Dovobet Oint
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Dovobet Oint - Scientific Information

Manufacture: LEO Pharma
Country: Canada
Condition: Atopic Dermatitis, Dermatitis, Dermatological Disorders, Lichen Planus, Lichen Sclerosus, Plaque Psoriasis
Class: Topical steroids
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: calcipotriol, betamethasone dipropionate, white soft paraffin, liquid paraffin, polyoxypropylene-11-stearyl ether (contains butylhydroxytoluene), alpha-tocopherol.

Pharmaceutical Information

Drug Substance

Proper name (I.N.N.): Calcipotriol hydrate Betamethasone dipropionate
Chemical name: 9,10-Secochola-5,7,10(19),22-
tetraene-1,3,24-triol, 24-cyclo-
propyl (1α,3β,5Z,7E,22E,24S)
9-fluoro-11β,17,21-trihydroxy-
16β-methylpregna-1,4-diene-
3,20-dione 17,21-dipropionate
Alternative chemical name: 20(R)-(3'(S)-Cyclopropyl-3'-
hydroxyprop-1'(E)-enyl)-
1(S),3(R)-dihydroxy-9-10-
secopregna-5(Z),7(E),10(19)-
triene
Pregna-1,4-diene-3,20-dione,9-
fluoro-11-hydroxy-16-methyl-
17,21-bis(1-oxopropoxy)-
(11β,16β)
Laboratory code name: MC 903 or MC 903-000 433 or 433/M
Molecular formula: C27H40O3, H2O C28H37FO7
Molecular mass: 430.6 504.59
Chirality: The calcipotriol molecular is one
single stereoisomer. The
absolute configuration of the
chiral centres at carbon atoms
nos. 1, 3, 13, 14, 17, 20 and 24 is
indicated in the structural
formula below.
Structural formula:
Calcipotriol hydrate



Betamethasone dipropionate



Physicochemical properties: Calcipotriol hydrate Betamethasone dipropionate
Physical Form: White or almost white
crystalline substance.
White or almost white odourless
powder.
Solubility at room
temperature:
Freely soluble in ethanol,
soluble in chloroform and
propylene glycol, practically
insoluble in liquid paraffin.
Solubility in water is 0.6
mcg/ml.
Freely soluble in acetone, in
dioxane, in dichloromethane
and in chloroform; soluble in
methanol; sparingly soluble in
alcohol; slightly soluble in
ether; insoluble in water and in
hexane.
Melting point: 166-168/C 176-180/C
Polymorphism: So far no signs have indicated
the existence of polymorphic
forms.
Other characteristics:

Calcipotriol is a vitamin D derivative. It is well-known that vitamin
D in solution forms a reversible temperature dependent equilibrium
between vitamin D and pre-vitamin D (described in (i.e.) J Pharm
Sci 1968; 57:1326). In the same way, solutions of calcipotriol
establish an equilibrium with “pre-calcipotriol”. The structural
formula of “pre-calcipotriol” is shown below.


Clinical Trials

A large multicentre, randomized, double-blind clinical trial has shown DOVOBET ointment (50 mcg/g calcipotriol plus 0.5 mg/g betamethasone (as dipropionate)) administered twice daily to be more efficacious and to provide faster onset of action than either of the individual components alone (calcipotriol or betamethasone dipropionate) for the treatment of plaque psoriasis. These findings were supported by a second large, multicentre, randomised, double-blind trial comparing DOVOBET twice daily to calcipotriol and betamethasone dipropionate, each in their currently marketed formulations. A third large, multicentre, randomised, double-blind trial found DOVOBET once daily to be more efficacious than vehicle alone and calcipotriol twice daily (betamethasone alone was not evaluated). It was also demonstrated that once daily DOVOBET was similar to twice daily DOVOBET for most of the efficacy measures. In all three studies, DOVOBET was effective in terms of reducing PASI (Psoriasis Area and Severity Index) score and thickness of target lesions. Furthermore, a significant proportion of patients on DOVOBET achieved marked improvement or clearance at the end of 4 weeks of treatment. Clinical improvement occurred rapidly and a significant improvement was evident within 1 week of treatment. DOVOBET was well tolerated with the most common adverse reaction being mild pruritus. In one additional study, patients were treated with DOVOBET once daily for 8 weeks. Optimal population results in this study were seen between 4 and 5 weeks of treatment. The therapeutic goal envisioned with DOVOBET is to provide an effective, rapid acting topical agent for initial treatment of psoriasis and/or for treatment of flare-ups of psoriasis.

In a randomized, double-blind, parallel group, safety study, patients with at least moderate disease severity were given DOVOBET ointment intermittently on an 'as needed' basis under medical supervision (N=207). Patients were followed for up to 52 weeks. The median amount of study drug used was 15.4 g/week. The effects of DOVOBET ointment on calcium metabolism were not studied and the effects on adrenal suppression were not adequately studied. The following adverse drug reactions were reported in 1% or more of patients: pruritus (5.8%), psoriasis (5.3%), skin atrophy (based on a dermatologist‟s visual assessment) (1.9%), folliculitis (1.9%), burning sensation (1.4%), skin depigmentation (1.4%), and erythema (1.0%). One case of serious flare-up of psoriasis was reported.

Summary of Clinical Trials

STUDY
CODE
STUDY DESIGN EVALUATION CRITERIA AND RESULTS
MCB 9903 DE Design:
Randomised, double-blind, right/left comparison on the forearm.

Inclusion Criteria: Healthy volunteers.

Treatment Period: Twice daily topical application for 4 weeks (28 days).

