Silkis - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Silkis - Scientific Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Psoriasis
Class: Antipsoriatics, Topical non-steroidal anti-inflammatories
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: Calcitriol, vitamin E (dl-α tocopherol) added as an antioxidant, mineral oil, and white petrolatum

Pharmaceutical Information

Drug Substance

Proper name: Calcitriol
Chemical name: (5Z, 7E)-9, 10-secocholesta-5, 7, 10(19)-triene-1 α, 3β, 25-triol (1α, 3β, 5Z, 7E)-9, 10-secocholesta-5, 7 10(19)-triene-1, 3, 25-triol
Molecular formula: C27H44O3
Molecular mass: 416.6
Structural formula:     
Physicochemical properties: White to almost white crystalline powder. Air, heat, and light sensitive. Calcitriol is practically insoluble in water, freely soluble in alcohol, and soluble in fatty oils.

Clinical Trials

The efficacy of Silkis (calcitriol) Ointment 3 μg/g for the treatment of psoriasis has been demonstrated in two randomized, double-blind, placebo-controlled studies in adult patients with mild to moderate psoriasis. Patients were treated twice daily for 8 weeks with Silkis or vehicle ointment. The primary efficacy parameter in both studies was Success Rate at Endpoint for the ITT population, defined as the proportion of subjects with a Global Severity Score of 0 (clear) or 1 (minimal) on the global, static, dichotomized, 6-point scale.

Study Demographics and Trial Design

Table 1 - Summary of Patient Demographics for Pivotal Clinical Trials in PsoriasisIndication
Study # Trial design Dosage, route of administration and duration Study subjects (n=number) Mean age (Range), years Gender M/F
RD.06.SRE.18053 Randomized, double blind placebo controlled 3 µg/g or vehicle sufficient to treat up to 35% BSA twice daily (up to 30 g/day) Topical 8 weeks 418 209 Silkis 209 Vehicle 47.1 (12-81) 278/140
RD.06.SRE.18054 421 210 Silkis 211 Vehicle 48.6 (13-87) 254/167

Study Results

Table 2 - Results of Pivotal Studies in Psoriasis - Treatment Success Rate, Based onAssessment of Global Severity of Psoriasis
Study # Number (%) of Patients Treated with Silkis Who Achieved Treatment Success at Endpoint2 Number (%) of Patients Treated with Vehicle Who Achieved Treatment Success at Endpoint2 P value3
RD.06.SRE.18053 72 (34.4%) 47 (22.5%) p=0.005
RD.06.SRE.18054 70 (33.3%) 26 (12.3%) p<0.001

1Success was defined as "Clear" or "Minimal" (up to light red or pink coloration; surface dryness; difficult to ascertain, slight elevation above normal skin) on the global severity score of psoriasis (score of 0 or 1). 2Endpoint was defined as the last observation for a subject during the treatment period, including Baseline if no post-baseline data were available 3P values are based on the Cochran-Mantel-Haenszel test, controlling for centre

Efficacy (success rate) was seen as early as Week 2 with a statistically significant difference from vehicle of 7%. At the end of treatment (Week 8) success rate was 37.3% and 36.9% in the Silkis ointment groups and 25.3% and 13.3% in the vehicle groups in Study 18053 and Study 18054 (p=0.009 and p<0.001), respectively.

In one long-term (52 week) uncontrolled, open label study in 324 subjects, efficacy did not appear to change over time.

Detailed Pharmacology

Safety Pharmacology

ECGs were recorded in a 13-week dermal dog and in a 9-month dermal mini-pig study. Ointments containing 3 µg/g calcitriol were applied in the dog study and up to 15 µg/g were applied to 10% body surface area (BSA) in the mini-pig study. There were no calcitriol-related effects on ECG morphology, heart rate or cardiac conduction.

Clinical Pharmacology

Pharmacodynamics and Pharmacokinetics

Twenty three adult male and female subjects with psoriasis applied 15 g of calcitriol ointment 3 µg/g twice daily to 35% of their body surface area (BSA) for 3 weeks. To ensure homogeneity in daily calcium intake, a 500 mg calcium tablet was taken daily for the duration of the study. Blood samples to determine calcitriol plasma levels and serum levels of calcium, phosphorus, albumin and creatinine were drawn on Days -8, -1, 0, and 21 (at times 0, 1, 2, 3, 4, 6, 9, 12,16, and 24 hours) and on Day 14 (at times 0, 1, 2, 3, 4, 6, 9, and 12 hours).

The pharmacodynamic parameters (serum albumin adjusted calcium, serum phosphorus, urinary calcium and urinary phosphorus) were used for the assessment of any effects of the topical application of calcitriol ointment 3 μg/g on calcium homeostasis.

The calcitriol plasma profiles in all subjects were relatively flat, and no terminal log-linear segment corresponding to a marked concentration decrease appeared on the concentration-time curves. Therefore, the terminal half-life was not determined.

