Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: GlaxoSmithKline UK Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS Trading as Stiefel
Pharmacotherapeutic group: other dermatologicals
ATC code: D11AH04
The pharmacological action of retinoids may be explained by their effects on cell proliferation, cell differentiation, apoptosis, angiogenesis, keratinization, sebum secretion and immunomodulation. Unlike other retinoids, which are specific agonists of either RAR or RXR receptors, alitretinoin binds to members of both receptor families. The mechanism of action of alitretinoin in chronic hand eczema is unknown. Alitretinoin has demonstrated immunomodulatory and anti-inflammatory effects that are relevant to skin inflammation. Alitretinoin suppresses the production of chemokines that are involved in recruitment of leukocytes to sites of skin inflammation, reduces expansion of T lymphocytes and antigen-presenting cells, and inhibits effect on cell differentiation. CXCR3 ligands and CCL20 chemokines, expressed in eczematous skin lesions, are down-regulated by alitretinoin in cytokine-stimulated keratinocytes and dermal endothelial cells. In addition, alitretinoin suppresses the expansion of cytokine activated leucocytes subsets and antigen presenting cells.
It has been observed that in humans alitretinoin only minimally affects sebum secretion.
The safety and efficacy of Toctino in patients with severe chronic hand eczema (CHE) unresponsive to treatment with potent topical corticosteroids has been evaluated in two randomised, double blind, placebo-controlled Phase 3 studies.
The primary endpoint in these studies was the proportion of patients achieving Physicians Global Assessment (PGA) ratings of clear or almost clear hands at the end of therapy (see Table 1). The treatment duration was 12 to 24 weeks.
The BAP00089 study (BACH) was conducted in Europe and Canada, and included 1032 severe CHE patients who had no response or a transient response (initial improvement and worsening of disease despite continued treatment) to potent topical corticosteroids or were intolerant of potent topical corticosteroids. All phenotypes of CHE were included; approximately 30% of patients had hyperkeratotic only CHE, however the majority of patients had multiple phenotypes. Essentially all patients had signs of skin inflammation, comprising of erythema and/or vesicles. Treatment with alitretinoin led to a significantly higher proportion of patients with clear/almost clear hands, compared to placebo. The response was dose dependent (see Table 1).
Secondary endpoints included the proportion of partial responders (patients achieving at least mild disease), time to response (achieving clear to almost clear hands), reduction in modified total lesion symptom score (mTLSS), patient global assessment (PaGA) of disease severity, and reduction in extent of disease (see Table 1).
The second study, BAP001346 (HANDEL) was conducted in the US and included 596 with severe CHE who had no response or a transient response (initial improvement and worsening of disease despite continued treatment) to potent topical corticosteroids or who were intolerant of potent topical corticosteroids. Subjects were considered unresponsive if they had severe CHE after at least 2 weeks of treatment with a very potent topical corticosteroid during a 16-week run-in period. All phenotypes of CHE were included.
Secondary endpoints included estimated median time to response (time from the start of randomised study treatment to first PGA assessment of clear or almost clear), reduction in modified total lesion symptom score (mTLSS), patient global assessment (PaGA) of disease severity, and reduction in extent of disease at end of therapy (see Table 1).
Table 1. Results: Primary and Key Secondary Endpoints:
| BAP00089 (BACH) | BAP01346 (HANDEL) | ||||
|---|---|---|---|---|---|
| Primary Endpoint | 10 mg | 30 mg | Placebo | 30 mg | Placebo |
| ITT Population | N=418 | N=409 | N=205 | N=298 | N=298 |
| PGA at end of treatment n (%) | |||||
| Total Response | 115 (27.5%) | 195 (47.7%) | 34 (16.6%) | 118 (39.6%) | 44 (14.8%) |
| Clear | 39 (9.3%) | 90 (22.0%) | 6 (2.9%) | 58 (19.5%) | 14 (4.7%) |
| Almost Clear | 76 (18.2%) | 105 (25.7%) | 28 (13.7%) | 60 (20.1%) | 30 (10.1%) |
| Comparison to Placeboa | P=0.004 | P<0.001 | NA | P<0.001 | NA |
| Secondary Endpoints | |||||
| PaGA at the end of treatment n (%) | |||||
| Clear or Almost Clear | 101 (24.2%) | 163 (39.9%) | 31 (15.1%) | 117 (39.3%) | 41 (13.8%) |
| Comparison to Placeboa | P=0.013 | P<0.001 | NA | P<0.001 | NA |
| *Percent Change from Baseline mTLSS at the end of treatment | |||||
| Mean (STD) | -50.79 (36.13) | -60.80 (38.58) | -37.30 (37.65) | -53.99 (40.16) | -29.86 (37.83) |
| Median | -56.25 | -75.0 | -38.68 | -67.70 | -24.40 |
| Min – Max | -100 – 66.7 | -100 – 175 | -100 – 72.7 | -100 – 60 | -100 – 63.6 |
| Comparison to Placebob | P<0.001 | P<0.001 | NA | P<0.001 | NA |
| Percent Change from Baseline in Extent of Disease at the end of treatment | |||||
| Mean (STD) | -40.01 (49.57) | -54.15 (46.89) | -31.93 (45.56) | -46.56 (53.75) | -24.20 (48.21) |
| Median | -50.0 | -75.0 | -33.33 | -62.50 | -18.20 |
| Min – Max | -100 – 200 | -100 – 140 | -100 – 130 | -100 – 166.7 | -100 – 140 |
| Comparison to Placebob | P=0.016 | P<0.001 | NA | P<0.001 | NA |
| Median Time to Response for Responders at the end of treatment | |||||
| Median (Days) | 115.0 | 85.0 | 141 | 65.0 | 117.0 |
| Comparison to Placeboc | P=0.01 | P<0.001 | NA | P<0.001 | NA |
| Partial Response Rate (clear, almost clear, or mild disease) | |||||
| N (%) | 207 (49.5%) | 254 (62.1%) | 74 (36.1%) | NA | NA |
a From pairwise continuity corrected chi-square tests versus placebo based on proportion of responders.
