Development and introduction of a pediatric liquid formulation of
6-mercaptopurine for treatment of leukemia.

Background:
Patients with acute lymphoblastic leukemia (ALL) are currently treated in the Netherlands according to the Dutch Childhood Oncology Group (DCOG) ALL10 protocol, in which the oral cytotoxic drug 6-mercaptopurine (6MP) is administered daily, for a period between one and two years. Because of the lack of a commercially available pediatric formulation of 6MP, 6MP needs to be prepared as capsules containing the specific dosage needed for each patient by community pharmacies. Every 2 weeks the dosage of 6MP is adapted according to the leukocyte count. Since most pharmacies are not equipped to prepare capsules of cytotoxic compounds such as 6MP, the availability (within an acceptable time-window) of 6MP in the correct dosage, after discharge of the patient and after every dosage adaptation, is problematic and may lead to inadequate patient care. Moreover, in order to prepare a drinking solution for younger children, the parents have to dissolve the capsules at home with water before administration. This may lead to unwanted drug exposure of the parents, and may also increase the risk for errors in dosing or administration.
The aim of this study is to improve 6MP treatment in pediatric leukemia patients, by developing and licensing a pediatric liquid formulation of 6MP, assessing its stability and bioequivalence, and ensuring a nationwide introduction of the new formulation.

Study design:
A crossover open label study will be performed, with 20 patients from different age groups (infants 1 month- 2 years of age; young children 2-6 years; school children 6-12 years; adolescents 12-18 years). Patients will receive 4 weeks treatment with capsules, followed by 4 weeks treatment with liquid formulation, or vice versa. Patients will participate in the study during a regular treatment phase with 6MP, according to the ALL-10 or Interfant protocol.

Endpoints:
Bioequivalence will be assessed by determining blood levels of the active metabolites of 6MP in red blood cells. Two-weekly leukocyte counts will be performed to monitor hematological toxicity. Compliance and acceptance of the different formulations by children and parents will be assessed.

6MP treatment in pediatric ALL patients can be improved by developing a pediatric oral drinking solution of 6MP, assessing its bioequivalence, and -when successful- introducing the new formulation nationwide.

For each participant, the study period is 8 weeks, with a cross-over to a different formulation after 4 weeks.

Patients will be randomized to receive 4 weeks 50 mg/m2 /day 6MP as a capsule and subsequently 4 weeks the same dosage of 6MP as a liquid drinking solution, or vice versa. Patients will participate in the study during a regular treatment phase with 6MP, according to the ALL-10 or Interfant protocol. Bioequivalence will be assessed by determining blood levels of the active metabolites of 6MP in red blood cells. Two-weekly leukocyte counts will be performed to monitor hematological toxicity. Compliance and acceptance of the different formulations by children and parents will be assessed.