Treatment Groups:
Phase I: (1) Dovobet ointment (50 mcg/g calcipotriol plus 0.5 mg betamethasone
dipropionate); (2) Betamethasone dipropionate ointment (0.5 mg/g). (n=30)
Phase II: (1) Dovobet ointment (50 mcg/g calcipotriol plus 0.5 mg betamethasone
dipropionate); (2) Placebo ointment. (n=15)
Evaluation Criteria:
Sonography was performed on day 1. Sonography and clinical assessments of atrophy, telangiectasia and
erythema) were performed on days 8, 15, 22 and 29. Skin biopsies were taken from 10 subjects on day 29
for morphometric determination of epidermal and dermal thickness and epidermal cell layers.
Sonography and clinical assessments were repeated 2 weeks after treatment (day 43) in subjects who did
not have a biopsy taken.

Results:
There were no clinical signs of atrophy, telangiectasia or irritation (erythema). Sonography demonstrated skin thinning with Dovobet relative to placebo ointment but similar to betamethasone (12.3% and 13.2% respectively) after 4 weeks of treatment. There were no histological differences in epidermal or dermal thickness between Dovobet and betamethasone.
MCB 9902 FR Design:
Single centre, randomised, double-blind, bioequivalence study according to FDA guideline for
vasoconstrictor assays.

Inclusion Criteria: Healthy volunteers.

Treatment Period:
Pilot Phase: Single 10 mcl application on the ventral forearm for 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 6
hours followed up to 24 hours.

Pivotal Phase: (1) Single 10 mcl application of Dovobet and betamethasone dipropionate ointment
(Diprosone*) at a dose-duration corresponding to ED50 (1h04min) on two sites each per forearm.
(2) Betamethasone was also applied on two sites per forearm at dose-durations corresponding to 0.5
times ED50 (32 min.) and 2 times ED50 (2h08min.)

Treatment:
Pilot Phase: Diprosone* (0.5 mg/g betamethasone as dipropionate). (n=12)
Pivotal Phase: (1) Dovobet (50 mcg/g calcipotriol plus 0.5 mg/g betamethasone as dipropionate)
ointment; (2) Diprosone* (0.5 mg/g betamethasone as dipropionate). (n=90)
Evaluation Criteria:
Skin blanching (vasoconstrictor) assessed using the chromametric a value and visual
scoring.

Results:
Pilot Part: Betamethasone dipropionate ointment (Diprosone*) produced a dose-duration
dependent vasoconstriction with an ED50 (half maximal response) of 1h04min., D1 (0.5
times ED50) of 32 min and D2 (2 times ED50) of 2h08 min. 67% of the included subjects
were „detectors‟ (AUC at D1 was at least 1.25 time the AUC at D2).
Pivotal Part: Betamethasone dipropionate in Dovobet ointment is bioequivalent to the
reference product, Diprosone* ointment, as the 90% confidence interval for the skin
blanching response ratio (test to reference) is [0.81 ; 1.04] and within the interval [0.80 ;
1.25] as defined by the applicable FDA guideline.


* registered trademark of Schering-Plough Ltd.
MCB 9801 NL Design:
Single centre, open, randomised, multiple (2 application sites on the thigh) topical absorption study.

Inclusion Criteria: Healthy volunteers.

Treatment Period: Single 12 hour application.

Treatment:
Dovobet (50 mcg/g calcipotriol plus 0.5 mg/g betamethasone (as dipropionate)) ointment containing 3H-
labelled calcipotriol. (n=4)
Evaluation Criteria:
Pharmacokinetic parameters: Recovery of 3H-radioactivity from gauzes, gloves, swabs
and shorts; excretion of 3H-radioactivity in urine and faeces; 3H-radioactivity levels in
serum. Safety parameters: adverse events, local tolerability results, vital signs, ECG
parameters and clinical laboratory parameters.

Results:
Excretion and recovery data suggest that there is only minimal systemic absorption of
calcipotriol. The ointment was well tolerated.
MCB 9901 NL Design:
Single centre, open, randomised, multiple (2 application sites on the thigh) topical absorption study.

Inclusion Criteria: Healthy volunteers.

Treatment Period: Single 12 hour application of 3H labelled ointment and single 12 hour application after 4
weeks of twice daily topical application of unlabelled ointment.

Treatment Groups:
Group I: Single 12 hour application of 2.5 g Dovonex (50 mcg/g calcipotriol) ointment containing 3H labelled
calcipotriol. Four weeks (28 days) of twice daily treatment with unlabelled Dovonex. On day 36, another single
12 hour application of Dovonex containing 3H labelled calcipotriol. (n=6)
Group II: Single 12 hour application of 2.5 g Dovobet (50 mcg/g calcipotriol plus 0.5 mg/g betamethasone
dipropionate) ointment containing 3H labelled calcipotriol. Four weeks (28 days) of twice daily treatment with
unlabelled Dovobet. On day 36, another single 12 hour application of Dovobet containing 3H labelled
calcipotriol. (n=6)

Group III: Single 12 hour application of 2.5 g Dovobet ointment vehicle containing 3H labelled calcipotriol.

Group IV: Single 12 hour application of 2.5 g Dovobet ointment containing 3H labelled betamethasone.

Group V: Single 12 hour application of 2.5 g Dovobet ointment vehicle containing 3H labelled betamethasone.
Evaluation Criteria:
Pharmacokinetic parameters: Recovery of 3H radioactivity from gauzes, gloves,
swabs and shorts; excretion of 3H radioactivity in urine and faeces; 3H radioactivity
levels in serum.
Safety parameters: adverse events, local tolerability results, vital signs, ECG
parameters and clinical laboratory parameters.

Results:
The absorption of calcipotriol after a single application of Dovobet is similar to
absorption after application of the other marketed formulation of calcipotriol (i.e.
Dovonex; 50 mcg/g calcipotriol). Thus, the safety profile of Dovonex is
applicable to Dovobet. Betamethasone dipropionate in Dovobet does not influence
the absorption rate of calcipotriol and vice versa calcipotriol does not affect the
absorption of betamethasone. Absorption of calcipotriol is similar after 4 weeks of
treatment with Dovobet as it is after a single application.
MCB 9802 INT Design:
Multi-centre, randomised, double-blind, vehicle-controlled, parallel-group study.

