Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Nova Laboratories Ireland Limited, 3rd Floor, Ulysses House, Foley Street, Dublin 1, D01 W2T2, Ireland
Pharmacotherapeutic group: Immunosuppressants, Other immunosuppressants,
ATC code: L04AX01
Azathioprine is an inactive pro-drug of 6-mercaptopurine (6-MP), which acts as a purine antagonist but requires cellular uptake and intracellular anabolism to thioguanine nucleotides (TGNs) for immunosuppression. TGNs and other metabolites (e.g. 6-methylmercaptopurine ribonucleotides) inhibit de novo purine synthesis and purine nucleotide interconversions. The TGNs are also incorporated into nucleic acids and this contributes to the immunosuppressive effects of the medicinal product.
Other potential mechanisms of azathioprine include:
Because of these mechanisms, the therapeutic effect of azathioprine may be evident only after several weeks or months of treatment (see section 4.2).
Unlike 6-MP, the activity of the azathioprine metabolite 1-methyl-4-nitro-5-thioimidazole has not been clearly determined. However, compared with 6-MP it appears to modify the activity of azathioprine in several systems.
In a controlled study in patients with myasthenia gravis, azathioprine (2.5 mg/kg body weight/day) in combination with prednisolone proved to be significantly better in comparison to prednisolone and placebo in terms of treatment failure. Furthermore, a glucocorticosteroid-sparing effect was seen after 15 months. After 36 months, 63% in the azathioprine group required no further glucocorticosteroids, compared with only 20% in the placebo group.
Azathioprine is incompletely and variably absorbed. The mean absolute bioavailability of 6-MP after administration of azathioprine 50 mg is 47% (range: 27-80%). The extent of absorption of azathioprine is similar throughout the gastrointestinal tract, including the stomach, jejunum and caecum. The extent of 6-MP absorption after application of azathioprine however, varies depending on where the absorption occurs, with the highest level in the jejunum, followed by the stomach and caecum.
In a comparative bioavailability study in healthy adult volunteers (n=29), 50 mg of azathioprine oral suspension was demonstrated to be bioequivalent to the reference 50 mg tablet for AUC, but not Cmax. The mean (90% CI) Cmax with the oral suspension was 12% (93% - 135%) higher than the tablet although the range of Cmax observations was more or less the same for the oral suspension and tablet; 5.7 – 40.0 and 4.4 – 39.5 ng/ml, respectively.
Although interactions with food were not studied, pharmacokinetic studies with 6-mercaptopurine have been conducted that are relevant to azathioprine. The mean relative bioavailability of 6-mercaptopurine was approximately 26% lower after administration with food and milk compared to after fasting. 6-mercaptopurine is not stable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes) (see “Biotransformation”). Azathioprine should be taken at least 1 hour before or 2 hours after a meal or milk (see section 4.2).
There is no correlation between the plasma concentrations of azathioprine and 6-mercaptopurine and the therapeutic efficacy or toxicity of azathioprine.
Azathioprine is rapidly distributed in the body. The steady-state volume of distribution (Vdss) of azathioprine is unknown. The mean (± SD) apparent Vdss of 6-MP is 0.9 (± 0.8) l/kg, although this value is probably too low, since 6-MP is metabolised throughout the body and not just in the liver. Approximately 30% of azathioprine is bound to plasma proteins.
Azathioprine and its metabolites pass through the central nervous system. 6-MP concentration in the cerebrospinal fluid are low or negligible after intravenous or oral use.
Azathioprine is rapidly metabolised in vivo by glutathione S-transferase into the metabolites 6-MP and 1-methyl-4-nitro-5-thioimidazole. 6-MP passes cell membranes rapidly and is extensively metabolised in numerous multistep metabolic processes into active and inactive metabolites without any enzyme being predominantly active. Due to the complex metabolism, all cases of non-efficacy and/or myelosuppression cannot be explained by the inhibition of a single enzyme. The enzymes mainly responsible for the metabolism of 6-MP and its metabolites are the polymorphic enzyme thiopurine methyltransferase (TPMT) (see sections 4.4 and 4.5), xanthine oxidase (see sections 4.5 and 5.2), inosine monophosphate dehydrogenase (IMPDH) (see section 4.5) and hypoxanthine-guanine phosphoribosyltransferase (HPRT). Other enzymes involved in the formation of active and inactive metabolites are guanosine monophosphate synthetase (GMPS, which forms TGNs) and inosine triphosphate pyrophosphatase (ITPase). Azathioprine is also metabolised by aldehyde oxidase to the probably active 8-hydroxy-azathioprine. Furthermore, various inactive metabolites are also formed in further metabolic processes.
