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Dovonex - Scientific Information

Manufacture: LEO Pharma
Country: Canada
Condition: Plaque Psoriasis, Psoriasis
Class: Topical antipsoriatics
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: Calcipotriol, white soft paraffin, propylene glycol, liquid paraffin, polyoxyethylene-(2)-stearyl ether, purified water,disodium phosphate dehydrate, disodium edentate, DL-α-tocopherol, white soft paraffin, cetostearyl alcohol, liquid paraffin, glycerol 85%, macrogol cetostearyl ether, disodium phosphate dehydrate, disodium edentate, chloroallylhexaminium (dowicil 200), purified water

Pharmaceutical information

Drug Substance

Proper name (I.N.N.): Calcipotriol
Chemical abstracts name: 9,10-Secochola-5,7,10(19),22-tetraene-1,3,24-triol,24-cyclopropyl-
,(1∝,3ß,5Z,7E,22E,24S)
Alternative chemical name: 20(R)-(3'(S)-Cyclopropyl-3'-hydroxyprop1'(E)enyl)-1(S),3(R)-dihydroxy-9,10-secopregna-5(Z),7(E),10(19)-triene
Laboratory code name: MC 903 or MC 903-000
Molecular formula and mass: C27H4003; 412.6
Chirality: The calcipotriol molecule is one single stereoisomer. The absolute configuration of the chiral centers at carbon atoms nos. 1, 3, 13, 14,17, 20 and 24 is indicated in the structural formula below..

Structural formula:


Calcipotriol                                   “Pre-calcipotriol”
Physicochemical properties:
Physical form:
Solubility at RT:


Melting point:
Polymorphism:
Derivation:
Calcipotriol is a white or almost white crystalline substance.
Freely soluble in ethanol, soluble in chloroform and propylene glycol,practically insoluble in liquid paraffin. Solubility in water is 0.6 mcg/mL.

166-168oC
So far no signs have indicated the existence of polymorphic forms.
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-alcipotriol" is shown bove.

Clinical trials

DOVONEX Used as Monotherapy

Twice daily DOVONEX (calcipotriol) administration has been shown to be effective for the treatment of psoriasis deemed amenable to topical treatment regardless of the baseline severity. Although once daily administration is clinically effective with respect to PASI reduction and attainment of marked clinical improvement or clearance of symptoms, it is less effective than twice daily administration. Therefore, once daily administration is only recommended for the maintenance phase of DOVONEX treatment. For further details, please see information on studies DE127-001, DE127-003, DE127-007, DE127-009, and MC 9302 INT in the Summary of Clinical Trials table below.

DOVONEX Used as Combination Therapy with Topical Steroids

Combination of DOVONEX once daily plus once daily administration of a potent or very potent topical corticosteroid has been shown to improve efficacy. Two weeks of combination treatment with DOVONEX ointment plus 0.05% halobetasol propionate ointment decreased overall severity by approximately 80% as compared to DOVONEX twice daily monotherapy (56%). Eight weeks of combination treatment with DOVONEX cream plus 0.1% betamethasone-17- valerate cream reduced the baseline PASI score by almost 60% as compared to DOVONEX twice daily monotherapy (48%). For further details, please see information on studies DE127- 019 and MC 9302 INT in the Summary of Clinical Trials table below.

DOVONEX Used as Combination Therapy with Cyclosporin or Acitretin

In a clinical trial of 6 weeks duration, combination of DOVONEX twice daily plus low dose oral cyclosporin A (2 mg/kg/day) was significantly more effective than cyclosporin monotherapy. Combination treatment resulted in an approximate 80% reduction in PASI versus a 58% PASI reduction with cyclosporin monotherapy. For further details, including efficacy and safety information, please see study MC 9101 F in the Summary of Clinical Trials table below.