Inclusion Criteria: Plaque psoriasis amenable to topical treatment.

Treatment Period: Twice daily topical application for 4 weeks of active treatment.

Treatment Groups:
(1) Combination ointment (50 mcg/g calcipotriol plus 0.5 mg betamethasone
dipropionate; Dovobet), (n=301); (2) Calcipotriol ointment (50 mcg/g), (n=308);
(3) Betamethasone dipropionate ointment (0.5 mg/g), (n=313); (4) Ointment
vehicle, (n=108)
Evaluation Criteria:
Change in PASI score after 4 weeks of treatment, speed of
response (change in PASI score after 1 week of treatment), change in plaque thickness of a target lesion, investigators‟ overall assessment of treatment
response (clearance or marked improvement) at the end of treatment, patient assessment of overall treatment
response, patient assessment of treatment acceptability, adverse events, and serum biochemistry.

Results:
Dovobet combination treatment was effective and provided a more rapid onset of action than either of the
individual components (calcipotriol or betamethasone dipropionate). At the end of 4 weeks treatment, PASI
score was reduced by 73% with Dovobet, 49% with calcipotriol, 63% with betamethasone and 29% with
vehicle (p<0.001). After 1 week of treatment PASI score was reduced by 48% with Dovobet, 28% with
calcipotriol, 41% with betamethasone and 22% with vehicle (p<0.001). The greatest reduction in target
lesion thickness was observed with Dovobet. Plaque thickness was reduced by 79% with Dovobet
compared to 54% with calcipotriol, 67% with betamethasone and 27% with vehicle (p<0.001). The greatest
treatment response according to the investigators‟ overall assessment was also observed in the Dovobet
group. With Dovobet combination treatment 76% of patients achieved clearance or marked improvement
compared to 33% with calcipotriol, 56% with betamethasone and 8% with vehicle (p<0.001). Adverse
reactions associated with Dovobet were similar to reactions with betamethasone. Mild pruritus was the
most common adverse reaction.
MCB 9904 INT Design:
Multi-centre, randomised, double-blind, vehicle-controlled, parallel-group study.

Inclusion Criteria: Plaque psoriasis amenable to topical treatment.

Treatment Period: Phase 1: Twice daily topical application of active treatment
(double-blind) for 4 weeks.

Phase 2: twice daily maintenance therapy with Dovonex (open-label) for 4 weeks.
Treatment Groups:
Phase 1: (1) Dovobet ointment (50 mcg/g calcipotriol plus 0.5 mg betamethasone
dipropionate), (n=369); (2) Dovonex ointment (50 mcg/g calcipotriol, Leo
Pharmaceutical Products), (n=365); (3) Diprosone* ointment (0.5 mg/g
betamethasone dipropionate, Schering-Plough Ltd.), (n=363)
Phase 2: Patients from each of the above groups (n=344, 332, and 344, respectively)
transferred to Dovonex ointment.
Evaluation Criteria:
Phase 1: Change in PASI score after 4 weeks of treatment, speed of response (change in PASI score after 1
week of treatment), change in plaque thickness of a target lesion, investigators‟ overall assessment of
treatment response (clearance or marked improvement) at the end of treatment, patient assessment of
overall treatment response, change in redness and scaliness of a target lesion, adverse events, and serum
biochemistry. Phase 2: general evaluation of transfer to Dovonex® maintenance therapy.

Results:
Dovobet combination treatment was effective and provided a more rapid onset of action than either of the
individual components in their currently marketed formulations (Dovonex and Diprosone*). At the end
of 4 weeks treatment, PASI score was reduced by 74% with Dovobet, 55% with Dovonex, and 61% with
Diprosone* (p<0.001). After 1 week of treatment PASI score was reduced by 47% with Dovobet, 31%
with Dovonex, and 40% with Diprosone* (p<0.001). The greatest reduction in target lesion thickness
was observed with Dovobet. Plaque thickness was reduced by 79% with Dovobet compared to 63% with
Dovonex, and 62% with Diprosone* (p<0.001). The greatest treatment response according to the
investigators‟ overall assessment was also observed in the Dovobet group. With Dovobet combination
treatment 68% of patients achieved clearance or marked improvement compared to 39% with Dovonex,
and 47% with Diprosone* (p<0.001). Adverse reactions associated with Dovobet were predictable based
on the individual components with mild pruritus being the most common adverse reaction. Patients were
safely transferred to maintenance therapy with Dovonex.
MCB 9905 INT Design:
Multi-centre, randomised, double-blind, vehicle-controlled, parallel-group study.

Inclusion Criteria: Plaque psoriasis amenable to topical treatment.

Treatment Period: Active topical treatment once or twice daily for 4 weeks. To
maintain blinding, the once daily group received vehicle in the morning and study
medication in the evening.

Treatment Groups:
(1) Dovobet combination ointment (50 mcg/g calcipotriol plus 0.5 mg betamethasone
dipropionate) once daily, (n=150); (2) Dovobet ointment twice daily, (n=234);
(3) Dovonex ointment (50 mcg/g calcipotriol) twice daily, (n=227); (4) Ointment
vehicle twice daily, (n=207).
Evaluation Criteria:
Change in PASI score after 4 weeks of treatment, speed of response (change in PASI score after 1 week
of treatment), change in plaque thickness of a target lesion, investigators‟ overall assessment of treatment
response (clearance or marked improvement) at the end of treatment, patient assessment of overall
treatment response, patient assessment of treatment acceptability, change in redness and scaliness of
target lesion, adverse events, and serum biochemistry.
Results:
Once daily Dovobet combination treatment was as effective as twice daily Dovobet treatment but more
effective than twice daily Dovonex treatment. At the end of 4 weeks, PASI score was reduced by 69%
with Dovobet once daily, 59% with Dovonex® twice daily, and 27% with vehicle twice daily (p<0.001).
Reduction in PASI after 4 weeks of twice daily Dovobet treatment (74%) was similar to that after once
daily Dovobet treatment (p=0.052). After 1 week of treatment PASI score was reduced by 46% with
Dovobet once daily, 34% with Dovonex® twice daily, and 20% with vehicle twice daily (p<0.001). The
speed of response to Dovobet twice daily treatment was similar to that after Dovobet once daily
treatment, with the reduction in PASI after one week being 48%. The greatest reduction in target lesion
thickness was observed with Dovobet, with similar reductions occurring after once daily (74%) and twice
daily (78%) treatment. The greatest treatment response according to the investigators‟ overall assessment
was also observed in the Dovobet groups, with twice daily treatment favoured over once daily.
Adverse reactions associated with Dovobet were predictable based on the individual components with
mild pruritus being the most common adverse reaction.
MCB 0003 INT Design:
Multi-centre, randomised, double-blind, vehicle-controlled, parallel-group study.

