Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS, 
IMMUNOSUPPRESSANTS, Other immunosuppressants, ATC code: L04AX01

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and a methylnitroimidazole moiety. The 6-MP readily crosses cell membranes and is converted intracellularly into a number of purine thioanalogues, which include the main active nucleotide, thioinosinic acid. The rate of conversion varies from one person to another. Nucleotides do not traverse cell membranes and therefore do not circulate in body fluids. Irrespective of whether it is given directly or is derived in vivo from azathioprine, 6-MP is eliminated mainly as the inactive oxidised metabolite thiouric acid. This oxidation is brought about by xanthine oxidase, an enzyme that is inhibited by allopurinol. The activity of the methylnitroimidazole moiety has not been defined clearly.
However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP.
Determination of plasma concentrations of azathioprine or 6-MP have no prognostic values as regards effectiveness or toxicity of these compounds.

While the precise modes of action remain to be elucidated, some suggested mechanisms include: 
1. the release of 6-MP which acts as a purine antimetabolite.

2. the possible blockade of-SH groups by alkylation.
3. the inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of the immune response.

4. damage to deoxyribonucleic acid (DNA) through incorporation of purine thio-analogues.

Because of these mechanisms, the therapeutic effect of Imuran may be evident only after several weeks or months of treatment.

Imuran appears to be well absorbed from the upper gastro-intestinal tract.

Studies in mice with [35S]-azathioprine showed no unusually large concentration in any particular tissue, and there was very little [35S]-label found in brain.

Plasma levels of azathioprine and 6-mercaptopurine do not correlate well with the therapeutic efficacy or toxicity of Imuran.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption
Azathioprine is well absorbed following oral administration. Although there are no food effect studies with azathioprine, pharmacokinetic studies with 6-mercaptopurine have been conducted that are relevant to azathioprine. The mean relative bioavailability of 6-mercaptopurine was approximately 27% lower following administration with food and milk compared to an overnight fast. 6-mercaptopurine is not stable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes) (see Section 4.2). Azathioprine should be administered at least 1 hour before or 3 hours after food or milk (see Section 4.2 Posology and method of administration).
Azathioprine is principally excreted as 6-thiouric uric acid in the urine. 1-methyl-4-nitro-5-thioimidazole has also been detected in urine as a minor excretory product. This would indicate that, rather than azathioprine being exclusive cleaved by nucleophilic attack at the 5-position of the nitroimidazole ring to generate 6-mercaptopurine and 1-methyl-4-nitro-5-(S-glutathionyl)imidazole. A small proportion of the drug may be cleaved between the S atom and the purine ring. Only a small amount of the dose of azathioprine administered is excreted unmetabolised in the urine.
Distribution
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).

Approximately 30% of azathioprine is protein bound.

Concentrations of 6-MP in cerebrospinal fluid (CSF) are low or negligible after i.v. or oral administration of 6-MP.
Biotransformation
Thiopurine S-Methyl Transferase (TPMT)
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 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).

Elimination
After oral administration of 100mg 35S-azathioprine, 50% of the radioactivity was excreted in the urine over 24 hours 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.

Mercaptopurine, a metabolite of azathioprine, has been identified in the colostrum and breast-milk of women receiving azathioprine treatment.


Special Patient Populations

Paediatric population -Overweight children
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-mercaptopurine and the dosage was calculated based on their body surface area. The mean AUC (0- ∞) of 6-mercaptopurine 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).

Patients with renal impairment
Studies with azathioprine have shown no difference in 6-mercaptopurine 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.

Patients with hepatic impairment
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).