Chemical formula: C₂₀H₂₈O₂ Molecular mass: 300.442 g/mol PubChem compound: 5538
According to the FAB (French-American-British) classification of haematological disease, acute promyelocytic leukaemia (APL) is classified as M3 and M3v form of acute myeloid leukemia (AML). The mechanism of action of tretinoin in APL is not entirely known, and may be linked to specific binding of tretinoin to a nuclear retinoic acid receptor (RAR) given that the nuclear receptor alpha of retinoic acid (RARa) is altered in APL patients by fusion with a protein called PML. Pharmacological doses of tretinoin induce proteolytic degradation of the PML/RARa chimeric protein, hallmark of APL. Transcriptome analyses suggest that tretinoin may clear PML/RARa from promoters, thereby restoring the wild-type RARa function and releasing the differentiation block.
Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.
In vitro studies with tretinoin have demonstrated induction of differentiation and inhibition of cell proliferation in transformed hemopoietic cell lines, including human myeloid leukaemia cell lines.
In children, the treatment combining tretinoin with chemotherapy gives comparable results as with adults. For example, compared to data from adults in the APL93 trial 576 patients with 31 newly diagnosed children (5%) were investigated and no difference between adults and children was seen for complete remission rate, 5-year relapse rate, event free survival, and overall survival, but significantly better survival was seen in children after adjustment on white blood cell counts and incidence of microgranular M3 variant of APL.
In terms of toxicity and compared to adults, a higher frequency of pseudotumor cerebri has been observed in children and adolescents. The incidence decreases with the use of lower dose of tretinoin.
There are only limited data concerning the use of tretinoin in combination with arsenic trioxide in the paediatric population.
APL is less frequently diagnosed in the elderly (patients above 60 years). Elderly patients seem at least as responsive to therapy as younger patients but rates of response and survival are lower in this age setting owing to a higher incidence of early deaths and deaths in remission when conventional treatment with tretinoin and chemotherapy is used. The higher rate of early deaths in this cohort is due to greater comorbidities compared to those of younger patients.
There are only limited data concerning the use of tretinoin in combination with arsenic trioxide in the elderly population.
Tretinoin is an endogenous metabolite of vitamin A and is normally present in plasma.
After oral administration, tretinoin is absorbed by the digestive tract, and maximum plasma concentrations in healthy volunteers are attained after 3 hours.
There is a large inter-patient and intra-patient variation in plasma levels of tretinoin.
Tretinoin is extensively bound to plasma proteins. Following peak levels, plasma concentrations decline with a mean elimination half-life of 0.7 hours. Plasma concentrations return to endogenous levels following a single 40 mg dose after 7 to 12 hours. No accumulation is seen after multiple doses and tretinoin is not retained in body tissues.
During continuous administration a marked decrease in plasma concentration can occur, possibly due to cytochrome P450 enzyme induction which increases clearance and decreases bioavailability after oral doses.
Renal excretion of metabolites formed by oxidation and glucuronidation is a major route (60%) of elimination, while 30% is excreted in the faeces. Tretinoin (all-trans retinoic acid) is isomerised to 13-cis retinoic acid and oxidized to 4-oxo-metabolites. These metabolites have longer half-lives than tretinoin and may show some accumulation.
The requirement for dosage adjustment in patients with kidney or liver dysfunction has not been investigated. As a precautionary measure, the dose will be decreased to 25 mg/m²/day.
Tretinoin occurs in the body as a metabolite of retinol, and it exhibits a certain degree of Vitamin A growth-promoting activity. Representative well-controlled clinical studies conclude that topically applied tretinoin does not increase plasma alltrans retinoic acid (tretinoin). Following a single topical application of radiolabelled tretinoin, the blood concentration of retinoic acid was found to be unchanged from 2-48 hours. Neither single-dose nor long-term treatment with topical tretinoin formulations does alter systemic retinoid levels, which remain within the range of body’s natural endogenous levels.
Oral administration of tretinoin to animals indicated that the compound had very low acute toxicity in all species investigated.
In animal experimental tests it was shown that in all investigated species the acute toxicity of tretinoin administered orally is low. After a longer period of administration rats exhibit a dose- and time-dependent bone matrix dissolution, a decrease in erythrocyte count and toxic alterations in kidney and testes.
Dogs mainly exhibited disorders concerning spermatogenesis and hyperplasia of the bone marrow.
The major metabolites of tretinoin (4-oxo-tretinoin, isotretinoin and 4-oxo-isotretinoin) are less effective than tretinoin in inducing differentiation of human leukaemic cells (HL-60).
Sub-chronic and chronic toxicity studies in rats indicated that the no effect oral dose was at or below 1 mg/kg/day; in dogs, 30 mg/kg/day was associated with toxic effects including weight loss, dermatological and testicular changes.
Reproduction studies in animals have demonstrated the teratogenic activity of tretinoin.
No evidence of mutagenicity has been found.
In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1% topical tretinoin applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight).
Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.
The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.
In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose adjusted for total body surface area) and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with topical tretinoin has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical dose adjusted for total body surface area).
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