Population pharmacokinetics of high-dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data

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 >or=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 x (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 x 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.