Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Other dermatological preparations, other dermatologicals, ATC code: D11AX22

Mechanism of action

Ivermectin is a member of the avermectin class. Avermectin has antiinflammatory effects by inhibiting lipopolysaccharide-induced production of inflammatory cytokines. Anti-inflammatory properties of cutaneous ivermectin have been observed in animal models of skin inflammation. Ivermectin also causes death of parasites, primarily through binding selectively and with high affinity to glutamate-gated chloride channels, which occur in invertebrate nerve and muscle cells. The mechanism of action of Soolantra in treating the inflammatory lesions of rosacea is not known but may be linked to anti- inflammatory effects of ivermectin as well as causing the death of Demodex mites that have been reported to be a factor in inflammation of the skin.

Clinical efficacy and safety

Soolantra applied once daily at bedtime was evaluated in the treatment of inflammatory lesions of rosacea in two randomised, double-blind, vehicle- controlled clinical studies, which were identical in design. The studies were conducted in 1371 subjects aged 18 years and older who were treated once daily for 12 weeks with either Soolantra or vehicle.

Overall, 96% of subjects were Caucasian and 67% were female. Using the 5- point Investigator Global Assessment (IGA) scale, 79% of subjects were scored as moderate (IGA=3) and 21% scored as severe (IGA= 4) at baseline.

The co-primary efficacy endpoints in both clinical studies were the success rate based on the IGA outcome (percentage of subjects “clear” and “almost clear” at Week 12 of the study) and absolute change from baseline in inflammatory lesion counts. The IGA scale is based on the following definitions:



Table 2: Investigator Global Assessment (IGA) scale
Grade           Score      Clinical Description
Clear           0          No inflammatory lesions present, no erythema 
Almost Clear    1          Very few small papules/pustules, very mild erythema present
Mild            2           Few small papules/pustules, mild erythema 
Moderate        3           Several small or large papules/pustules, moderate erythema

Severe          4          Numerous small and/or large papules/pustules, severe erythema
The results from both clinical studies demonstrated that Soolantra applied once daily for 12 weeks was statistically superior to vehicle cream in terms of IGA success rate and absolute change in inflammatory lesion counts (p<0.001, see table 3 and Figure 1, Figure 2, Figure 3 and Figure 4).

The following table and figures present efficacy outcomes from both studies.

Table 3: Efficacy Results
Study 1                  Study 2
Soolantra    Vehicle     Soolantra    Vehicle
(N=451)      (N=232)     (N=459)      (N=229)
Investigator Global
Assessment
Number (%) of Subjects
173              27          184          43
Clear or Almost Clear in
(38.4)           (11.6)      (40.1)       (18.8) the IGA at Week 12
Inflammatory Lesions
Mean Inflammatory
Lesion Count at Baseline 31.0             30.5        33.3         32.2 
Mean Inflammatory
Lesion Count at Week 12 10.6              18.5        11.0         18.8 
Mean Absolute Change
(%Change) in
Inflammatory Lesion          -20.5        -12.0       -22.2        -13.4 Count from Baseline at       (-64.9)      (-41.6)     (-65.7)      (-43.4) Week 12
Figures 1 and 2: IGA Success Rates Over Time in weeks

Study 1                                         Study 2

•• Vehicle                                                       vehicle 
— *—Soolantra
Soolantra


001


 p=0.021                                                   - p=0.014


4            6                                 2           4           6           4 Analysis visit                                             Analysis visit 


Figures 3 and 4: Mean Absolute Change in Inflammatory Lesion Counts from Baseline Over Time in weeks

Study 1                                         Study 2
Analysis visit                                            Analysis visit 

 p<0.001                           it -16
-16


Vehide                                                       Vehicle 
Soolantra



Soolantra was statistically superior to vehicle cream on the co-primary efficacy endpoints with a time to onset of efficacy of 4 weeks of treatment (p<0.05).

IGA was assessed during the 40-week extension of the two clinical studies and the percentages of subjects treated with Soolantra achieving an IGA score of 0 or 1 continued to increase up to Week 52. The Success Rate (IGA=0 or 1) at Week 52 was 71% and 76% in Studies 1 and 2, respectively.

The efficacy and safety of the medicinal product in the treatment of inflammatory lesions of rosacea were also evaluated in a randomised, investigator-blinded, active- controlled clinical study. The study was conducted in 962 subjects aged 18 years and older who were treated for 16 weeks with either Soolantra once daily or Metronidazole 7.5 mg/g cream twice daily. In this study, 99.7% of subjects were Caucasian and 65.2% were female; on the IGA scale, 83.3% of subjects were scored as moderate (IGA=3) and 16.7% scored as severe (IGA=4) at baseline (see figure 5).
The results of the study demonstrated that Soolantra was statistically superior to Metronidazole 7.5 mg/g cream on the primary efficacy endpoint (Mean Percent Change in Inflammatory Lesion Counts) with a reduction of 83.0% and 73.7% from baseline after 16 weeks of treatment for the ivermectin and metronidazole groups respectively (p<0.001). The superiority of Soolantra at Week 16 was confirmed on Success Rate based on IGA and Absolute Change in Inflammatory Lesion Counts (secondary endpoints (p<0.001)).
Approximately 300 subjects aged 65 years and older were treated over all clinical trials with the medicinal product. No meaningful differences in the efficacy and safety profile were observed between elderly subjects and subjects 18 to 65 years of age.

The safety profile, as described in section 4.8 remained stable over conditions of long-term use as observed in long-term treatments up to one year.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
The absorption of ivermectin from Soolantra was evaluated in a clinical trial in adult subjects with severe papulopustular rosacea under maximal use conditions.
At steady state (after 2 weeks of treatment), the highest mean (± standard deviation) plasma concentrations of ivermectin peaked within 10 ±8 hours postdose (Cmax: 2.1 ± 1.0 ng/mL range: 0.7 - 4.0 ng/mL) and the highest mean (± standard deviation) AUC0-24hr was 36± 16 ng.hr/mL (range: 14-75ng.hr/mL).
Ivermectin systemic exposure levels reached a plateau by two weeks of treatment (steady state conditions). In the longer treatment durations of the Phase 3 studies, ivermectin systemic exposure levels were similar to those observed after two weeks of treatment. At steady state conditions, the ivermectin systemic exposure levels (AUC0-24hr:36 ±16 ng.hr/mL) were lower than those obtained following a single 6-mg oral dose of ivermectin in healthy volunteers (AUC0- 24hr:134 ± 66 ng.hr/mL).


Distribution
An in vitro study demonstrated that ivermectin is greater than 99% bound to plasma proteins and is bound primarily to human serum albumin. No significant binding of ivermectin to erythrocytes was observed.

Biotransformation
In vitro studies using human hepatic microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4.
In vitro studies show that ivermectin does not inhibit the CYP450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 4A11 or 2E1. Ivermectin does not induce CYP450 enzyme expression (1A2, 2B6, 2C9 or 3A4) in cultured human hepatocytes.

Two major metabolites of ivermectin were identified in a maximal use clinical pharmacokinetic study and assessed during Phase 2 clinical studies (3''-O- demethyl ivermectin and 4a-hydroxy ivermectin). Similar to the parent compound, metabolites reached steady state conditions by 2 weeks of treatment, with no evidence of accumulation up to 12 weeks. Furthermore, the metabolites systemic exposures (estimated with Cmax and AUC) obtained at steady state were much lower than those observed following oral administration of ivermectin.

Elimination
The terminal half-life averaged 6 days (mean: 145 hours, range 92-238 hours) in patients receiving a once daily cutaneous application of the medicinal product for 28 days, in the maximal use clinical pharmacokinetic study. Elimination is absorption-dependent following topical treatment with Soolantra.
Pharmacokinetics of ivermectin have not been studied in patients with renal and hepatic impairment.