Also known as: Alitretinoin 9-cis-retinoic acid
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 exact mechanism of action of alitretinoin in the topical treatment of cutaneous lesions of AIDS-related KS is unknown. Alitretinoin (9-cis-retinoic acid), a naturally-occurring endogenous hormone related to vitamin A, binds to and activates all known intracellular retinoid receptor subtypes (RARα, RARβ, RARγ, RXRα, RXRβ, RXRγ). Once activated, these receptors function as ligand dependent transcription factors that regulate the expression of specific genes. The regulation of gene expression by alitretinoin controls the process of cellular differentiation and proliferation in both normal and neoplastic cells. The efficacy of alitretinoin gel in treating KS lesions may be related to the demonstrated ability of alitretinoin to inhibit the in vitro growth of KS cells.
Alitretinoin gel can be expected to have local therapeutic effects only and it has no role in the prevention or treatment of visceral KS.
Plasma concentrations of 9-cis-retinoic acid were evaluated during clinical studies in patients with cutaneous lesions of AIDS-related KS after repeated multiple-daily dose application of alitretinoin for up to 60 weeks. A subset of these patients were followed during treatment of up to 64 lesions (range 4-64, median 11.5 lesions) for up to 44 weeks (range 2-44, median 15 weeks). In this latter group, the range and frequency of detection of quantifiable 9-cis-retinoic acid plasma concentrations in patients with KS after application of the medicinal product were comparable to the range and frequency of detection of quantifiable plasma concentrations of circulating, naturally-occurring 9-cis-retinoic acid in untreated individuals.
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.
Pharmacokinetic in special populations
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.
Preclinical Safety Data
Three doses of alitretinoin (0.01%, 0.05%, or 0.5%) in a topical gel formulation were given to rats in a 28-day dermal toxicology study. Observed effects at the application site included erythema, epidermal thickening, scaling and loosening of the stratum corneum. Clinical pathology evaluations revealed significant increases in absolute polymorphonuclear leukocyte counts, monocyte counts, percentage of monocytes and decreases in percentage of lymphocyte differential white blood cell counts on day 29 of rats treated with alitretinoin 0.5% gel. Clinical chemistry evaluations revealed biologically relevant significant increases in the mean BUN and alkaline phosphatase values in females after the 28-day treatment. Serum LDL was increased in both male and female groups at Day 29. There were no biologically relevant haematology differences or serum chemistry differences after the 14-day period. Observed increases in mean heart-to-final body weight differences were attributed principally to the difference in the terminal body weights. Following treatment with alitretinoin 0.5% gel, mean plasma concentrations in the female rats were generally below the lower limit of quantitation (5 nMol) and mean plasma concentrations in the male rats were about 200 nMol. In contrast to these findings in rats, plasma concentrations of 9-cis-retinoic acid in patients with KS applying alitretinoin never exceeded 0.638 ng/ml (2.13 nMol). This level is about 1/100 the mean concentration measured in male rats.
Alitretinoin was studied for genotoxic potential using the Ames test, the in vivo mouse micronucleus assay, the chromosomal aberration test in human lymphocytes, and the CHO cell mutation test. The medicinal product was not genotoxic.
Carcinogenesis, mutagenesis, impairment of fertility
Studies have not been performed to determine the carcinogenic potential of alitretinoin. However, the mutagenic potential has been evaluated, and alitretinoin has tested negative in the Ames test, the in vivo mouse micronucleus assay, the chromosomal aberration test in human lymphocytes, and the CHO cell mutation test.
In an oral dose-ranging study in rabbits, alitretinoin induced gross malformations at a dose 35 times the topical human dose. This dose in rabbits resulted in plasma concentrations more than 60 times the highest observed plasma concentration in patients with KS following topical application of alitretinoin. No gross malformations were observed following oral administration to rabbits of doses 12 times the human topical dose (which resulted in plasma concentrations 60 times the highest observed plasma concentration in patients with KS following topical application of the gel). However, an increased rate of fused sternebrae was observed.
The phototoxicity potential of alitretinoin was assessed based on its chemical properties and data from a battery of in vitro tests. The results suggest that alitretinoin absorbs light in the UV range and is subject to photodegradation to other isomers (predominantly all-trans-retinoic acid). Alitretinoin was shown to have a weak potential to be a photo-irritant based on histidine and photoprotein binding. In cell-based in vitro assays, alitretinoin showed weak phototoxic potential.