There are indications that polymorphisms in the genes which encode the various enzyme systems involved in the metabolism of azathioprine may predict adverse reactions in azathioprine therapy.
TPMT activity is inversely related to red blood cell 6-mercaptopurine-derived thioguanine nucleotide concentration, with higher thioguanine nucleotide concentrations resulting in greater reductions in white blood cell and neutrophil counts. Individuals with TPMT deficiency develop very high cytotoxic TGN concentrations.
Genotypic testing can determine a patient’s allelic pattern. Currently, 3 alleles – TPMT*2, TPMT*3A and TPMT*3C – account for 95% of individuals with reduced levels of TPMT activity. Approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable enzyme activity. Approximately 10% of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate TPMT activity, whereas 90% of individuals have normal TPMT activity with two functional alleles. For a group of about 2% it can also lead to very high TPMT activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in red blood cells and can further provide other information (see section 4.4).
The plasma half-life is 3 to 5 hours. After oral administration of 100 mg 35S-azathioprine, 50% of the radioactivity is excreted in the urine within 24 hours and 12% in the faeces within 48 hours. The main component in the urine was the inactive oxidized metabolite thiourea. Less than 2% was excreted in urine, in the form of azathioprine or 6-MP. In healthy subjects, azathioprine is eliminated rapidly with a total clearance greater than 3 L/min. There are no data available on the renal elimination or half-life of azathioprine. The renal clearance of 6-MP and half-life of 6-MP are 191 ml/min/m² and 0.9 hours respectively.
6-mercaptopurine has been detected in the colostrum and breast milk of women who were treated with azathioprine (6-mercaptopurine is excreted in breast milk at concentrations of 3.4 ng/ml to 18 ng/ml).
No specific studies have been carried out in the elderly (see section 4.2).
In a clinical trial in the United States, 18 children between the ages of 3 and 14 were evenly split into two groups; the crucial factor was whether the ratio of weight to height was greater or less than the 75th percentile. Each child was undergoing maintenance treatment with 6-MP, whereby the body surface was the basis for the dose calculation. The mean AUC(0-∞) of 6-MP in the group greater than the 75th percentile was 2.4 times smaller than that in the group less than the 75th percentile. Therefore, under certain circumstances, overweight children need azathioprine doses in the upper range of the dose spectrum, and close monitoring of their response to treatment (see section 4.2).
Studies with azathioprine showed no difference in the pharmacokinetics of 6-MP in uraemic patients compared with patients with a kidney transplant. Since little is known about the active metabolites of azathioprine in renal dysfunction, a dose reduction in patients with impaired renal function should be considered (see section 4.2).
Azathioprine and/or its metabolites are removed by haemodialysis, with approximately 45% of the radioactive metabolites being removed during an 8-hour dialysis session.
In case of hepatic impairment, the metabolism of azathioprine is altered. Conversion into the active metabolites is restricted. However, the elimination of metabolites is reduced (see sections 4.2 and 4.4).
An azathioprine study was carried out on a group of kidney transplant patients. They were split into three groups: patients with no liver disease, patients with hepatic dysfunction (but with no cirrhosis) and patients with hepatic dysfunction and cirrhosis. The study showed that the 6-mercaptopurine level was 1.6 times higher in patients with hepatic dysfunction (but with no cirrhosis) and 6 times higher in patients with hepatic dysfunction and cirrhosis, compared with patients with no liver disease. Therefore, a dose reduction should be considered in the case of patients with impaired liver function (see section 4.2).
In embryotoxicity studies azathioprine showed teratogenicity or embryo lethality in various animal species. In rabbits, a dose of 5-15 mg/kg body weight/day produced skeletal abnormalities. In mice and rats, doses of 1-2 mg/kg body weight/day were lethal to embryos.
Azathioprine was mutagenic in a number of in vitro and in vivo genotoxicity assays.
In long-term carcinogenicity studies of azathioprine in mice and rats receiving doses that were up to 2-fold the human therapeutic dose and in lower doses administered in immuno-compromised mice, an increased incidence of lymphosarcomas (mice) and squamous cell tumours and carcinomas (rats) were observed.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
