[Investigation on individualized adjustment of target range of high-dose methotrexate].
OBJECTIVE
To explore the way of individualized adjustment of target range of each high-dose methotrexate (MTX) 24 hours infusion to treat acute lymphoblastic leukemia in children.


METHODS
Twenty-four children and 105 infusions were included in the study. According to 1 h and 6 h plasma MTX concentrations after infusion, based on established high-dose MTX population pharmacokinetics model, the course predicted value of drug concentration at steady state (C(SS)) was calculated. MTX infusion rate and dosage was adjusted 8 h after the start according to the predicted value of C(SS). Then MTX concentration at 23 h (actual value of C(SS)) was measured.


RESULTS
To achieve the target range of C(SS), adjustments of MTX dosage were required in 17 (71%) patients. Adjustments of MTX dosage were required in 45 (43%) infusions, the dose was increased in 42 infusions and decreased in 3 infusions. There were 29 infusions of high-dose MTX during consolidation therapy (after remission induction therapy). Among them, 16 infusions had increased dosage, and 1 infusion had decreased dosage. There were 76 infusions during maintenance therapy. Among them, 26 infusions increased dosage, and 2 infusions decreased dosage. Overall 95 (90%) infusions achieved the target range of C(SS), while in 8 infusions the doses were lower than the target range in 2 infusions the doses were higher than the target range. If there had been no adjustments, only 74 (70%) infusions could have achieved the target range. Adjustments of MTX dosage, compared with no adjustments, could remarkably enhance the rate of achieving the target range of C(SS) (chi(2) = 13.366, P = 0.000). Among 60 infusions of no adjustments, the actual values of C(SS) were well correlated with the predicted values of C(SS) (r = 0.487, P = 0.000), and the actual values of C(SS) were also correlated with the 6 h plasma MTX concentrations after infusions (r = 0.389, P = 0.002). The actual values of total clearance (CL) of MTX of 105 infusions were 7.01 +/- 2.06 L/(m(2).h). Inter-courses variability in CL was up to 4.4-fold. Intra-patient variability in CL was up to 2.9-fold. Predisposing factors that correlated with decreased CL of MTX were old age, heavy body weight, low blood phosphate, high blood bilirubin and infusions during maintenance therapy (P < 0.05).


CONCLUSIONS
High-dose methotrexate chemotherapy needed individualized adjustment, as inter-courses variability of CL was up to 4.4-fold among 105 infusions. According to 1 h and 6 h plasma MTX concentrations after infusion, adjusting MTX infusion rate and dosage, overall 90% infusions achieved the target range of C(SS). High-dose MTX infusions during consolidation therapy needed individualized adjustment of target range more.
Hua
Ying
Y
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Zhao
Wei-hong
WH
Lu
Xin-tian
XT
Yang
Li-hua
LH
Lu
Wei
W
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy*
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate