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Pharmacology: Pharmacodynamics: Mechanism of action: Ruxolitinib is a Janus Kinase (JAK) inhibitor with selectivity for the JAK1 and JAK2 isoforms. Intracellular JAK signalling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, and subsequent modulation of gene expression. Autoimmune IFNγ producing cytotoxic T-lymphocytes are thought to be directly responsible for melanocyte destruction in human vitiligo. Recruitment of cytotoxic lymphocytes to lesional skin is mediated via IFNγ dependent chemokines, such as CXCL10. Downstream signalling of IFNγ is JAK1/2 dependent and treatment with ruxolitinib reduces CXCL10 levels in vitiligo patients.
Clinical efficacy and safety: Two double-blind, randomised, vehicle-controlled studies of identical design (TRuE-V1 and TRuE-V2) enrolled a total of 674 patients who have vitiligo on the face and total body vitiligo area (facial and nonfacial) not exceeding 10% BSA, with disease extent at initiation ranging from 3.2% to 10.1% of BSA, aged 12 years and older (10.7% of patients were 12 to 17 years of age and 6.7% were 65 years or older). Females constituted 53.1% of patients, 81.9% of patients were White, 4.7% were Black, and 4.2% were Asian. The majority of patients had Fitzpatrick skin types III, IV, V, or VI (67.5%).
In both studies, patients were randomised 2:1 to treatment with ruxolitinib cream or vehicle twice daily for 24 weeks with affected BSA not exceeding 10%, followed by an additional 28 weeks of treatment with ruxolitinib cream BID for all patients. The primary efficacy endpoint was the proportion of patients achieving a 75% repigmentation in the facial Vitiligo Area Scoring Index (F-VASI75) at week 24. Key secondary endpoints included the proportions of patients achieving a 90% repigmentation in F-VASI (F-VASI90), 50% improvement in total body Vitiligo Area Scoring Index (T-VASI50), and a Vitiligo Noticeability Scale (VNS) score of 4 or 5 (vitiligo "a lot less noticeable" or "no longer noticeable").
Repigmentation of treated vitiligo lesions and superiority of ruxolitinib cream over vehicle cream were observed for both studies, as demonstrated by statistically significant differences in response rates for F-VASI75/90, T-VASI50, and VNS score of 4 or 5 at week 24 (Table 1).
The treatment effect difference from vehicle emerges numerically as early as week 12. Continued repigmentation as assessed by VASI and VNS scores was observed through week 52 for patients who had continuously applied ruxolitinib cream twice daily from baseline. The proportion of patients who achieved F-VASI75 over the 52-week treatment period in pooled data from study TRuE-V1 and TRuE-V2 are shown in the figure as follows.
Similar treatment responses at week 52 are seen for those who crossed over from vehicle to ruxolitinib (figure as follows). (See Table 1 and figure.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageAt week 52, the observed response rate for F-VASI90, T-VASI50 and VNS was 30.3%, 51.1%, and 36.3% respectively for the ITT pooled population.
Durability of response: A Phase 3, double-blind, vehicle-controlled, randomised, withdrawal and treatment-extension study of ruxolitinib cream twice daily enrolled 458 eligible patients with vitiligo who had completed either of the parent studies using ruxolitinib (TRuE-V1 and TRuE-V2; week 52); patients were assigned to either cohort A or B with a follow-up up to 104 weeks.
Cohort A comprised 116 patients who reached ≥ F-VASI90 at week 52 of the parent study. These patients were re-randomised to either ruxolitinib or vehicle (i.e. withdrawal) to study relapse (< F-VASI75). A relapse occurred in 15% of patients in the ruxolitinib group, and in 29% of patients in the vehicle group. In the latter group, the majority of relapses (9/16) occurred during the first 4 months after stopping ruxolitinib cream. Among the 16 patients in the vehicle group who relapsed and were retreated, re-treatment resulted in a regained F-VASI75 in 12 (75%) patients in a median of 12 weeks and F-VASI90 was regained by 11 (69%) patients in a median of 15 weeks. Cohort B comprised 342 patients who reached < F-VASI90 at week 52 of the parent study. These patients continued with open-label ruxolitinib treatment; at week 104, among patients originally randomised to ruxolitinib cream twice daily, 66% reached F-VASI75, and 34% reached F-VASI90.
Paediatric population: A total of 72 adolescents (12 to <18 years; n = 55 ruxolitinib cream, n = 17 vehicle) were included in the pivotal studies. Adolescents showed equal response rates in primary and key secondary endpoints at 24 weeks when treated with ruxolitinib, as compared to adults from 18-65 years of age.
The European Medicines Agency has deferred the obligation to submit the results of studies with Lumirix in one or more subsets of the paediatric population for the treatment of vitiligo (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Absorption: The pharmacokinetics of ruxolitinib cream were investigated in 429 subjects with vitiligo aged 12 years and older (12.6% were 12-17 years of age) with a mean ± STD BSA involvement of 7.31 ± 2.02% (range 3.2% to 10.0%). Subjects applied approximately 1.58 mg/cm2 of ruxolitinib cream (dose range was approximately 0.18 grams to 8.4 grams of ruxolitinib cream per application) to the same skin areas twice daily for 24 weeks.