Inclusion Criteria: Plaque psoriasis amenable to topical treatment.

Treatment Period: Active topical treatment once daily for 4 weeks.

Treatment Groups:
(1) Dovobet combination ointment (50 mcg/g calcipotriol plus 0.5 mg betamethasone
dipropionate) once daily, (n=490); (2) Calcipotriol ointment (50 mcg/g calcipotriol)
once daily, (n=480); (3) Betamethasone ointment (0.5 mg/g betamethasone
dipropionate) once daily, (n=476); (4) Vehicle ointment once daily, (n=157).
Evaluation Criteria:
Change in PASI score after 4 weeks of treatment, controlled disease after 4 weeks of treatment, speed
of response (change in PASI score after 1 week of treatment), treatment success, and adverse events.

Results:
Once daily Dovobet combination treatment was more effective than once daily application of its
individual components or vehicle. At the end of 4 weeks, PASI score was reduced by 71% with
Dovobet, 46% with calcipotriol, 57% with betamethasone and 23% with vehicle (p<0.001). The
percentage of patients with controlled disease at the end of treatment was 56% for Dovobet, 22% for
calcipotriol, 37% for betamethasone and 10% for vehicle (p<0.001). After 1 week of treatment PASI
score was reduced by 39% with Dovobet, 23% with calcipotriol, 33% with betamethasone and 18%
with vehicle ( p<0.001). The proportion of patients with treatment success was 65% with Dovobet,
29% with calcipotriol, 46% with betamethasone, and 10% with vehicle (p<0.001). Adverse reactions
associated with Dovobet were predictable based on the individual components with mild pruritus being
the most common adverse reaction.

Detailed Pharmacology

Preclinical Pharmacology

Animal Pharmacodynamic Studies with Calcipotriol

The pharmacodynamic studies performed with calcipotriol have been aimed at establishing the activity of the compound as a regulator of cell differentiation and proliferation in cells possessing the receptor for the active form of vitamin D3, 1,25(OH)2D3. These studies are relevant for the intended clinical use in patients with psoriasis, due to the characteristic findings of epidermal hyperproliferation and incomplete keratinocyte differentiation in this disease.

Other current therapeutic agents act mainly through non-specific cytostatic/cytotoxic effects on the proliferating cells or suppression of underlying inflammatory and immunological reactions. In contrast, calcipotriol was shown to induce differentiation of low-differentiated human histiocytic lymphoma cells, of skin cells from newborn mice and of human keratinocytes. At the same time, proliferation was inhibited without evidence of any cytotoxic effect. The therapeutic goal envisaged with calcipotriol is thus a normalization of epidermal growth.

Calcipotriol was also found to inhibit cell proliferation induced by interleukin-1 but not by other related cellular mediators. Interleukin-1 is produced both by keratinocytes in the epidermis and by activated macrophages in the dermis. It is thought to play a pathogenetic role in psoriasis by activating both keratinocytes and immunological cells. Inhibition of interleukin-1 mediated effects in psoriatic skin by calcipotriol may therefore provide a way of regulating epidermal/dermal interactions in affected skin areas.

The pharmacodynamic studies performed in-vitro have shown that the activity of calcipotriol is very similar, both qualitatively and quantitatively, to that of 1,25(OH)2D3. This is not surprising given the structural analogy of the two compounds and the ability of calcipotriol to bind to the cellular 1,25(OH)2D3 receptor with the same affinity as 1,25(OH)2D3 itself. In-vivo however, the effects of calcipotriol were significantly different from those of 1,25(OH)2D3. The active form of vitamin D3, 1,25(OH)2D3, had potent effects on calcium metabolism and overdosage resulted in hypercalcemia and hypercalciuria.

From studies performed in rats, it was shown that the effect of calcipotriol on calcium metabolism was at least 100 to 200 times lower than that of 1,25(OH)2D3. This low activity on calcium metabolism might be an intrinsic property of the calcipotriol molecule. However, the pharmacokinetic studies performed with calcipotriol suggested that the low activity on calcium metabolism was associated with a rapid metabolic degradation of the active compound.

Animal Pharmacokinetic Studies with Calcipotriol

Pharmacokinetic studies are summarized briefly here and in more detail by species in tabular form following this section. Pharmacokinetic studies with 3H-calcipotriol have been performed in rats and minipigs.

In vivo: Oral absorption of calcipotriol was approximately 60% in rats and 40% in minipigs. The half-life of calcipotriol was 12 minutes in rats and 60 minutes in minipigs. The major metabolite of calcipotriol MC1080 was present in the first plasma sample at 5 minutes; its half-life was 54 minutes in rats and 1.8 hours in minipigs. Drug-related radioactivity was excreted in urine and faeces and clearance was considered to be almost exclusively metabolic, as less than 5% of the administered radioactivity was excreted at the time of disappearance of all calcipotriol from plasma. Determination of the tissue distribution of calcipotriol was complicated by the appearance of 3H-H20 from the metabolic degradation of 3H-calcipotriol. Autoradiography studies performed in rats, however, established that calcipotriol concentrations were highest in the liver, kidney and intestine. No drug-related radioactivity was present 24 hours after administration of 3H-calcipotriol.