In a clinical trial of 12 weeks duration, the following treatments were compared: DOVONEX ointment twice daily plus oral acitretin (20-70 mg/day) versus placebo ointment twice daily plus oral acitretin (20-70 mg/day). At the end of treatment, combination with acitretin reduced baseline PASI by approximately 72% versus 48% in the acitretin group. Combination treatment provided marked improvement or clearance to a significantly greater number of patients while requiring significantly less acitretin as compared to acitretin monotherapy. For further details, including efficacy and safety information, please see study MC 9306 INT in the Summary of Clinical Trials table below.

DOVONEX Used as Combination Therapy with PUVA or UVB Phototherapy

DOVONEX in combination with PUVA or UVB phototherapy is not indicated for the topical treatment of psoriasis due to the observation in a hairless mice model of a reduced time to UVR- induced tumour formation. This preclinical finding suggests a possible enhancement effect for calcipotriol on the known carcinogenic effect of UVR. (see TOXICOLOGY, Photo(co)- carcinogenicity)

In a clinical trial of 12 weeks duration, the following treatments were compared: DOVONEX ointment twice daily for 2 weeks followed by twice daily DOVONEX in combination with PUVA (3 times weekly) for an additional 10 weeks versus placebo ointment twice daily for 2 weeks followed by twice daily placebo ointment in combination with PUVA (3 times weekly). At the end of treatment, combination of DOVONEX plus PUVA phototherapy resulted in a 91% PASI reduction with 91% of patients achieving marked improvement or clearance. Combination treatment was significantly more effective than PUVA alone and required significantly less UVA exposure (ie. 37% lower cumulative dose, 26% fewer irradiations and a 24% shorter duration of treatment). For further details, including efficacy and safety information, please see study MC 590 in the Summary of Clinical Trials table below.

In a clinical trial involving 12 weeks active treatment and 12 weeks follow-up, the following treatments were compared: DOVONEX cream twice daily plus UVB 2 times weekly versus placebo cream plus UVB phototherapy 3 times weekly. DOVONEX plus UVB phototherapy twice weekly was equally effective as UVB three times weekly (ie. 77% PASI reduction versus 81%) but required a significantly lower cumulative dose of UVB and fewer treatments. For further details, including efficacy and safety information, please see study MCC 9504 CAN in the Summary of Clinical Trials table below. For additional studies, refer to study MC 9307 INT and MC 390 using DOVONEX ointment.

SUMMARY OF CLINICAL TRIALS
STUDY
CODE       
STUDY DESIGN   EVALUATION CRITERIA AND RESULTS    
TOPICAL TREATMENT OF PSORIASIS
DE127-001 Design:
Multi-centre, randomised, double-blind, vehicle-controlled, parallel-group study.

Inclusion Criteria:Stable plaque psoriasis involving 5-20% body surface.

Treatment Period:2 week washout period and 8 weeks active treatment.

Treatment Groups:
(1) Dovonex ointment (50 mcg/g calcipotriol), twice daily topical application; n=167
vs. (2) Placebo ointment, twice daily topical application;n=168
Evaluation Criteria:
Severity of erythema, scaling, plaque elevation, and overall disease severity, physician's global assessment,adverse events, serum biochemistry,haematology and urinalysis.

Results:
Severity scores for all symptoms, overall severity score and physician's global assessment were significantly lower for Dovonex at weeks 1 through 8. At week 8, 70% of calcipotriol subjects were clear or markedly improved versus 22% with vehicle.No difference between groups in adverse reactions, frequency or time of onset of skin related adverse events. No effect on indices of haematology, or serum or urine biochemistry. Efficacy was similar between patients with "low" versus "high" baseline severity of psoriasis.
DE127-003 Design:
Multi-center, randomised, double-blind vehicle-controlled parallel group study.

Inclusion Criteria:Stable plaque psoriasis involving 5-20% body surface.

Treatment Period:2 week washout period and 8 weeks active treatment.

Treatment Groups:
(1) Dovonex ointment (50 mcg/g calcipotriol), twice daily topical application; n=139 vs. (2) Placebo ointment, twice daily topical application; n=138
Evaluation Criteria:
Severity of erythema,scaling, plaque elevation, and overall disease severity, physician's global assessment, adverse events, haematology, serum biochemistry and urinalysis.