The mean ± STD steady-state trough plasma concentrations was 56.9 ± 62.6 nM with a projected AUC at 683 ± 751 h*nM, which is approximately 25% of the observed mean AUC at steady state (2716 h*nM) following 15 mg twice daily oral administration in healthy participants. The mean (geometric mean) topical bioavailability for ruxolitinib cream in vitiligo participants in the pooled data of the two Phase 3 studies was 9.72% (5.78%).
Distribution: Based on an in vitro study, ruxolitinib is 97% bound to human plasma proteins, mostly to albumin.
Biotransformation: Ruxolitinib is metabolised by CYP3A4 and to a lesser extent by CYP2C9.
Elimination: The mean elimination half-life of orally administered ruxolitinib is approximately 3 hours. The mean apparent terminal half-life of ruxolitinib following topical application of Lumirix was estimated in 9 adult and adolescent patients with ≥25% BSA involvement with atopic dermatitis and is approximately 116 hours, reflecting the slow drug absorption rate rather than the drug elimination rate.
Special populations: Renal impairment: The estimated AUC which is adjusted for the pharmacological activity of ruxolitinib plus the metabolites increases approximately two-fold in case of end stage renal disease (ESRD). As a precautionary measure, Lumirix should not be used by patients with ESRD, due to lack of data regarding the safety.
Hepatic impairment: Although the AUC was increased following oral administration of ruxolitinib to patients with hepatic impairment, there was no clear relationship between the severity of hepatic impairment and the increase in AUC. A dosing advice for patients with hepatic impairment is not necessary.
Toxicology: Preclinical safety data: Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicity, and carcinogenicity studies following oral administration. Additional studies were conducted following dermal administration in minipigs and mice. Target organs associated with the pharmacological action of ruxolitinib in repeated dose oral studies include bone marrow, peripheral blood and lymphoid tissues. Infections generally associated with immunosuppression were noted in dogs. Margins (based on unbound AUC) at non-adverse levels in chronic toxicity studies were approximately 6- and 200-fold in male and female rats, and 10-fold in dogs, relative to systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. Adverse decreases in blood pressure along with increases in heart rate were noted in a dog telemetry study, and an adverse decrease in minute volume was noted in a respiratory study in rats. The margins (based on unbound Cmax) at the non-adverse level in the dog and rat studies were approximately 300-fold and 100-fold greater, respectively, than systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. No adverse effects were noted in an evaluation of the neuropharmacological effects of ruxolitinib in rats.
A 3-month dermal repeat dose study revealed decreased lymphocyte counts in mice. Margins (based on unbound AUC) at non-adverse levels were approximately 10-fold in male and 24-fold in female mice relative to systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. Non-adverse decreased peripheral lymphocyte counts were also noted in minipigs in a 9-month dermal toxicity study. Margins (based on unbound AUC) at non-adverse levels in minipigs were approximately 3-fold relative to systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. This effect was not observed in a 3-month dermal toxicity study in minipigs. No evidence of systemic toxicity was observed in Gottingen minipigs following topical administration of 1.5% ruxolitinib cream formulation twice daily for up to 9 months.
In juvenile rat studies, oral administration of ruxolitinib resulted in effects on growth and bone measures. Reduced bone growth was observed at dose ≥5 mg/kg/day when treatment started on postnatal day 7 (comparable to human newborn) and at ≥15 mg/kg/day when treatment started on postnatal days 14 or 21 (comparable to human infant, 1-3 years). Fractures and early termination of rats were observed at dose ≥30 mg/kg/day when treatment was started on postnatal day 7. Based on unbound AUC, the exposure at the NOAEL (no observed adverse effect level) in juvenile rats treated as early as postnatal day 7 was approximately 20-fold that of adult patients with vitiligo, while reduced bone growth and fractures occurred at exposures that were 22- and 150-fold that of adult patients with vitiligo, respectively. The effects were generally more severe in males and when administration was initiated earlier in the postnatal period. Other than bone development, the effects of ruxolitinib in juvenile rats were similar to those in adult rats. Juvenile rats are more sensitive than adult rats to ruxolitinib toxicity.
In embryofetal development studies, oral administration of ruxolitinib to rats and rabbits during gestation resulted in decreased foetal weight and increased post-implantation loss at doses associated with maternal toxicity. There was no evidence of a teratogenic effect in rats and rabbits. Margins (based on unbound AUC) at non-adverse levels for developmental toxicity in rats were approximately 25-fold the systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. No effects of oral ruxolitinib were noted on fertility in male or female rats. In a pre- and postnatal development study, a slightly prolonged gestation period, reduced number of implantation sites, and reduced number of pups delivered were observed. In the pups, decreased mean initial body weights and short period of decreased mean body weight gain were observed. In lactating rats, ruxolitinib and/or its metabolites were excreted into the milk with a concentration that was 13-fold higher than the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic.
Ruxolinitib showed no carcinogenic potential following topical administration in mice or following oral administration in Sprague-Dawley rats and Tg.rasH2 mice.
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