Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia

Abstract

Although high-dose methotrexate has been extensively studied in children with newly diagnosed acute lymphoblastic leukemia (ALL), there are fewer data in children with relapsed ALL, many of whom have been heavily pretreated and have subclinical kidney dysfunction. We characterized the pharmacokinetics of adaptively controlled methotrexate given as a 24-h infusion during consolidation therapy in 24 children with relapsed ALL. To achieve the target steady-state concentration of 65 M, dosage adjustments were required in 14 patients, with doses ranging from 2854 to 6700 mg/m 2 per course. The mean steady-state plasma concentration (Cp ss ) of 68.0 M was different (P = 0.025) than the predicted Cp ss (mean = 87.4 M; range 35.7-184 M) had no adjustment in dose been made. The coefficient of variation in Cp ss was reduced from 41% to 18% by individualizing doses. Predisposing factors that correlated with decreased methotrexate clearance were female sex (P = 0.03), age greater than 6 years (P = 0.01), and prior history of heavy amphotericin B treatment (Ͼ30 mg/kg) (P = 0.03), but no factor predicted low clearance as well as the measured initial methotrexate clearance during the infusion (P Ͻ 0.0001). There was no life-threatening toxicity with the regimen. We conclude that dosage individualization decreases interpatient variability and avoids potentially toxic methotrexate exposures in heavily pretreated ALL patients. Leukemia (2000) 14, 221-225.

Sex-Dependent Expression and Activity of the ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (BCRP/ABCG2) in Liver

“…This is in agreement with the sex difference observed in the pharmacokinetics of several known BCRP substrates in humans. Significantly higher plasma clearance was noted in men compared with women for topotecan (Gallo et al, 2000;Loos et al, 2003), methotrexate (Godfrey et al, 1998;Wall et al, 2000), doxorubicin (Dobbs et al, 1995), and epirubicin (Wade et al, 1992). This sex difference can thus have important pharmacological and toxicological implications.…”

“…Inappropriate dosing may, for example, lead to suboptimal treatment in some patients and expose others to the risk of unacceptable toxicity. For methotrexate, it has been suggested that higher effective exposure to the drug because of lower clearance in women could contribute to their better chemotherapeutic overall outcome (Wall et al, 2000). Along the same lines, it has been suggested that women are at higher risk for methotrexate toxicity; therefore, lower dosing may be appropriate in female patients (Godfrey et al, 1998).…”

“…Several anticancer drugs that are known BCRP substrates such as topotecan, methotrexate, and doxorubicin have displayed sex-dependent pharmacokinetics in humans (Wade et al, 1992;Dobbs et al, 1995;Godfrey et al, 1998;Gallo et al, 2000;Wall et al, 2000;Loos et al, 2003). Sex is one variable that contributes to interindividual dif-ferences in pharmacokinetics, including absorption, distribution, metabolism, and excretion (Morris et al, 2003), and a potentially important determinant for the clinical effectiveness of drug therapy.…”

Diversity of the apoptotic response to chemotherapy in childhood leukemia

“…Host factors such as polymorphisms of drug metabolizing genes are also likely to impact the apoptotic response since these variables would influence the timing and magnitude of the initial apoptotic stimulus. [40][41][42][43][44] However, despite any potential differences in drug pharmacokinetics, the apoptotic response was initiated in all patients with three exceptions since blast counts fell significantly within 24 h following the start of treatment. Thus the character of the apoptotic pathway could be assessed.…”

Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia

“…All specimens were collected prospectively for pharmacokinetic analysis, and some results have been reported previously. 17,[24][25][26] The population pharmacokinetics were determined by using the 2-stage approach. 27 First, the pharmacokinetic parameters for each individual were estimated for each of the courses by using compartmental analysis.…”