The intra-individual endogenous calcitriol plasma levels (determined on Days -1 and -8) were stable during the day. No marked concentration peak appeared. The variability of calcitriol plasma level was also low. Conversely, the inter-subject variability was high, as shown by the coefficients of variation of approximately 50% both for Cmax and AUC(0-12h). The maximum endogenous calcitriol plasma levels (Cmax) varied from 20 to 121 pg/mL. Arithmetic Mean Cmax SD was 56.1 26.3 pg/mL on Day -8 and 58.2 28.6 pg/mL on Day -1.

Steady-state was achieved by Day 14 with no significant differences in pharmacokinetic parameters between Day 14 and Day 21. The mean values of C12h, Cmax, and AUC(0-12h) on Day 21 were 27%, 32% and 37% higher than the corresponding mean Baseline values (mean values for Days -1 and -8). No marked concentration peak appeared on Day 21, the mean value of Cmax was approximately 40% higher than the mean value of C12h.

There were no clinically meaningful changes in albumin-adjusted calcium values, although some mean values were statistically significant. The mean serum levels of albumin-adjusted calcium decreased from 2.37 mmol/L at Baseline to 2.32 mmol/L at Day 14 (p=0.0162), and the mean serum levels of phosphorus decreased from 1.2 mmol/L at Baseline to 1.13 mmol/L at Day 14 (p=0.0372). Although neither mean value returned to Baseline at Day 21 (calcium 2.33 mmol/L; phosphorus 1.17 mmol/L), neither was statistically significant at this point (p=0.0618 and p=0.2713, respectively).

There were no statistically significant or clinically meaningful changes in the mean 24-hour urine calcium value over the course of this study. The mean 24- hour urine phosphorus value increased from 25.53 mmol/dL at Baseline to 28.77 mmol/dL at Day 21(p=0.0064). Individual values were within the normal range, except for two subjects who had elevated urine phosphorus on Day -1 and on Day 21.

Local Tolerance

Local tolerance, as the primary endpoint, was assessed in healthy subjects in five Phase 1 local tolerance studies of calcitriol ointment 3 μg/g. In these studies, 50 μL of calcitriol ointment 3 μg/g was applied under an occlusive patch, which would result in greater exposure levels than expected clinically with unoccluded use. These studies are summarized in Table 3 below. In these studies, there was no evidence suggesting that calcitriol ointment 3 μg/g was irritating, sensitizing, phototoxic, or photosensitizing.

Table 3 - Tolerance Assessments from Phase 1 Studies for Which Local Tolerance was the Primary Endpoint: Calcitriol Ointment 3 µg/g
Study Study objective Subjects (N) Treatment duration Type of control Tolerance scale
1 Cumulative irritancy potential 25 21 days Tacalcitol 4 μg/g calcipotriol 50 μg/g white petrolatum a



- Erythema response on 5-point scale

- Cumulative Irritation Index calculated for each zone and subject

- Local reactions recorded

- Data regarding patch application collected
2 Cutaneous contact sensitization and cumulative irritancy potential 225 21 days (induction) 2 weeks (rest period 48 hours (challenge) single applicationa Vehicle ointment white petrolatumb
3 Photoallergic contact sensitization potential 25 21 days (induction) 24 hours (challenge) a,b Vehicle ointment white petrolatum
4 Phototoxicity potential 28 24 hours Vehicle ointment white petrolatum no treatment
5 Cumulative irritancy potential 25 21 days Calcipotriol 50 μg/g ointment calcipotriol 50 μg/g cream

a Sensitization reaction ratings: 0=negative, 1=equivocal, 2=positive
b Investigator opinion of photoallergic contact sensitization made at end of challenge phase

Toxicology

Single-Dose Toxicity

In rats and mini-pigs, single dermal application of 15 μg/g ointment to 20% BSA, providing an acute dose of 42 and 51 μg/kg respectively, was not associated with any calcitriol-related signs of toxicity. In rabbits, treatment with 15 μg/g ointment to 20% BSA (19.1 μg/kg) caused severe toxicity including mortality. The observed differences in species sensitivity to calcitriol may be related to (a) higher permeability of rabbit skin (rabbit>rat>mini-pig) and/or (b) inter-species differences in the regulation of calcitriol metabolism and calcium homeostasis.

Repeat-dose Toxicity

The chronic toxicity profile of calcitriol was primarily evaluated in a series of dermal repeat -dose studies up to 26 weeks in rats at daily doses of 0, 0.3, 1, 3 and 9 µg/g calcitriol to 10% BSA (unoccluded), and 9 months in mini-pigs at daily doses of 0, 1, 3, 9 and 15 µg/g calcitriol to 10% BSA (semi-occluded). Total daily calcitriol intake corresponded to 0, 0.6, 2, 6, 18 µg/kg/day in rats and 0, 1.7, 5.1, 15.3 and 25.5 µg/kg/day in mini-pigs. Other repeat-dose dermal studies were conducted in dogs, mice and rabbits. Of the species evaluated, the dermal permeability and skin characteristics of mini-pigs most closely resembles that of humans. The primary effects observed were consistent with exaggerated pharmacological alterations including marked increases in serum calcium concentration, urinary calcium and phosphorus excretion, and mineralization in multiple tissues.

