title: Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments.
abstract: OBJECTIVE
  It is advantageous to individualize high-dose methotrexate (HDMTX) to maintain adequate exposure while minimizing toxicities. Previously, we accomplished this through within-course dose adjustments.
  
  
  METHODS
  In this study, we evaluated a strategy to individualize HDMTX based on clearance of each individual's previous course of HDMTX in 485 patients with newly diagnosed acute lymphoblastic leukemia. Doses were individualized to achieve a steady-state plasma concentration (Cpss) of 33 or 65 μM (approximately 2.5 or 5 g/m(2)/day) for low- and standard-/high-risk patients, respectively.
  
  
  RESULTS
  Individualized doses resulted in 70 and 63 % of courses being within 20 % of the targeted Cpss in the low- and standard-/high-risk arms, respectively, compared to 60 % (p < 0.001) and 61 % (p = 0.43) with conventionally dosed therapy. Only 1.3 % of the individualized courses in the standard-/high-risk arm had a Cpss greater than 50 % above the target compared to 7.3 % (p < 0.001) in conventionally dosed therapy. We observed a low rate (8.5 % of courses) of grade 3-4 toxicities. The odds of gastrointestinal toxicity were related to methotrexate plasma concentrations in both the low (p = 0.021)- and standard-/high-risk groups (p = 0.003).
  
  
  CONCLUSIONS
  Individualizing HDMTX based on the clearance from the prior course resulted in fewer extreme Cpss values and less delayed excretion compared to conventional dosing.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Pauley
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Crews
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: John
authors.initials: J
authors.lastname: McCormick
authors.forename: Scott C
authors.initials: SC
authors.lastname: Howard
authors.forename: John T
authors.initials: JT
authors.lastname: Sandlund
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.forename: Raul
authors.initials: R
authors.lastname: Ribeiro
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rubnitz
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000465:Algorithms; D000931:Antidotes / Q000008:administration & dosage / Q000627:therapeutic use; D000963:Antimetabolites / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D016231:Fluorescence Polarization Immunoassay; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007278:Injections, Spinal; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008954:Models, Biological; D057285:Precision Medicine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*
chemical_list: D000931:Antidotes; D000963:Antimetabolites; D002955:Leucovorin; D008727:Methotrexate