Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, antimetabolites, purine analogues, ATC Code: L01BB02 
Mechanism of action

Mercaptopurine is sulphydryl analogue of the purine bases, adenine and hypoxanthine and acts as a cytotoxic antimetabolite.



Mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular uptake and intracellular anabolism to thioguanine nucleotides for cytotoxicity. The mercaptopurine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The thioguanine nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the active substance.

Cross-resistance usually exists between mercaptopurine and 6-thioguanine.

Pharmacodynamic effects
The cytotoxic effect of mercaptopurine can be related to the levels of red blood cell mercaptopurine derived thioguanine nucleotides, but not to the plasma mercaptopurine concentration.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Absorption

The bioavailability of oral mercaptopurine shows considerable inter-individual variability, which probably results from its first-pass metabolism. When administered orally at a dosage of 75 mg/m2 to seven paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%.

After oral administration of mercaptopurine 75 mg/m2 to 14 children with acute lymphoblastic leukaemia, the mean Cmax was 0.89μM, with a range of 0.29 - 1.82μM and Tmax was 2.2 hours with a range of 0.5 - 4 hours.

The mean relative bioavailability of mercaptopurine was approximately 26 % lower following administration with food and milk compared to an overnight fast. Mercaptopurine is not stable in milk due to the presence of xanthine oxidase (30 % degradation within 30 minutes) (see Section 4.2 Posology and method of administration).

Distribution
Concentrations of mercaptopurine in cerebrospinal fluid (CSF) are low or negligible after IV or oral administration (CSF: plasma ratios of 0.05 to 0.27). Concentrations in the CSF are higher after intrathecal administration.

Biotransformation
Mercaptopurine is extensively metabolized by many multi-step pathways to active and inactive metabolites. 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 mercaptopurine or its downstream metabolites are: the polymorphic enzyme thiopurine S-methyltransferase (TPMT), xanthine oxidase, inosine monophosphate dehydrogenase (IMPDH) 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). 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 mercaptopurine may predict adverse drug reactions to mercaptopurine therapy. For example, individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations (see Section 4.4).

Elimination
In a study with 22 adult patients the mean mercaptopurine clearance and half-life after IV infusion was 864 mL/min/m2 and 0.9 hours respectively. The mean renal clearance reported in 16 of these patients was 191 mL/min/m2. Only about 20 % of the dose was excreted in the urine as intact drug medicinal product after IV administration. In a study with 7 children patients the mean mercaptopurine clearance and half-life after IV infusion was 719 (+/-610) ml/min/m2 and 0.9 (+/-0.3) hours respectively.


Special patient populations
Elderly
No specific studies have been carried out in the elderly (see Section 4.2 Posology and method of administration).

• Renal impairment
Studies with a pro-drug of mercaptopurine have shown no difference in mercaptourine pharmacokinetics in uremic patients compared to renal transplant patients. Since little is known about the active metabolites of mercaptopurine in renal impairment (see Section 4.2 Posology and method of administration).

Mercaptopurine and/or its metabolites are eliminated by haemodialysis, with approximately 45 % of radioactive metabolites eliminated during dialysis of 8 hours.

• Hepatic impairment
A study with a pro-drug of mercaptopurine 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 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 (see Section 4.2 Posology and method of administration).