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, V₁(L) = 26·9, Q(L/h) = 0·0778, V₂(L) = 2·27, CL_nr(L/h) = 0·567 × 3·39^DOSE10G, where V₁ and V₂ 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.

The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients ( n = 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (≥90%) against Escherichia coli , Klebsiella pneumoniae , and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was ≥90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.

A high-performance liquid chromatography (HPLC) method using ultrafiltration to pretreat peritoneal fluid and bile samples is developed to measure meropenem and biapenem concentrations in human peritoneal fluid and bile. Meropenem or biapenem in peritoneal fluid or bile samples is stabilized by mixing with 1 mol/L 3-morpholinopropanesulfonic acid buffer (pH 7.0) (1:1). The mixture is transferred to a Nanosep 10K centrifugal filter device; after centrifugation, the filtrate is subjected to reversed-phase HPLC, and the eluate is monitored at 300 nm. No interference from endogenous substances is observed. The lower limits of quantification are 0.05 μg/mL for peritoneal fluid and 0.1 μg/mL for bile. The new method has been applied to comparative sitespecific- pharmacokinetic investigations in surgery patients.