Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Sandoz Limited, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR, United Kingdom
Therapeutic Group: Antineoplastic and Immunosuppressive agents
ATC code: L04AX01
Azathioprine is a pro-drug of 6-mercaptopurine (6-MP). 6-MP is inactive but acts as a purine antagonist and requires cellular uptake and intracellular anabolism to thioguanine nucleotides (TGNs) for immunosuppression. The TGNs and other metabolites (e.g. 6-methyl-mecaptopurine 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 drug. Other potential mechanisms of azathioprine include the inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of the immune response.
Because of these mechanisms, the therapeutic effect of azathioprine may be evident only after several weeks or months of treatment.
The activity of the methylnitroimidazole moiety, a metabolite of azathioprine but not 6-MP, has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP.
Plasma levels of azathioprine and 6-mecaptopurine do not correlate well with the therapeutic efficacy or toxicity of azathioprine.
The absorption of azathioprine is incomplete and variable. The median (range) absolute bioavailability of 6-MP after administration of azathioprine 50 mg is 47% (27–80%). The extent of absorption of azathioprine is similar across the gastrointestinal tract, including the stomach, jejunum, and cecum. However, the extent of 6-MP absorption, after azathioprine administration is variable and differs between the sites of absorption, with the highest extent of absorption in the jejunum, followed by the stomach and then the cecum.
Although there are no food effect studies with azathioprine, pharmacokinetic studies with 6-MP have been conducted that are relevant to azathioprine. The mean relative bioavailability of 6-MP was approximately 26% lower following administration with food and milk compared to an overnight fast. 6-MP is not stable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes) (see section 5.2: Metabolism). Azathioprine should be administered at least 1 hour before or 3 hours after food or milk (see section 4.2).
The volume of distribution at steady state (Vdss) of azathioprine is unknown. The mean (± SD) apparent Vdss of 6-MP is 0.9 (±0.8) L/kg, although this may be an underestimate because 6-MP is cleared throughout the body (and not just in the liver).
Concentrations of 6-MP in cerebrospinal fluid (CSF) are low or negligible after IV or oral administration of 6-MP.
Azathioprine is rapidly broken down in vivo by glutathione-S-transferase into 6-MP and a methylnitroimidazole moiety. The 6-MP readily crosses cell membranes and is extensively metabolized by many multi-step pathways to active and inactive metabolites, with no one enzyme predominating. Because of the complex metabolism, inhibition of one enzyme does not explain all cases of lack of efficacy and/or pronounced myelosuppression. The predominant enzymes responsible for the metabolism of 6-MP or its downstream metabolites are: the polymorphic enzyme thiopurine S-methyltransferase (TPMT) (see section 4.4: Aminosalicylates), xanthine oxidase (see section 4.5: Allopurinol/oxipurinol/h3. thiopurinol and section 5.2: Absorption), inosine monophosphate dehydrogenase (IMPDH) (see section 4.5: Ribavirin), and hypoxanthine guanine phosphribosyltransferase (HPRT). Additional enzymes involved in the formation of active and inactive metabolites are: guanosine monophosphate synthetase (GMPS, which form TGNs) and inosine triphosphate pyrophosphatase (ITPase).
Azathioprine itself is also metabolized by aldehyde oxidase to form 8-hydroxy azathioprine, which may be active.
There are also multiple inactive metabolites formed via other pathways.
There is evidence that polymorphisms in the genes encoding the different enzyme systems involved with metabolism of azathioprine may predict adverse drug reactions to azathioprine therapy.
TPMT activity is inversely related to red blood cell 6-MP 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 thioguanine nucleotide concentrations.
Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles—TPMT*2, TPMT*3A and TPMT*3C—account for about 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 and 90% of individuals have normal TPMT activity with two functional alleles. There may also be a group of approximately 2% who have very high TPMT activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in red blood cells and can also be informative (see section 4.4).
After oral administration of 100mg 35 S-azathioprine, 50% of the radioactivity was excreted in the urine and 12% in the faeces after 24 hours. In the urine, the major compound was the inactive oxidised metabolite thiouric acid. Less than 2% was excreted in the urine as azathioprine or 6-MP. Azathioprine has a high extraction ratio with a total clearance greater than 3L/min in normal volunteers. There are no data on the renal clearance or half-life of azathioprine. The renal clearance of 6-MP and the half-life of 6-MP are 191 mL/min/m² and 0.9 hr respectively.
No specific studies have been carried out in the elderly (see section 4.2).
In a US clinical study, 18 children (aged 3 to 14 years) were evenly divided into two groups; either a weight to height ratio above or below the 75th percentile. Each child was on maintenance treatment of 6-MP and the dosage was calculated based on their body surface area. The mean AUC(0-∞) of 6-MP in the group above the 75th percentile was 2.4 times lower than that for the group below the 75th percentile. Therefore, children considered to be overweight may require azathioprine doses at the higher end of the dose range and close monitoring of response to treatment is recommended (see section 4.2).
Studies with azathioprine have shown no difference in 6-MP pharmacokinetics in uremic patients compared to renal transplant patients. Since little is known about the active metabolites of azathioprine in renal impairment, consideration should be given to reducing the dosage in patients with impaired renal function (see section 4.2).
Azathioprine and/or its metabolites are eliminated by haemodialysis, with approximately 45% of radioactive metabolites eliminated during dialysis of 8 hours.
A study with azathioprine was performed in three groups of renal transplant patients: those without liver disease, those with hepatic impairment (but no cirrhosis) and those with hepatic impairment and cirrhosis. The study demonstrated that 6-mercaptopurine exposure was 1.6 times higher in patients with hepatic impairment (but no cirrhosis) and 6 times higher in patients with hepatic impairment and cirrhosis, compared to patients without liver disease. Therefore, consideration should be given to reducing the dosage in patients with impaired hepatic function (see section 4.2).
Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5-15 mg/kg bodyweight/day over the period of organogenesis have shown varying degrees of foetal abnormalities.
Teratogenicity was evident in rabbits at 10 mg/kg bodyweight/day.
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