A 13-week oral repeat-dose toxicity study was conducted in rats at doses of 0, 0.01, 0.1 and 0.3 µg/kg/day. Calcitriol-related findings were consistent with the results of dermal studies and were attributed to the pharmacological effects of the compound.

Mutagenicity

Calcitriol is an endogenous substance with no anticipated genotoxicity potential. Calcitriol was not mutagenic in an in vitro mouse lymphoma assay.

Carcinogenicity

A 12-month photocarcinogenicity study was conducted in UVR-irradiated hairless mice. Animals were dermally administered calcitriol at doses corresponding to 0, 0.3, 0.6 and 1.0 µg/kg five days per week. Toxicity was observed in mid- and high-dose mice, necessitating premature discontinuation of calcitriol administration. UVR exposure continued as scheduled and vehicle was applied for the remainder of the study. Topical administration of the vehicle slightly enhanced photocarcinogenicity with a reduced latency period of 3-4 weeks for appearance of skin tumours of ≤1 mm diameter when compared with UVR-irradiated control mice. The effect was attributed to the presence of mineral oil in the formulation, which is represented at ~44% w/w in the drug product (see Warning and Precautions). Topical administration of calcitriol at dose levels ≤ 1 µg/kg/day did not enhance photocarcinogenicity above the effect observed with the vehicle.

A 104-week mouse carcinogenicity study was conducted wherein males and females were dermally administered calcitriol at doses of 0, 0.3, 0.6 and 1.0 ppm to 10 % BSA. Toxicity, including mortality and likely related to exaggerated pharmacological effects, was observed at 0.6 and 1.0 ppm and the frequency of application was reduced from daily to 3 times a week. There was no evidence to suggest that application of calcitriol was associated with an increased incidence of tumours in male or female mice.

A 104-week rat carcinogenicity study was conducted wherein males and females were orally administered calcitriol at doses of 0, 0.005, 0.03, and 0.1 µg/kg/day. An increased incidence of proliferative non-neoplastic and neoplastic lesions was observed in the adrenal medulla (hyperplasia, pheochromocytoma) of males and females at 0.03 and 0.1 µg/kg/day. In the thyroid, focal C-cell hyperplasia and C-cell adenoma was observed at 0.1 µg/kg/day, particularly in females. These changes are likely due increased calcemia and are considered to be specific to the rat.

Reproduction

There were no effects on fertility (males or females) or early embryonic development in the rat at oral doses of 0.1, 3, and 0.6 µg/kg/day.

Embryo-fetal and Post-natal Development

Calcitriol was orally administered to pregnant rats at doses of 0.1, 0.3, or 0.9 µg/kg/day. Results indicated that calcitriol, at up to toxic dose levels, was not associated with any effect on gonad function, mating behaviour and reproductive performance of the male and female rats. Fetal toxicity and teratogenicity were not observed at any dose levels, despite a significant maternal toxicity.

Calcitriol 3 g/g ointment was dermally administered to pregnant rabbits onto 0.4, 1.6 and 6.4% BSA (corresponding to 0.08, 0.32 and 1.26 µg/kg/day). Teratogenicity was not observed. Developmental anomalies were attributed to high maternal toxicity and were not considered a direct calcitriol-mediated effect. Specifically, mid- and high-dose groups exhibited an increased incidence of retarded ossification of the pubic bones, and the high-dose displayed an increased incidence of skeletal variations. Overt maternal toxicity was observed in high-dose rabbits, which was associated with an increased incidence of post-implantation loss and a reduced number of live fetuses.

In a rat post-natal development study, no effects were observed on fertility, development, or reproductive performance of offspring at oral doses at 0.1, 0.3, or 0.6 µg/kg calcitriol per day.

Pregnancy and Nursing

The placental transfer of total radioactivity following a single oral administration of 0.9 μg/kg [3H]-calcitriol was evaluated in pregnant female rats. Peak radioactivity in fetal tissue occurred 22 hours later than in maternal plasma. A maximum of 0.8% of the administered dose was recovered in the whole fetus at 72 hours post-dose. The total exposure of the fetus was 3-fold lower than the total exposure of maternal plasma.

The secretion of total radioactivity in the milk of lactating rats was evaluated following

administration of a single oral dose of 0.6 µg/kg [3H]-calcitriol. Drug-related radioactivity (calcitriol and/or calcitriol metabolites) was detected in milk. The mean concentration of radioactivity was the highest at 4 hours post-dose and was higher in plasma than in milk at all time points evaluated. Radioactivity was cleared in plasma and milk at the same rate.

Local Tolerance

There was no evidence to suggest that calcitriol and calcitriol-containing ointment exhibits the potential to induce delayed contact hypersensitivity in guinea pigs.

Single or repeated dermal applications and single ocular exposure to 15 µg/g calcitriol ointment induced slight local irritation in rabbits and guinea pigs. Repeated dermal administration of 2.5 or 8.75 µg/g calcitriol ointments was not associated with signs of local irritation in rats or rabbits. Thus, although calcitriol ointment is well tolerated slight, individual, local irritation may occur.