Results:
Severity scores for all symptoms, overall severity score and physician's global assessment were significantly lower for Dovonex at weeks 1 to 8. At week 8, 70% of calcipotriol subjects were clear or markedly improved versus 19% with vehicle.No difference between groups in adverse reactions, frequency, severity or time of onset of skin related adverse events. No effects on indices of haematology or serum or urine biochemistry. Efficacy was similar between patients with "low" versus "high" baseline severity of psoriasis.
ONCE DAILY ADMINISTRATION
DE127-007 Design:
Multi-centre, randomised, double-blind, vehicle-controlled, parallel-group study.

Inclusion Criteria: Plaque psoriasis.

Treatment Period:8 weeks.

Treatment Groups:
(1) Calcipotriol ointment (50 mcg/g) applied once daily; n=118 vs. (2) Placebo ointment applied once daily; n=117
Evaluation Criteria:
Severity of scaling, erythema and plaque elevation, assessment of overall disease severity, physician's global assessment of improvement/worsening of psoriasis and adverse events.

Results:
Mean scores for erythema, scaling, plaque elevation and overall disease severity for calcipotriol ointment were significantly lower than vehicle from week 1 through the end of treatment (week 8). The physician's global assessment was significantly in favour of Dovonex from week 1 through to the end of treatment.No significant differences between treatment groups in the time to onset and frequency of skin-related adverse events.
DE127-009 Design:
Multi-centre, randomised, double-blind, vehicle-controlled, parallel-group study.

Inclusion Criteria: Plaque psoriasis.

Treatment Period:8 weeks.

Treatment Groups:
(1) Calcipotriol ointment (50 mcg/g) applied once daily;n=99 vs. (2) Placebo ointment applied once daily; n=99
Evaluation Criteria:
Severity of scaling, erythema and plaque elevation, assessment of overall disease severity, physician's global assessment of improvement/worsening and adverse events.

Results:
Mean scores for plaque elevation at week 1 and week 2 and scaling at week 2 were significantly lower for Dovonex compared tovehicle. Mean scores for all measures (erythema, scaling, plaque elevation, and overall disease severity) were significantly lower with Dovonex from week 4 through the end of treatment (week 8). The physician's global assessment was significantly in favour of Dovonex at week 1 through to the end of treatment.There were no statistically significant differences in the time to onset and frequency of skin-related adverse events between the treatment groups.
MC 9302
INT
Design:
Multi-centre, randomised, double-blind, comparative, parallel-group study.

Inclusion Criteria:
Psoriasis vulgaris. Lesions on the upper or lower extremities or trunk amenable to treatment with up to 120 g of cream per week.

Treatment Period:2 week washout period and 8 weeks active treatment.

Treatment Groups:
(1)Dovonex cream (50 mcg/g alcipotriol) once daily plus clobetasone 17-butyrate 0.05% cream once daily;n=175 vs. (2) Dovonex cream once daily plus betamethasone 17-valerate 0.1% cream once daily; n=176 vs. (3) Dovonex cream twice daily; n=174 vs.(4) Dovonex cream once daily plus placebo cream once aily; n=174
Evaluation Criteria:
Investigator assessment of PASI, investigator and patient assessment of overall response, adverse events, haematology and serum biochemistry.

Results:
Although twice daily administration of Dovonex was more effective, once daily administration resulted in a 41% decrease in PASI and 28% of patients were judged to have marked improvement or clearance at the end of treatment.No difference between treatment groups in total adverse events.
COMBINATION TREATMENT WITH MODERATE TO VERY POTENT TOPICAL CORTICOSTEROIDS
DE127-019 Design:Multi-centre, randomised, double-blind, comparative, parallel group study.

Inclusion Criteria:
Adults with stable plaque psoriasis having plaque elevation of at least moderate severity (grade 4 on a scale of 0-8) and 5% to 20% body coverage.

Treatment Period:2 week washout period followed by 2 weeks active treatment.