b From non-parametric Kruskal Wallis test versus placebo based on mean change from baseline.
c From Log Rank Test versus placebo based on median time to response.
A longitudinal dose response analysis of Phase 3 studies (BAP00089, BAP001346, & BAP00091 – Cohort A) showed that once subjects had clear or almost clear hands, there was no relationship between the duration of treatment and the likelihood of relapse. Therefore, discontinuation of therapy is recommended in patients who have achieved clear or almost clear hands earlier than 24 weeks (see section 4.2). In the pivotal clinical studies 67% of subjects who responded to alitretinoin treatment did not return to severe disease 24 weeks after stopping treatment and therefore would not be candidates for retreatment within that time period.
A retreatment study (BAP00091 – Cohort A) investigated the efficacy and safety of a second course of treatment in patients who previously responded to treatment in the BAP00089 study, but who relapsed. Patients were randomised to the same dose they received in their initial treatment (10 or 30 mg) or to placebo in a 2:1 ratio. (N=70 alitretinoin, N=47 placebo). Results suggest that patients who previously responded to alitretinoin treatment may benefit from retreatment.
Alitretinoin is a low solubility, low permeability compound with a low and variable bioavailability. Alitretinoin is not consistently absorbed from the gastrointestinal tract in fasted state. The systemic exposure is substantially (>2-fold) enhanced when taken with a high-fat meal.
In vitro data from a gastrointestinal system suggest the amount of alitretinoin available for absorption differs with fat intake (when given with an approximately 25% fat meal, the amount available for absorption is less than when given with ~40% or ~60% fat meal). Therefore, alitretinoin should be administered with a main meal once daily, preferably at the same time of day to maximise exposure.
After administration of alitretinoin 30 mg once daily with a meal containing approximately 40% fat, the median Tmax is 4 hours, the average Cmax is 177 ng/mL, and the average AUC(0-τ) is 405 ng*hr/mL.
Peak plasma concentrations (Cmax) and exposure (AUC) of alitretinoin increase with increasing single doses over the range of 5 to 150 mg. AUC values of alitretinoin increases proportionally with dose for once daily doses of 10 mg to 30 mg. The Cmax of alitretinoin may increase less than proportionally with increasing dose.
Alitretinoin is 99.1% bound to plasma proteins. The volume of distribution of alitretinoin is estimated to be greater than the extracellular volume (>14L), but less than total body water.
Alitretinoin is metabolized by CYP2C9, CYP2C8, and CYP3A4 isoenzymes to form 4-oxo-alitretinoin. Both compounds undergo isomerisation into tretinoin (or isotretinoin) and their 4-oxo metabolites. After oral administration of alitretinoin 4-oxo-alitretinoin is the main observed active circulating metabolite with an AUC which accounts for >70% of the AUC of the parent drug. The isomers of alitretinoin (tretinoin, isotretinoin) and 4-oxo-alitretinoin (4-oxo-tretinoin and 4-oxo-isotretinoin) are minor accounting for ≤12% of exposure of parent drug. 4-oxo-alitretinoin is further glucuronidated and eliminated in urine.
There are no consistent time-dependent changes (neither induction nor accumulation) in the pharmacokinetics of alitretinoin or its measured metabolites
Alitretinoin is an endogenous retinoid. Alitretinoin concentrations return to endogenous levels within 2 to 3 days after treatment cessation.
