Pharmacokinetics and Pharmacodynamics of Oral Methotrexate and Mercaptopurine in Children With Lower Risk Acute Lymphoblastic Leukemia: A Joint Children’s Cancer Group and Pediatric Oncology Branch Study

Abstract

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 μmol•h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 μmol•h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P = .007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P = .043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.

Methotrexate and aminopterin exhibit similar in vitro and in vivo preclinical activity against acute lymphoblastic leukaemia and lymphoma

“…These results indicate that AMT is more potent than MTX in cultured ALL and lymphoma cells. In paediatric patients, the peak concentration of MTX reaches above 1 μmol/l after an oral dose (Balis et al , 1998) while AMT can achieve 0·15 μmol/l after an oral dose (Cole et al , 2005). Thus, considering clinically achievable concentrations of AMT and MTX, the activity of AMT does not appear to be superior to MTX, as suggested by our xenograft data (see below).…”

Thiopurine methyltransferase genotype–phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia

“…The United Kingdom Medical Research Council (MRC) national trial ALL97 compared the efficiacy and toxicity of both thiopurines during the maintenance phases of chemotherapy. Both drugs are directly inactivated by the polymorphic enzyme thiopurine methyltransferase (TPMT) [3] and both form cytotoxic thioguanine nucleotides (TGNs), metabolites linked to both treatment efficacy and toxicity [4,5] However, mercaptopurine forms intermediate nucleotide metabolites prior to the TGNs (Figure 1). These mercaptopurine nucleotides are substrates for TPMT, and the resulting methylmercaptopurine nucleotides (MeMPNs) are formed at the expense of TGNs.…”

A Step Toward More Accurate Dosing for Mercaptopurine in Childhood Acute Lymphoblastic Leukemia

“…However, it is well established that plasma 6-MP levels correlate poorly with therapeutic end points. 9,10 Indeed, in ALL, 6-MP dosing is adjusted according to peripheral blood white cell (WBC) and platelet counts.…”