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Pharmacokinetics and distribution of 6-mercaptopurine administered intravenously in children with lymphoblastic
E Jacqz-Aigrain1, S Nafa, Y Médard
1Department of Clinical Pharmacology, Hôpital Robert Debré, Paris, France.
Insights
Intravenous 6-mercaptopurine achieved high concentrations in cerebrospinal fluid (CSF) and increased erythrocyte thioguanine nucleotides in children with acute lymphoblastic leukemia (ALL). Further trials will assess if IV administration reduces central nervous system relapses.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Clinical Pharmacology
Background:
- Acute lymphoblastic leukemia (ALL) is a common childhood cancer.
- Chemotherapy, including 6-mercaptopurine, is a cornerstone of ALL treatment.
- Understanding drug distribution and metabolite concentrations is crucial for optimizing therapy.
Purpose of the Study:
- To determine the pharmacokinetics of intravenous 6-mercaptopurine in children with ALL.
- To measure cerebrospinal fluid (CSF) distribution and erythrocyte 6-thioguanine nucleotide concentrations.
- To compare intravenous (IV) versus oral administration of 6-mercaptopurine.
Main Methods:
- Children with ALL were randomized to receive IV 6-mercaptopurine per EORTC protocol ALL n.58881.
- Pharmacokinetic parameters (clearance, volume of distribution, half-life) were determined after IV administration.
- Erythrocyte thioguanine and CSF concentrations were measured at various time points.
Main Results:
- IV 6-mercaptopurine showed a systemic clearance of 23.02 L/h and elimination half-life of 1.64 h.
- Significant increases in erythrocyte thioguanine concentrations were observed post-infusion.
- High CSF concentrations of 6-mercaptopurine were detected after IV administration, unlike oral doses.
Conclusions:
- Intravenous 6-mercaptopurine leads to high CSF concentrations and increased active metabolites.
- The study sets the stage for a clinical trial comparing IV and oral 6-mercaptopurine to evaluate CNS relapse rates.
- Optimizing 6-mercaptopurine delivery may improve outcomes in pediatric ALL.
Objective:
The pharmacokinetics of 6-mercaptopurine, including cerebrospinal-fluid (CSF) distribution, and the erythrocyte 6-thioguanine nucleotide concentrations were determined in children randomised to receive intravenous mercaptopurine for acute lymphoblastic leukaemia (ALL), according to the EORTC protocol ALL n.58881.
Results:
After 1 month of oral treatment at a dose of 50 mg.m-2.day-1, the pharmacokinetic parameters were determined after the first i.v. administration of 1 g.m-2 (bolus dose of 0.2 g.m-2 followed by an 8-h infusion of 0.8 g.m-2) in 11 patients: systemic clearance was 23.02 1.h-1, volume of distribution was 0.75 l.kg-1, and elimination half-life was 1.64 h. The erythrocyte thioguanine concentrations were measured in the same 11 patients and increased significantly between the beginning and the end of infusion (10 pmol x 10(8) packed RBC) or within 24 h of infusion (223 pmol x 10(8) packed RBC). The CSF concentration was 3.78 mumol.1(-1), 1-6 h after the beginning of infusion (n = 28) and the CSF to plasma ratio was 0.15 (n = 16). In patients receiving the oral dose of 50-165 mg.m-2.day-1 of 6-mercaptopurine, CSF concentrations were below 0.18 mumol.1(-1), 1-24 h after drug intake (n = 67), and the CSF to plasma ratio was not calculated.
Conclusion:
Following the i.v. administration of 6-mercaptopurine, we observed high CSF concentrations of 6-mercaptopurine and an acute increase of erythrocyte thioguanine nucleotide concentrations. The clinical trial (EORTC protocol ALL n[symbol: see text]5881), comparing the oral and i.v. administrations of mercaptopurine, will demonstrate if the i.v. administration reduces the incidence of CNS relapses.