Excretion of a radio-labelled dose of alitretinoin was complete, with approximately 94% of the dose recovered within 14 days. Radio-labelled material was eliminated mainly in urine as metabolites (63%, with <1% as unchanged parent drug) with a smaller fraction (approx. 30% with 1% as unchanged parent drug) in faeces. The most abundant excretion compound is the glucuronide of 4-oxo-alitretinoin amounting to 6.5% of the dose in urine.
The elimination half-life averaged 9 hours for alitretinoin and 10 hours for 4-oxo-alitretinoin.
The pharmacokinetics of alitretinoin and its measured metabolites in special populations (obesity, gender, age, and renal impairment) were evaluated in a study in 32 subjects with moderate to severe CHE receiving alitretinoin for 12 to 24 weeks. These analyses showed:
Increased body weight or body mass index (BMI) does not result in clinically significant changes in alitretinoin or 4-oxo-alitretinoin exposure.
There are no clinically significant gender-related differences in alitretinoin or 4-oxo-alitretinoin AUC and Cmax.
While the pharmacokinetic data in elderly subjects is limited (n=6 over 60 years of age and n=3 over 65 years of age), there does not appear to be a relationship between increasing age and the dose-normalized AUC or Cmax of alitretinoin or 4 oxo-alitretinoin.
A longitudinal dose-response model from clinical efficacy studies shows that elderly subjects (n=126) have an earlier and more pronounced response to treatment and are less likely to relapse, but are more likely to experience elevated triglyceride levels after 12 to 16 weeks of treatment.
While pharmacokinetic data in subjects with moderate renal impairment is not available, the pharmacokinetics of alitretinoin are not affected by mild renal impairment, with an average AUC of 342 (range: 237-450) and 312 (195-576) ng*h/mL in those with an estimated creatinine clearance 60-90 mL/min (n=8) or ≥90 mL/min (n=23), respectively normalised to an alitretinoin 30 mg dose. The Cmax and AUC(0-tau) of 4-oxo-alitretinoin may be slightly higher in subjects with mild renal impairment, although the effect is small (<20%).
No data are available in subjects with severe renal impairment (CrCl <30 mL/min) or end stage renal disease.
A pharmacokinetic study conducted in 8 subjects with liver cirrhosis and Child-Pugh Class A (mild, n=6) or B (moderate, n=2) and in 8 gender, age, height and weight-matched healthy subjects shows that there are no clinically relevant differences between patients with hepatic impairment and healthy subjects in the Cmax (mean± standard deviation [SD]: 101 ± 40 ng/mL vs 144±40 ng/mL, respectively) or AUC (mean±SD: 248 ± 116 ng/mL vs 314 ± 86 ng/mL, respectively) of alitretinoin. The Cmax (mean± SD: 30 ± 20 ng/mL vs 56 ± 25ng/mL, respectively) and AUC (mean±SD: 162± 82 ng/mL vs 219 ± 49 ng/mL, respectively) of 4-oxo-alitretinoin are lower in patients with hepatic impairment.
There are no data available in subjects with severe hepatic impairment and limited data in patients with moderate hepatic impairment.
Alitretinoin kinetics has not been studied in patients below 18 years.
As with other retinoids, the acute toxicity of alitretinoin was low in mice and rats. The LD50 after intraperitoneal administration was >4000 mg/kg after 24 hours and 1400 mg/kg after 10 days. The approximate LD50 after oral administration in rats was 3000 mg/kg.
Alitretinoin was tested in long-term studies up to 9 months in dogs and 6 months in rats. Signs of toxicity were dose-related and occurred at exposures similar to the human therapeutic exposure based on AUC. Effects were characteristic for retinoids (consistent with hypervitaminosis A), and were generally spontaneously reversible.
Like other retinoids, alitretinoin has been shown to be teratogenic in vitro and in vivo.
Due to the teratogenic potential of alitretinoin, women of childbearing potential must adhere to strict pregnancy prevention measures during and 1 month following alitretinoin therapy (see section 4.3, section 4.4 and section 4.6).
Alitretinoin was tested in a study of fertility and early embryonic development in rats. No effects on male or female reproductive parameters were observed at the highest dose tested which reached similar plasma concentrations as those observed in humans.
As with other retinoids reversible effects on male reproductive organs were observed in experimental animals in the form of disturbed spermatogenesis and associated degenerative lesions of the testes. The safety margin in dogs with regard to the no-effect level of toxicity to male reproductive organs was 1-6 for a human dose of 30 mg.
In in vitro or in vivo tests, alitretinoin has been shown not to be mutagenic.
Alitretinoin was tested in 2-year carcinogenicity studies in rats and mice. Dose-related retinoid-specific toxicity was seen at higher doses, but no carcinogenic potential was noted.
Alitretinoin was found to be phototoxic in vitro and in vivo.
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