Theresa Saklatvala PhD
Editor-in-Chief, Hospital Pharmacy Europe
Although mercaptopurine has been used for the slowing down of progression of acute lymphoblastic leukaemia (ALL) for many years, the only authorised form in the EU has been a 50mg tablet. This makes it difficult to adjust for children. Mercaptopurine Nova Laboratories (Xaluprine; mercaptopurine oral suspension 20mg/ml), recently authorised in the EU, allows more accurate dosing, and is more convenient for children who are unable to swallow tablets.
Acute lymphobastic leukaemia (ALL)
is a disease caused by the uncontrolled proliferation of genetically altered lymphoid progenitor cells, which, in turn, are the result of the altered expression of genes involved in the normal development of B cells and T cells.
The main symptoms of ALL are caused by the increased number of blast cells, which reduces the number of normal red blood cells, and include fatigue, paleness, a general feeling of being run-down, incidence of repeat infections and unusual bleeding (caused by a reduction in the number of platelets).
Diagnosis and treatment
Diagnostic tests include the following:
Blood tests (revealing too many white blood cells, not enough platelets or red blood cells, and the presence of blast cells);
Bone marrow aspiration (to determine whether the leukaemia has arisen from T cells or B cells, which information informs the treatment protocol);
Imaging tests (computerised tomography to determine spread); and
Spinal fluid tests (a lumbar puncture, to determine presence in the spinal fluid).
Treatment for ALL falls into phases:
- Induction therapy (to destroy leukaemia cells in the blood and bone marrow);
- Consolidation therapy (to destroy leukaemia cells in the brain and spinal cord);
- Maintenance therapy (to prevent leukaemia cells from regrowing); and
- Preventive treatment to the spinal cord (injection of chemotherapy drugs directly into the spinal fluid).
Treatment for ALL typically spans 2½ to 3½ years, and may include:
- Chemotherapy (principally used as induction therapy);
- Targeted drug therapy (which targets specific cancer cell abnormalities, for example, imatinib for cancer cells with the Philadelphia chromosome);
- Radioactive therapy; and
- Stem cell transplant (for consolidation or relapse therapy).
ALL in children
ALL is the most common malignancy diagnosed in children, accounting for one-third of all paediatric cancers. The annual incidence in the US is 3.7–4.9 cases per 100,000 children aged up to 14 years, peaking in the 2–5-year-old bracket. Although cancer in children and adolescents is rare, the overall incidence has been increasing over the past 35 years. As treatment of ALL in children entails many potential complications, it is best co-ordinated by paediatric oncologists and performed in centres that have all the necessary paediatric care facilities.
Although few factors associated with increased risk of ALL have been identified, the primary ones are:
- Prenatal exposure to X-ray;
- Postnatal exposure to high doses of radiation;
- Down syndrome and other genetic conditions; and
- Inherited genetic polymorphisms.
Among children with ALL, 95% attain remission and 75–90% survive free of leukaemic recurrence at least five years after diagnosis.
Mercaptopurine, long established in the EU for the treatment of ALL, belongs to the pharmacotherapeutic group: antineoplastic agent, antimetabolites, purine analogues, ATC code L01BB02. It is an inactive pro-drug which acts as a purine antagonist, requiring cellular uptake and intracellular anabolism to thioguanine for cytotoxicity. Metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. Cytotoxicity occurs when the thioguanine nucleotides are incorporated into nucleic acids.
Biovariability studies show considerable inter-individual variability, as a result of its first-pass metabolism.
Bioequivalence of 50mg Mercaptopurine Nova Laboratories oral suspension with the reference 50mg tablet has been demonstrated in a study with 60 volunteers, but not Cmax. The mean Cmax with the oral suspension was 39% higher than the tablet, although there was less between-subject variability with the suspension (46%) than with the tablet (69%). The elimination half-life of 6-mercaptopurine is between 60 and 120 minutes (five hours for active metabolites). The main route of elimination is through metabolism (only 7% of an oral dose being excreted as unchanged 6-mercaptopurine within 12 hours of administration).
Benefits of oral suspension 20mg/ml
Mercaptopurine is a cytotoxic purine analogue that interferes with nucleic acid metabolism and inhibits growth of malignant cells. It induces and primarily helps maintain remission of disease, with benefits that are well established. As an oral suspension, the added benefits include better precision, ease of administration (especially in small children), and more flexible and more consistent dosing. A higher rate of absorption compared with tablet is seen, and therefore dose must be adjusted when patients switch from tablet to oral formulation.
A 1ml suspension contains 20mg mercaptopurine (monohydrate), with excipients 3mg aspartame, 1mg methyl hydroxyl, 0.15mg propyl hydroxybenzoate and trace sucrose, and it appears as a pink-to-brown suspension.
Closely monitored haemotoxicity governs the dose to suit the patient. Depending on treatment phase, target doses vary between 25–75mg/m2 body surface area per day, but is lower in patients with reduced or absent thiopurine methyl transferase (TPMP) enzyme activity (which metabolises 6-mercaptopurine). For the elderly and for patients with renal or hepatic impairment, no pharmacokinetics have been performed. Therefore, careful monitoring with a view to reducing dosing is essential. Switching from tablet to oral suspension needs intensified haematological monitoring due to non-bioequivalence with respect to peak plasma concentration.
Mercaptopurine Nova Laboratories is orally administered after vigorous redispersing (shaking) with the use of dosing syringes (1ml and 5ml). It is taken in the evening either with food or on an empty stomach, provided the method is standardised, and at least one hour before or two hours after milk or dairy products.
There exists one major adverse reaction: the method of action causes bone marrow suppression, which leads to leucopenia and thrombocytopenia and sometimes anaemia, with leucocyte and platelet counts falling after treatment is stopped.
Medicines containing mercaptopurine in tablet form have been used for many years in the EU to treat patients with ALL. An age-appropriate formulation has been identified as a priority research area of the EMA’s Paediatric Committee: Mercaptopurine Nova Laboratories (Xaluprine) represents this major advance in the treatment of ALL, particularly in children.
- Xaluprine (Mercaptopurine Nova Laboratories 20mg/ml oral suspension) is used to treat children, adolescents and adults who have acute lymphoblastic leukaemia (ALL), a cancer of the lymphocytes.
- Xaluprine is administered orally by syringe once per day in the evening, either with food (except dairy products) or on an empty stomach.
- Xaluprine is converted within cells into metabolites, notable thioguanine, which interfere with DNA synthesis, thereby halting cell division.
- While possessing the well-known effectiveness of tablet-form mercaptopurine in slowing down the progression of ALL, added benefits of Xaluprine include accuracy and ease of dosing in children.