In vitro: Two main metabolites of calcipotriol were observed in incubations of calcipotriol with rat liver homogenate supernatants. The two metabolites, MC1046 and MC1080, were isolated, identified and synthesized. Both metabolites were also present in supernatants from minipig, rabbit and human liver homogenates and in plasma samples from rats and minipigs. Although the necessity of using very high dosages of calcipotriol precludes the study of calcipotriol metabolism in humans, the present evidence strongly suggests that calcipotriol metabolism is qualitatively similar in rats, minipigs, rabbits and humans. In addition, both metabolites had lost most of the biological activity associated with calcipotriol thus constituting a deactivation pathway for the drug.

In Vivo Pharmacokinetic Studies with Calcipotriol

TYPE OF STUDY METHODS MAJOR RESULTS AND INTERPRETATION
(1) Acute administration
of 3H-MC903 by i.v. and
oral routes to rats.
Female rats dosed with 3H-
MC903, 0.10 mg/kg i.v. or 0.20
mg/kg p.o. In experiment 1, rats
sacrificed at different time points
for measurement of radioactivity
in plasma and tissues. In
experiment 2, same doses, radio-
ctivity measured in urine and
faeces during first few hours and
for several days. Six rats per
dose per route.
Rapid metabolism of MC903, with a half-life of 12 min. after i.v. Main metabolite: MC1080 in first plasma sample after 5
min; half-life of MC1080 54 min. Much lower levels after oral dosing. After both routes slow decline in the late phase due to
further metabolic degradation leading to formation of 3H-H2O. MC903 also metabolized to MC1046 then to more polar
compounds later [possible glucuronides and sulphates, as well as putative metabolism to calcitronic acid, discussed in Study
(5) below].
Renal excretion 16% (p.o.) and 26% (i.v.) of administered dose, peaking on Day 1 at 6-24 h (both routes); declined slowly in
accordance with large volatile component, 3H-H2O.
Faecal excretion 43% (p.o.) and 40% (i.v.), also highest on the first day with both routes. Total excreted radioactivity 59%
(p.o.) and 67% (i.v.); <100% presumably due to exhalation of volatile components. Calculated absorption of MC903; by
ratio of urinary excretion after oral and i.v. dosing, approximately 60%.
Tissue levels: Highest amounts in liver, kidney and intestine; also in fat, muscle and spleen. Early measurements most
accurate, ie. before formation of volatile radioactivity.
(2) Acute topical
administration of
3H-MC903 to rats and
rabbits.
6 rats, 2 rabbits, dosed once with
topical 3H-MC903, 21-25 mcg/
kg in rats, 9-10 mcg/kg in
rabbits. Urine and faeces
collected every 24 h for 144 h.
Surplus ointment removed after
4 h to prevent licking. Samples
taken of serum, liver, treated
skin, urine, and faeces.
Surplus ointment removed at 4 h had accounted for about 60% of radioactivity. At 4 and 144 h less than 2% (in total)
recovered from cages. Small amount of radioactivity retained in skin at 144 h (0.5-3.1%); this is approximately 30 (rats) and
200 (rabbits) times higher than levels found after i.v. dosing. Serum levels of 3H-MC903 were 0.2-0.6 ng-eqv/mL. This
compares to 17 ng-eqv/mL after i.v. dosing of 0.1 mg/kg (see above study in rats). Percutaneous absorption based on total
recovery from urine and faeces was 17%, 27% and 10% for male rats, female rats and female rabbits, respectively. Liver
levels
of 3H-MC903 ranged from 0.4-1.1 ng-eqv/g.
(3) Acute oral and i.v.
dosing of 3H-MC903 to
rats, whole-body
autoradiography.
5 and 6 rats dosed orally and i.v.,
respectively, 2 controls, sacri-
iced at various times after
dosing. Distribution of radio-
ctively labelled, non-volatile
material assessed by examin-
tion of x-ray films after ≈ 7
months exposure to tissue
sections.
I.V.: Low radioactivity distributed uniformly to most tissues including brain. Higher levels in excreting organs, bile ducts,
liver and to a minor extent, kidneys.
Oral: Similar to i.v. dosing, except more radioactivity in oral cavity, oesophagus and stomach. Is noted that MC903 passes
the blood-brain barrier with p.o. or i.v. dosing, that biliary excretion was evident after 15 min. with both routes of
administration and no secretion to the stomach via gastric mucosa was observed. 24 h after dosing levels of non-volatile
MC903-like material were very low, with no evidence for accumulation.
(4) Acute oral and i.v.
dosing of 3H-MC903
to minipigs.
2 pigs/dose (1M,1F), doses 0.1
mg/kg i.v., 0.20 mg/kg oral, and
placebo. Blood samples at
specified times and collection of
urine and faeces for 10 days. 6
weeks later females crossed over
to alternate regimen, urine and
faeces and certain tissues (no
blood) examined for MC903.
Absorption with oral dosing rapid but incomplete (≈40%). No clear distribution phase following i.v.
administration. Short elimination half-life of 1 h for parent. Metabolite MC1080 apparent after 5 min, with half-
life of 1.8 h. No late elimination phase detected, indicating accumulation of MC903 with repeat dosing unlikely.
Rebound levels observed in 1 pig at 4 hours, likely indicative of enterohepatic recirculation for parent and
metabolite. Level of radioactivity after 12 h declined with half-life of ≈ 2.6 days, likely due to 3H2O. MC903
and metabolite MC1080 eliminated from plasma within 24 h; only 4% by renal, thus elimination mostly by
metabolism. Excretion: Total cumulative recovery of 16% in urine and 44% in faeces. Tissue (mainly liver and
kidney) radioactivity after 10 days mainly 3H2O [Putative metabolic pathways discussed in study (5) below.]
(5) Rats and Minipigs
treated as described in
1 and 4 above.
Metabolism further
studied.
Synthetic samples of MC1080,
MC1046, MC1024 and MC1235
obtained. Plasma samples from
rat and minipig obtained after
dosing described above in (1) and
(4). Samples analyzed by HPLC.
MC903 disappeared rapidly from plasma in both species, with half-lives of ≈ 12 min (rat) and 60 min (pig).
Metabolites of MC903, mainly MC1080, were observed in the first sample at 5 min after i.v. dosing. MC903,
MC1080 and MC1046 account for most of the radioactivity in the samples during first hour after dosing both
species. Distribution between parent and metabolites similar to in vitro studies; in rat MC1046 more prevalent
after oral than i.v., possibly due to first pass. Minor metabolites more polar than MC1046 observed in both
species. Content of radioactivity in eluate increases rapidly with time; 6 hours after dosing >80% radioactivity
found in this fraction, both species, both routes; due mainly to radioactive water. Metabolism of MC903
to MC1080 and MC1046 involves oxidation at the 24-position, similar to oxidation of 1,25 dihydroxyvitamin D3,
active form of vitamin D3. Likely that MC903 is metabolized to calcitronic acid, similar to 1,25
dihydroxyvitamin D3.