Treatment Groups:
(1) Dovonex intment (50 mcg/g calcipotriol) twice daily; n=42 vs. (2) Halobetasol propionate 0.05% ointment twice daily;n=42 vs. (3) Dovonex ointment once aily plus halobetasol once daily; n=42
Evaluation Criteria:
Severity of erythema, scaling, and plaque elevation, assessment of overall disease severity, physician's lob
assessment and adverse events.

Results:
Plaque elevation and overall severity were significantly lower in the combination group at day 14. The physician's global assessment was also lower at day 7 and 14.No difference between groups in adverse reactions.
MC 9302 INT Design:Multi-centre, randomised, double-blind, comparative, parallel-group study.

Inclusion Criteria:
Psoriasis vulgaris. Lesions on the upper or lower extremities or trunk amenable to treatment with up to 120 g of cream per week.

Treatment Period:2 week washout period and 8 weeks active treatment.

Treatment Groups:
(1) Dovonex cream (50 mcg/g calcipotriol) nce daily plus clobetasone 17-butyrate 0.05% cream once daily;n=175vs. (2)Dovonex cream once daily plus betamethasone 17-valerate 0.1% ream once daily;n=176vs. (3) Dovonex cream twice daily;n=174vs. (4)Dovonex cream once dailyplus placebo cream once daily; n=174
Evaluation Criteria:
Investigator assessment of PASI, investigator and patient assessment of overall response, adverse events haematology and serum biochemistry.

Results:
At the end of treatment, a significantly greater decrease in PASI was observed for Dovonex plus betamethasone versus all other treatment groups.No difference between groups in total adverse events. Significantly less skin irritation with the two steroid combinations.
COMBINATION WITH SYSTEMIC DRUG TREATMENT (CYCLOSPORIN OR ACITRETIN)
MC 9101 F Design:Multi-centre, randomised, double-blind, comparative, parallel-group study.

Inclusion Criteria:
Adults with severe psoriatic lesions (PASI≥20) without exceeding 50% body coverage and for whom cyclosporin A seemed appropriate.

Treatment Period:2 week washout period followed by 6 weeks active treatment.

Treatment Groups:
(1) Dovonex intment (50 mcg/g calcipotriol) twice daily in combination with low dose oral cyclosporin A (2 mg/kg/day); n=35 vs. (2) Placebo ointment wice daily in combination with low dose oral cyclosporin A (2 mg/kg/day); n=34
Evaluation Criteria:
Investigator assessment of PASI, investigator and patient assessment of overall response, adverse events, haematology and serum biochemistry.

Results:
Clearance or PASI reduction of ≥ 90% was achieved by 50% of combination treated patients versus 12% with cyclosporin alone. At the end of treatment PASI was reduced by 80% with Dovonex combination versus 58% with cyclosporin. Investigator and patient overall assessment favoured Dovonex combination treatment.No difference between groups in number of adverse events. No effect on laboratory values including serum calcium in either group.
MC 9306 INT Design:Multi-centre,randomised, double-blind, comparative, parallel group study.

Inclusion Criteria:Patients with a clinical diagnosis of severe or extensive psoriasis vulgaris deemed not responsive to topical treatment alone.

Treatment Period:2 week washout period and 12 weeks active treatment.

Treatment Groups:
(1) Dovonex ointment (50 mcg/g calcipotriol) twice daily plus oral acitretin (20-70 mg/day);n=76vs. (2)Placebo ointment twice daily plusoral acitretin (20-70 mg/day); n=59
Evaluation Criteria:
Investigator assessment of PASI, investigator and patient assessment of overall response, adverse events and serum biochemistry.

Results:
At the end of treatment, PASI reduction and the investigators overall assessment was significantly in favour of Dovonex combination treatment. A significantly lower (20% lower) cumulative dose of acitretin was required to obtain clearance or marked improvement (67% of patients receiving combination treatment versus 41% treatedwith acitretin).No difference in adverse events. No effect on laboratory parameters including serum calcium in either group.
COMBINATION WITH PHOTOTHERAPY (PUVA or UVB)
MC 590 Design:Multi-centre, randomised, double-blind, comparative, parallel-group study.

