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Arzneimittelforschung 2010; 60(12): 769-775
DOI: 10.1055/s-0031-1296353
Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

High-dose methotrexate in children with acute lymphoblastic leukemia: 7-hydroxymethotrexate systemic exposure and urinary concentrations at the steady state correlate well with those of methotrexate

Jiřina Chládková
1   Department of Paediatrics, Charles University in Prague, Faculty of Medicine and Hospital, Hradec Králové, Czech Republic
,
Jiří Hak
1   Department of Paediatrics, Charles University in Prague, Faculty of Medicine and Hospital, Hradec Králové, Czech Republic
,
Jiřina Martínková
2   Department of Pharmacology, Charles University in Prague, Faculty of Medicine, Hradec Králové, Czech Republic
,
Jaroslav Chládek
2   Department of Pharmacology, Charles University in Prague, Faculty of Medicine, Hradec Králové, Czech Republic
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Publikationsverlauf

Publikationsdatum:
03. Dezember 2011 (online)

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Abstract

The present study evaluated the pharmacokinetics of methotrexate (MTX, CAS 59-05-2) and 7-hydroxymethotrexate (7-OHMTX, CAS 5939-37-7) in children with acute lymphoblastic leukemia (ALL) with particular interest devoted to the renal excretion at the steady-state and to the relationships between total (CL) and renal clearances (CLR) of both compounds.

Ten children (seven girls) aged 8.5 years (2.9–16) years with standard or medium-risk ALL received four 24-h i. v. infusions of high-dose MTX (HDMTX, 5 g/m2) with leucovorin (CAS 58-05-9) rescue according to the ALL-BFM-95 protocol. MTX and 7-OHMTX were assayed in plasma and urine by high-performance liquid chromatography.

At the steady-state, the clearance (CL) of MTX (6.28 ± 2.79 l.h−1) was correlated with its CLR (rs = 0.79, p < 0.0001) which accounted for 61% (SD 26%) of the former. There were weak correlations between pretreatment values of creatinine clearance calculated using Schwartz’s formula and the drug’s CL (rs = 0.30, p < 0.05) or CLR (rs = 0.41, p < 0.02). In contrast, the CLR accounted for only 26% (SD 15%) of the metabolite’s CL which was estimated assuming 10% conversion of MTX to 7-OHMTX. The CL values of both compounds were highly correlated (rs = 0.86, p < 0.0001). The CLR of the parent compound was on the average 9-fold higher (range: 3.5− to 17-fold) and was strongly correlated with the CLR of the metabolite (rs = 0.87, p < 0.0001). The ratio 7-OHMTX/MTX of urinary concentrations was between 2.4 and 9.8% with the mean value of 4.1%.

This study suggests that during the 24-h i.v. infusions of HDMTX to children with ALL, the exposure of patients to 7-OHMTX can be reasonably well predicted from the knowledge of MTX concentrations. The steady-state renal CLs, total CLs as well as urinary concentrations of the parent compound and metabolite are highly correlated and the correlation of plasma concentrations is moderate. Therefore, it is unlikely that simultaneous evaluation of 7-OHMTX and MTX steady-state concentrations could improve the predictive performance of the latter towards the response or the risk of complications, although future larger studies should verify this conclusion.

Key words

Acute lymphoblastic leukemia - CAS 59-05-2 - CAS 5939-37-7 - 7-Hydroxymethotrexate, pharmacokinetics, renal clearance - Methotrexate, pharmacokinetics, renal clearance
 

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