In Vitro Pharmacokinetic Studies with Calcipotriol

TYPE OF STUDY METHODS MAJOR RESULSTS AND INTERPRETATION
(1) Identification of
metabolite of MC903
in rat liver
homogenates.
Livers removed from 6-week old
rats, homogenized, centrifuged
and super-natants collected.
Samples incubated at 37o with
MC903. Structure elucidation by
proton NMR and mass
spectrometry.
Structure elucidation by proton NMR and mass spectrometry revealed a metabolite that is identical to MC1080
detected in in vivo studies.
(2) Identification of
metabolites in liver
homogenates of rat,
minipig, rabbit, and
man.
Supernatants prepared from liver
samples from rat, minipig, rabbit
and man. Incubations with
labelled or unlabelled MC903.
Metabolite identified from rat as MC1080. Also formed in substantial amounts with liver supernatants from pig,
man and rabbit. Additional peak in man and rabbit due to metabolite MC1046; to a lessor extent in pig and rat.
MC1080 and MC1046, along with MC903 (parent) accounted for 71%-73% of radioactivity in rat, pig and
human; 7-15% due to more polar metabolites. Quantitative differences existed among the species, but the
pattern of metabolism was similar for all species.

Clinical Pharmacology

The atrophogenic potential and dermal tolerance of DOVOBET (calcipotriol and betamethasone dipropionate) ointment was compared with that of 0.5 mg/g betamethasone dipropionate ointment and placebo ointment in a randomized, double-blind, right/left comparison on the forearm of subjects (study MCB 9903 DE). Sonography demonstrated skin thinning with DOVOBET relative to placebo ointment when applied twice daily for 4 weeks. However, skin thinning with DOVOBET was similar to betamethasone (12.3% and 13.2% respectively). There were no clinical signs of atrophy, telangiectasia or irritation (erythema). There were no histological differences in epidermal or dermal thickness between DOVOBET and betamethasone.

The absorption and excretion balance of 3H-calcipotriol and 3H-betamethasone was evaluated after a single application of radiolabelled DOVOBET to healthy volunteers (study MCB 9901 NL). Subjects were also treated with DOVOBET for 4 weeks and then absorption and excretion was again evaluated after a single application of radiolabelled DOVOBET. The absorption of calcipotriol after a single application of DOVOBET is similar to absorption after application of the other marketed formulation of calcipotriol (i.e. DOVONEX, 50 mcg/g calcipotriol). Thus, the safety profile of DOVONEX is applicable to DOVOBET. Betamethasone dipropionate in DOVOBET does not influence the absorption rate of calcipotriol and vice versa calcipotriol does not affect the absorption of betamethasone. Absorption of calcipotriol is similar after 4 weeks of treatment with DOVOBET as it is after a single application.

A bioequivalence study of betamethasone dipropionate in DOVOBET ointment versus Diprosone® (Schering-Plough Ltd.) ointment, was conducted in healthy volunteers according to the FDA guideline for vasoconstrictor bioassay (study MCB 9902 FR). Betamethasone dipropionate is bioequivalent in the two preparations as the 90% confidence interval for the skin blanching response ratio (test to reference) is [0.81 ; 1.04] and within the interval of [0.80 ; 1.25] as defined by the FDA guideline.

Toxicology

Toxicologic studies are summarized briefly here and in more detail by species in tabular form following this section.

Systemic Toxicity of Calcipotriol

Despite the intended topical use of calcipotriol in the treatment of psoriasis, most of the toxicological studies were performed using the oral route of administration. This was done to assure maximum exposure to the compound. From these studies it was evident that toxicity associated with the administration of pharmacologically excessive doses of calcipotriol was due to the calcitropic activity of the compound. The maximum doses were 54 mcg/kg/day in rats, 18 mcg/kg/day in minipigs and 3.6 mcg/kg/day in dogs. In the acute, subacute and chronic toxicity studies the main signs of toxicity were loss of bodyweight, increases in plasma or serum calcium, creatinine and urea, renal toxicity and soft tissue calcifications. These changes resulted from the exaggerated absorption of calcium and phosphorous from the intestine and are characteristic of vitamin D overdosage. The kidney was the main target organ of toxicity and tubular lesions and calcifications were apparent after prolonged hypercalcemia in all species investigated. These types of changes, however, are not considered indicative of a human risk, since less than 1% of calcipotriol is absorbed through the skin in man and there is no evidence of calcitropic effects in man with the prescribed dose.

