s.
400 µL < 0.05 n.s. < 0.05 n.s. NA n.s. n.s. < 0.05
1 mL b.i.d. < 0.05 < 0.05 < 0.05 n.s. n.s. NA n.s. n.s.
1 mL o.d. < 0.05 < 0.05 < 0.05 n.s. n.s. n.s. NA n.s.
1 mg tablet < 0.05 < 0.05 < 0.05 n.s. < 0.05 n.s. n.s. NA

< 0.05 = statistically significant (p-value below 0.05); n.s. = not statistically significant (p-value above 0.05); NA = not applicable; DHT
= dihydrotestosterone.
Effects of finasteride on scalp and serum dihydrotestosterone in androgenetic alopecia 25

density of sebaceous glands, hair follicles, The findings of study I clearly showed
and blood vessels as well as differences in that o.d. applications of P-3074 for 1 week
desquamating part of the stratum corneum, already exerted a maximal effect on scalp
intercellular lipid matrix, and hydration level DHT concentrations (~  70% inhibition),
[25]. The difference in response between the suggesting that the final dose of the topical
o.d. and b.i.d. P-3074 dose regimens with re- solution applied to the scalp could be sig-
spect to scalp DHT reduction is most likely nificantly lower than the previously used
to be ascribed to the nature of the topical for- doses. Thus, study II was designed to evalu-
mulation, containing HPCH, which forms an ate whether lower doses of P-3074 applied to
elastic, smooth, and almost invisible film on the scalp of men with androgenetic alopecia
the scalp surface after homogeneous appli- could achieve a consistent inhibitory effect
cation, and to the finasteride release pattern on scalp DHT levels, minimizing at the same
from the film. Previous nonclinical studies in time the systemic effects on serum DHT. Re-
hairless rat skin showed that after application sults of the study showed that P-3074 applied
of the film-forming P-3074 solution, finaste- o.d. at the lower investigated doses resulted
ride permeated through the rat skin, with total in a more favorable scalp/serum DHT ratio
permeated drug corresponding to ~ 3.7% of (~ 3 times higher than for the reference 1-mg
the applied dose [19]. Permeated finasteride oral tablet) than when applied o.d. at the
was detectable starting from 8 to 12 hours af- higher doses. In fact, doses of 100 (0.2275
ter application, and transdermal penetration mg) and 200 µL (0.455 mg) P-3074 applied
lasted up to at least 24 hours postdose. This o.d. for 1 week resulted in a scalp DHT re-
permeation pattern could be explained by a duction of –47/–52%, i.e., similar to the one
very slow release of finasteride entrapped in obtained with 300 (0.6825 mg) and 400 µL
the HPCH matrix and/or by a slow degrada- (0.91 mg) (i.e., –37/–54%), and a reduction
tion of the film and subsequent release of in serum DHT of only –24/–26%. In compar-
the drug. A similar finasteride release profile ison, inhibition of DHT in serum at the high-
from the film was observed in the previous er doses of 300 and 400 µL was –44/–48%.
clinical study performed in 12 healthy vol- Notably, in the 100 and 200  µL dose
unteers with androgenetic alopecia adminis- groups, percentage of subjects with reduc-
tered P-3074 b.i.d. for 1  week [21]. In the tions greater than the maximal individual re-
few subjects for whom finasteride plasma duction observed in the vehicle group (–0.22
concentrations were above the quantifica- ng/g) was 100% and 83.3%, respectively.
tion limit of the assay, in fact, low finasteride Considering the two dose groups togeth-
levels were detectable starting from 16 hours er, subjects with a reduction in scalp DHT
after single dose application. After the last greater than for the vehicle corresponded to
multiple dose, on average slightly higher lev- 96.7% (11/12). This result confirms the re-
els were observed at 10 – 12 hours postdose. sults of study I with topical applications of
Considering finasteride-release pattern from 1 mL P-3074 o.d. and b.i.d. for 1 week, in
the film and the two dose regimens of the which 100% of the treated subjects showed
test formulation of study I, we can deduce a marked reduction in scalp DHT concentra-
that the P-3074 b.i.d. application does not tions.
improve the response and might somehow
The results obtained by comparing the
impair the release of the drug from the film.
DHT scalp/serum percentage of change ra-
From these findings and the consider- tios between treatment groups (both stud-
ations reported above, it seems that the o.d. ies) confirmed that low doses of the topical
application of P-3074 is preferable to the solution (100 and 200 µL P-3074 o.d.) have
b.i.d. one, leading to a better response in a stronger inhibitory effect on scalp than on
terms of inhibition of DHT formation in the serum DHT, as opposed to the higher doses
scalp. In addition, topical o.d. application of of the same topical solution (1  mL P-3074
P-3074 overcomes the limits of the oral ad- b.i.d. and o.d.) and to the reference oral tablet
ministration, which for its action is limited (1 mg), which exhibited a stronger effect on
by the concentration of blood vessels in the serum DHT. Thus, the pharmacodynamic as-
scalp skin dermis, which varies among indi- sessment showed that the candidates for fur-
viduals. ther clinical development of P-3074 are the
Caserini, Radicioni, Leuratti, et al. 26

100 (0.2275 mg) and the 200 µL (0.455 mg) and safety analyses, Analytisch Biochemisch
P-3074 doses. Laboratorium ABL BV, the Netherlands, for
No relevant changes in serum testoster- the analysis of dihydrotestosterone, testos-
one were observed in any of the studies re- terone, and finasteride and Ottavia Annoni,
ported in the literature [8, 12, 21, 24]. Simi- Cross Alliance group, for study II coordina-
larly, for all P-3074 dosages tested in the two tion.
studies presented in this paper, no relevant
changes occurred for serum testosterone,
also considering the marked interindividual
Conflict of interest
variation in testosterone levels both at base-
line and at all postdose assessment times. All authors have completed the Unified
Study II results on finasteride plasma Competing Interest form at http://www.
levels confirmed a negligible finasteride sys- icmje.org/coi_disclosure.pdf (available on
temic exposure at the doses of 100 – 400 µL request from the submitting author) and
P-3074 administered o.d. for 1 week. declare: M.C. and R.P. are employees of
The two studies also confirmed a favor- Polichem S.A.; M.R., C.L., and E.T. are em-
able safety and tolerability profile of P-3074, ployees of CROss Alliance group. M.I. is a
applied to the scalp of healthy men with an- consultant in Dermatology. Polichem S.A.,
drogenetic alopecia b.i.d. or o.d. However, Switzerland, funded this study. The relation-
as also previously discussed [21], the safety ships between the Sponsor, M.I., and CROSS
profile of the study products could not be Alliance group were regulated by financial
properly investigated, considering the short- agreements.
term treatment of the present studies (i.e., R.P. and M.C. made substantial contri-
1 week) as opposed to the clinical practice butions to the conception and design of the
long-term treatment of months or years. study and reviewed and approved the final
Study I was open-label whereas study II draft of the manuscript. M.R. was the Prin-
was double-blind. For both studies, however, cipal Investigator at the clinical site. C.L. is
the end-points were based on objective as- the author of the clinical study reports and of
sessments, i.e., the determination of DHT the manuscript. M.I. reviewed the final draft
and testosterone levels in the study samples of the manuscript. E.T. was study I clinical
by blinded analysts. In addition, to increase coordinator.
the reliability of the study end-points, the
subjects were confined in the clinical center
under the supervision of clinical staff either
during the entire treatment and evaluation
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