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Population pharmacokinetics of high‐dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data
Author(s) -
Fukuhara K.,
Ikawa K.,
Morikawa N.,
Kumagai K.
Publication year - 2008
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/j.1365-2710.2008.00966.x
Subject(s) - pharmacokinetics , urine , methotrexate , medicine , population pharmacokinetics , population , pharmacology , environmental health
Summary Objective: This study aimed to develop a population pharmacokinetic model for high‐dose methotrexate (MTX), specifically focusing on the drug urinary excretion process. Methods and results: Three hundred and forty‐eight serum samples and 416 urine samples from 51 Japanese adult patients with malignancies were concurrently fitted into a multi‐compartment model using the nonmem program. In the final model, creatinine clearance (CCR, mL/min) and the MTX dose (DOSE10G; 0 when <10 g, 1 when ≥10 g) were the most significant factors that affected the renal clearance (CL r ) and non‐renal clearance (CL nr ), respectively: CL r (L/h) = 5·57 × (CCR/80·0) 0·112 , V 1 (L) = 26·9, Q (L/h) = 0·0778, V 2 (L) = 2·27, CL nr (L/h) = 0·567 × 3·39 DOSE10G , where V 1 and V 2 are the volumes of distribution of the central and peripheral compartments, respectively, and Q is the inter‐compartmental (central–peripheral) clearance. For another nine patients, the model enabled a satisfactory Bayesian estimation using two time‐point serum concentrations. Conclusion: The newly developed population pharmacokinetic model should improve the quality of serum concentration monitoring of high‐dose MTX to predict and control toxic events.