Pharmacokinetics of continuous infusion of methotrexate and teniposide in pediatric cancer patients.
Laboratory studies have demonstrated the ability of teniposide to markedly enhance the intracellular accumulation of methotrexate suggesting that combination therapy with these agents may produce clinical benefit. Studies of methotrexate and teniposide were conducted in 19 children with relapsed acute lymphocytic leukemia to evaluate the pharmacokinetics of this previously untested combination of agents given alone or in combination and to demonstrate the feasibility of a Bayesian dose optimization strategy. Patients were randomly assigned to receive intermediate dose methotrexate as a 24-h continuous infusion, administered either simultaneously with continuous infusion teniposide or sequentially with the teniposide infusion beginning 12 h after the end of the methotrexate infusion. Plasma samples were obtained during and after infusions at appropriate times for a comprehensive pharmacokinetic study of each drug. Two measured drug concentrations obtained during the infusion were used to adjust each patient's dose rate to achieve target values of 10 microM for methotrexate and 15 microM for teniposide. Pharmacokinetic parameters for teniposide were not different for patients given simultaneous methotrexate from parameters estimated for patients receiving teniposide 12 h after the end of the methotrexate infusion. Despite similar end of infusion methotrexate concentrations, 24-h postinfusion methotrexate concentrations were lower (0.137 versus 0.235 microM; P less than 0.05) in the patients receiving simultaneous infusions. The patient specific dose regimens yielded acceptably precise, minimally biased steady state drug concentrations. These pharmacokinetic results provide the basis for further clinical studies with this combination of antileukemic agents.
Pharmaceutical Division, St. Jude Children's Research Hospital, Memphis, Tennessee 38101.
J H
JH
Rodman
M
M
Sunderland
R L
RL
Kavanagh
J
J
Ochs
J
J
Yalowich
W E
WE
Evans
G K
GK
Rivera
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D013713:Teniposide / Q000008:administration & dosage / Q000493:pharmacokinetics*
D013713:Teniposide; D011034:Podophyllotoxin; D002955:Leucovorin; D008727:Methotrexate