Dermal Toxicity of Calcipotriol

Dermal toxicity of calcipotriol was limited to a slight-to-moderate skin irritative effect. The studies performed with calcipotriol ointment showed that the incidence and severity of skin irritation was slightly less in the calcipotriol-treated group than in the placebo ointment group. The formulation of the ointment base is analogous to that employed for a number of steroids available for the treatment of psoriasis. Skin thinning, as seen with steroid application, was not observed with the calcipotriol ointment.

Dermal Tolerability of DOVOBET (50 mcg/g calcipotriol plus 0.5 mg/g betamethasone (as dipropionate)): Two dermal tolerability studies were conducted in rabbits. In the first study, no skin irritation was observed and only slight irritation attributed primarily to calcipotriol was observed in the second study. A gradual reduction in skin thickness was observed over 6 weeks which was attributed to betamethasone. However, the stratum corneum of rabbit skin is much thinner than that of humans and rabbits are very sensitive to skin irritants.

Reproduction and Mutagenicity with Calcipotriol

Reproduction studies have shown that calcipotriol has no effect on fertility in male and female rats nor on their F1 generation progeny. Fetal toxicity and teratogenicity studies showed no evidence of embryotoxic or teratogenic effects in rats and rabbits. Peri- and post-natal development studies indicated that calcipotriol had no toxic effects on the F1 or F2 generation. There was also no evidence for a mutagenic or clastogenic potential with calcipotriol.

Carcinogenicity with Calcipotriol

A dermal carcinogenicity study in mice showed no indications of increased carcinogenic risks. Calcipotriol solution was applied topically for up to 24 months at doses of 3, 10 and 30 mcg/kg/day (corresponding to 9, 30 and 90 mcg/m2/day). The high-dose was considered to be the Maximum Tolerated Dose for dermal treatment of mice with calcipotriol. Survival was decreased at 10 and 30 mcg/kg/day; particularly in the males. The reduced survival was associated with an increased incidence of obstructive uropathy, most probably caused by treatment-related changes in the urinary composition. This is an expectable effect of treatment with high doses of calcipotriol or other vitamin D analogues. There were no dermal effects and no dermal or systemic carcinogenicity.

Photo(co)carcinogenicity: In a study where albino hairless mice were repeatedly exposed to both ultraviolet radiation (UVR) and topically applied calcipotriol for 40 weeks at the same dose levels as in the dermal carcinogenicity study (see above), a reduction in the time required for UVR light to induce the formation of skin tumours was observed (statistically significant in males only), suggesting that calcipotriol may enhance the effect of UVR to induce skin tumours. The clinical relevance of these findings is unknown.

No carcinogenicity or photocarcinogenicity studies have been performed with betamethasone dipropionate.

Acute Toxicity of Calcipotriol
TEST COMPOUND ANIMAL ROUTE / DOSAGE IMPORTANT FINDINGS
Calcipotriol
(MC903)
Mouse

Rat
Oral 0-20 mg/kg
i.p. 0-20 mg/kg
Oral 0-40 mg/kg
i.p. 0-60 mg/kg
Oral and i.p. LD50 in mouse and oral LD50 in rat ≈ 20 mg/kg. i.p. LD50 in rat ≈ 40 mg/kg. Clinical symptoms
due to hypercalcemia; subsequent soft tissue calcification was main symptom. Cause of death: Renal failure.
Organs affected: Kidney, heart, thymus and liver in rat (at ≥ 20 mg/kg) and kidney in mouse (at ≥ 5 mg/kg).
MC1046 & MC1080
(main metabolites of
MC903)
Rat Oral 0-80 mg/kg
i.p. 0-80 mg/kg
for both compounds
Oral and i.p. LD50 for MC1046 ≈ 45 mg/kg. Oral LD50 for MC1080 ≈ 35 mg/kg and ≈ 2X as much for i.p.
Clinical symptoms due to hypercalcemia; subsequent soft tissue calcification was main symptom. Cause of
death: Renal failure. Organs affected: Kidney, heart, GI tract, lung and testes (at > 20 mg/kg).
Local Tolerance of Calcipotriol
TEST SYSTEM ANIMAL MC903 DOSAGE IMPORTANT FINDINGS
Skin irritation test Rabbit (n=6) 5 mcg/day for 3 weeks Only minor skin reactions were seen.
Skin irritation test Rabbit (n=6 /
group)
25 mcg/day ointment vs.
placebo for 6 weeks
Treatment caused clinically well-defined to moderate skin reactions, as did placebo ointment. Reaction
considered related to propylene glycol content in ointment base. No adverse histopathological changes
were observed.
Skin irritation test Rabbit (n=6) 100 mg of 50 mcg/g cream
vs placebo for 6 weeks
Only slight irritancy developed. The irritancy developed quicker with the calcipotriol group than the
placebo. The magnitude of the reactions was similar in both groups.
Skin irritation test Rabbit (n=6) 100 mcl of 50 mcg/mL
scalp solution vs placebo
for 6 weeks
Only very slight irritancy was observed. Thickening of the epidermis was observed in areas treated with
calcipotriol.
Acute eye irritation Rabbit (n=3) 5 mcg ointment single dose Only transient, fully reversible swelling of the conjunctivae was observed
Allergenic potential
maximization test
Guinea pig
(n=10, placebo;
n=20, MC903)
0.5-5 mcg/mL MC903 was classified as a mild potential allergen.
Long-Term Toxicity of Calcipotriol
TEST COMPOUND ANIMAL ROUTE / DOSAGE IMPORTANT FINDINGS
Calcipotriol
(MC903)
Rat
(20/dose)
Oral 0 (control), 6,18
and 54 mcg/kg/day
for 4 weeks.
Apart from a higher incidence of focal calcification at the cortico-medullary junction of the kidneys in the high
dose animals, no other adverse effects were seen. The focal calcification can be attributed to the pharmacological
effect of MC903. No mortality was seen.
Calcipotriol
(MC903)
Dog
(4/dose)
Oral 0 (control), 0.1,
0.3 and 0.9 mcg/kg/
day for the first 4
weeks, ≤1.8-3.6
mcg/kg/day for the last
2 weeks. Total 6 weeks.
No changes were seen at doses up to 0.9 mcg/kg/day for 4 weeks, whereas raising the dose to 1.8 mcg/kg/day at
week 5 and further to 3.6 mcg/kg/day at week 6 caused morphological changes in the kidneys, increases of kidney
functioning and plasma calcium, all of which are attributed to the pharmacological activity of MC903. No
mortality was seen.
Calcipotriol
(MC903)
Rat
(20/dose)
Dermal 0 (control) 6,
18 and 54 mcg/kg/day
for 13 weeks.
Topical treatment for 13 weeks gave rise to slight skin reactions and some minor changes in the clinical chemistry
parameters. The minimal focal calcification seen in the kidneys of all treatment group animals was a minor
change which may be attributed to the calcitropic effect of MC903. The same changes occur spontaneously in lab
rats. The changes recorded in the low dose group were within the level of spontaneous incidence.
Calcipotriol
(MC903)
Rat
(40/dose)
Oral 0 (control), 4, 12
and 36 mcg/kg/day for
26 weeks.
The target organ was identified as the kidneys. The main clinical chemistry findings were the dose-related
increases in serum calcium, indicating a calcitropic effect of MC903. This was further confirmed at autopsy by
increased kidney weights, lighter coloured appearance of kidneys, increased bone mineralization and renal focal
and soft tissue calcification. One low dose female died on day 77, not considered as treatment-related.
Calcipotriol
(MC903)
Minipig
(6/dose)
Oral 0 (control), 1, 3
and 6 mcg/kg/day for
the first 20 weeks and
then up to 9-18 mcg/
kg/day for the last 6
weeks. Total 26 weeks.
No changes were seen in low- and mid-dose animals. Increase in high-dose rapidly affected the animals by
inducing distress, lethargy and bodyweight loss. These changes were accompanied by a slight decrease, still
within normal range, in Hb, erythrocyte and hematocrit. Serum calcium and urea were increased, serum inorganic
phosphate was decreased. At autopsy high-dose animals showed enlarged kidneys with pronounced striation of
the medulla on cut surfaces. Urinary calculi were observed in 1 animal. Histopathology showed tubular necrosis
and calcifications in the kidneys and the parotid gland in high-dose animals. No mortality was observed.
Mutagenicity of Calcipotriol
TEST SYSTEM TEST MC903 DOSAGE IMPORTANT FINDINGS
Ames Test Salmonella
typhimurium
0.01-1 mg/plate MC903 was not found mutagenic in this in vitro bacterial test at the dose levels tested.
Mouse lymphoma TK
locus assay
Mouse
lymphoma
L5178Y
(TK+/-) cells
1-40 mcg/mL MC903 demonstrates no evidence of mutagenic potential in this in vitro test system.
Metaphase chromosome
analysis
Human
lymphocytes
2-1000 mcg/mL MC903 has shown no evidence of clastogenic activity in this in vitro cytogenetic test system.
Micronucleus test Mouse bone
marrow
1 mg/kg p.o. MC903 did not show a mutagenic potential under the conditions of this in vivo micronucleus test.
Reproduction and Teratology of Calcipotriol
STUDY ANIMAL MC903 DOSAGE IMPORTANT FINDINGS
Fertility and general
reproductive performance
Rat
(20M, 40F)
6-54 mcg/kg/day
p.o.
Treatment with MC903 did not give rise to any major abnormalities in the offspring or affect the reproductive performance,
morphological development or auditory, visual or behavioural systems.
Fetal development Rat
(32/dose)
6-54 mcg/kg/day
p.o.
A few minor deviations occurred in pregnant rats given p.o. MC903 during days 6-15 of gestation, attributable to the
pharmacological effects of MC903 on calcium metabolism. No teratogenic effects were observed.
Teratology Rabbit
(18/dose)
4-36 mcg/kg/day
p.o.
At 36 mcg/kg/day of MC903 from day 6-18 of gestation, maternal toxicity was observed, characterized by deaths, bodyweight
losses, reduced food intake, increased post-implantation loss, reduced mean fetal weight and increased minor ossification
changes. At 12 mcg/kg/day slight signs of maternal toxicity (bodyweight loss, reduced food intake, maternal death or abortion in
2/18 animals) and reduced mean fetal weight were seen. At 4 mcg/kg/day, no adverse maternal or fetal effects were observed.
Peri- and post-natal Rat
(32/dose)
6-54 mcg/kg/day
p.o.
Administration of MC903 to pregnant rats from day 15 of gestation to day 20 post-partum did not cause significant adverse
effects on late fetal development, labour and delivery, lactation, neonatal viability and growth of the young or give rise to any
major abnormalities.
Local Tolerance of Dovobet (50 mcg/g calcipotriol plus 0.5 mg/g betamethasone (as dipropionate))
STUDY ANIMAL DOVOBET DOSAGE IMPORTANT FINDINGS
Dermal tolerability Rabbit
(n=6)
Once daily application of
100 mg Dovobet and 100 mg
vehicle ointment on separate
skin areas for 6 weeks.
No skin irritation was observed. Histopathological changes consisting of squamous metaplasia of
pilosebaceous tissue and comedogenic activity attributable to the ointment vehicle were observed.
Dermal tolerability Rabbit
(n=6)
Once daily application of
100 mg of Dovobet,
calcipotriol (50 mcg/g),
betamethasone (0.5 mg/g),
and vehicle ointment on
separate skin areas for 6
weeks.
Slight skin irritation attributed primarily to calcipotriol was observed. Histopathological changes
consisting of squamous metaplasia of pilosebaceous tissue and comedogenic activity attributable
primarily to the ointment vehicle were observed.