Inclusion Criteria:
Adults with extensive psoriasis covering ≥20% and ≤50% of the body surface and
for whom PUVA therapy was indicated.

Treatment Period:2 week washout period followed by 12 weeks active treatment.

Treatment Groups:
(1) Dovonex ointment (50 mcg calcipotriol) twice daily for 2 weeks followed by twice daily Dovonex in combination with PUVA(3 times weekly) for 10 weeks; n=54vs. (2)Placebo ointment twice daily for 2 weeks followed by twice daily placebo ointment in combination with PUVA (3 times weekly) for 10 weeks; n=53
Evaluation Criteria:
Investigator assessment of PASI, patient assessment of overall response, adverse events and serum
biochemistry.

Results:
At the end of treatment, a significantly greater % decrease in PASI was observed with Dovonex plus UVA (91% versus 76%).Dovonex combination treatment required a significantly lower UVA dose (37%), fewer doses (26%) and shorter treatment period (24%). Patient assessment of overall response was significantly in favour of Dovonex combination.No difference between groups in number of adverse events. No effect on laboratory values including serum calcium. No phototoxicity or photosensitivity was reported.
MC 9307 INT Design:Multicenter, randomised, double-blind, right-left, comparative study.

Inclusion Criteria:
Adults with a clinical diagnosis of psoriasis vulgaris. Symmetrical lesions on 1) the trunk and on the arms and legs, 2) the trunk alone, 3) arms and egs.

Treatment Period:2 week washout period, 8 weeks active treatment and 8 weeks follow-up.

Treatment Groups:
(1)Dovonex ointment (50 mcg/g calcipotriol) twice daily plus UVB three times weekly on one side of the body vs. (2) Placebo ointment twice daily plus UVB three times weekly on the other side of the body; n=77
Evaluation Criteria:
Investigator assessment of PASI, investigator and patient assessment of overall response, adverse events and serum biochemistry.

Results:
After 2 weeks, the % PASI reduction and the overall assessment of response were significantly in favour of Dovonex plus UVB. At the end of treatment, all three assessments were similar between treatment groups. There was no effect on laboratory parameters including serum calcium.
MC 390 Design:Multi-centre, randomised, double-blind, right-left, comparative study.

Inclusion Criteria:
Adults with a clinical diagnosis of moderate tosevere plaque psoriasis vulgaris. Symmetrical lesions on 1) the trunk and on the arms and legs, 2) the trunk alone, 3) arms and legs.

Treatment Period:2 week washout period, 8 weeks active treatment and 8 weeks follow-up.

Treatment Groups:
(1)Dovonexointment (50 mcg/g calcipotriol) twice dailyplus UVB three times weekly on one side of the body vs. (2) Dovonex ointment twice daily on the other side of the body;n=101
Evaluation Criteria:
Investigator assessment of PASI, investigator and patient assessment of overall response, adverse events and serum biochemistry.

Results:
PASI reduction and the investigators overall assessment was significantly in favour of Dovonex plus UVB at all time points.No difference in adverse events. No effect on laboratory values, including serum calcium.
MCC 9504
CAN
Design:Multi-centre, randomised, single-blind (Investigator), parallel group,
comparative study.

Inclusion Criteria:Adults with a clinical diagnosis of extensive plaque psoriasis vulgaris (20-40% body coverage) for which UVB phototherapy was indicated.

Treatment Period:1 week washout period followed by 12 weeks active treatment and 12 weeks follow-up.

Treatment Groups:
(1) Dovonex cream (50 mcg/g calcipotriol) twicedaily plus UVB 2 times weekly; n=80 vs. (2) Placebo cream twice daily plus UVB phototherapy 3 times weekly; n=80
Evaluation Criteria:
Investigator assessment of PASI, investigator and patient assessment of overall response, adverse events and serum biochemistry.Secondary criteria included the number of UVB treatments required for clearance and the number of patients attaining an 80% decrease in PASI.

Results:
Dovonex plus UVB twice weekly was equally effective as UVB three times weekly based on reduction of PASI and overall response assessed by investigators and patients.The Dovonexgroup attained an 80% reduction in PASI or clearance of psoriasis with significantly fewer UVB treatments and a lower cumulative dose of UVB.No clinically significant effects on laboratory values(including serum calcium) were observed in either group.

Detailed pharmacology

Animal Pharmacodynamic Studies

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.

Current therapeutic agents exert their effects mainly by non-specific cytostatic/cytotoxic effects on the proliferating cells or by 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.

In addition, calcipotriol was 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. 1,25(OH)2D3, the active form of vitamin D3, 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

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 minipigs, 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.

TYPE OF STUDY METHODS                      MAJOR RESULTS AND INTERPRETATION     
IN VIVO PHARMACOKINETIC STUDIES IN THE RAT AND/OR RABBIT
(1) Acute administration of 3H-MC903 by i.v. and oral routes to rats. Femalerats dosed with 3H-MC903, 0.10 mg/kg i.v. or0.20 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, radioactivity 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, sacrificed at various times after dosing. Distribution of radioactivelylabelled, non-volatile material assessed by examination 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.
IN VIVO PHARMACOKINETIC STUDY IN THE RAT AND/OR MINIPIG
(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 andfaeces 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 morepolar 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 STUDY IN THE RAT AND/OR MINIPIG, RABBIT, MAN
(6) 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 37oC 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.
(7) 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

There are no consistent and generally accepted definitions for “mild”, “moderate” or “severe” psoriasis. There is also considerable variability among physicians in the interpretation of the existing guidelines for assessing the extent of psoriasis. In clinical practice, patients are not evaluated or categorized as having mild, moderate or severe psoriasis but rather whether they are amenable to topical treatment or whether they require systemic treatment. DOVONEX (calcipotriol) is indicated for the topical treatment of psoriasis. The following section is intended to provide clarity and consistency regarding the therapeutic positioning of DOVONEX.

For many patients no single therapy provides adequate long-term control of psoriasis. Various combination treatment regimens have therefore been developed to improve treatment efficacy and/or to minimize the development of adverse effects. DOVONEX has been shown to be safe and effective when used in combination with a moderate to very potent topical corticosteroid. When the extent and/or severity of psoriasis is such that topical therapy alone is no longer adequate, then various systemic treatments are used. No single quantitative grading system is used clinically to determine at which level of extent/severity of psoriasis that systemic treatments are used. It is difficult to assign a specific severity score below which psoriasis cannot be considered “severe”. To a large extent, the decision to use systemic treatment is patient specific and dependent on the level of disability (physical, occupational or psychological) associated with psoriasis.

Systemic treatments are generally reserved for severe/extensive psoriasis when topical monotherapy is inappropriate. However, treatment of extensive and/or severe psoriasis is by no means restricted to systemic monotherapy. Combination treatments are widely accepted and are widely used as an alternative approach to minimize exposure to systemic agents which are usually more potent but are also potentially more harmful. DOVONEX has been shown to be safe and effective when used in combination with systemic drug therapy (cyclosporin A or acitretin) or with phototherapy (PUVA or UVB). The use of DOVONEX in combination with other antipsoriatic therapies offers an additional means of treating psoriasis that is not amenable to topical treatment alone (See CLINICAL TRIALS).

Toxicology

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

Systemic Toxicity

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

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.

Reproduction and Mutagenicity

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

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 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.

ACUTE TOXICITY
TEST COMPOUND ANIMAL ROUTE/DOSAGE IMPORTANT FINDINGS
Calcipotriol
(MC903)
Mouse Oral 0-20 mg/kg i.p. 0-20 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 symptom 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).
Rat Oral 0-40 mg/kg i.p. 0-60 mg/kg
MC1046 and 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
TEST COMPOUND 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
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 pharmacologica 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 inlow-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
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 ocus 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
STUDY ANIMAL MC903 DOSAGE IMPORTANT FINDINGS
Fertility and general reproductive performance Rat (20 M, 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.