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Purpose: Leflunomide is an immunosuppressive drug indicated for the treatment of rheumatoid arthritis (RA). While the pharmacokinetics (PK) of its active metabolite A771726 reportedly show large interindividual variability, no efficient dose individualization strategy is currently available. The goal of this work was to develop a population PK model for A771726 and propose an optimal individualized dosing strategy., Methods: A771726 plasma concentration data were collected from 50 healthy male volunteers participating in two leflunomide PK studies given a single oral dose of 40 mg. Concentrations were elevated in low body weight (WT) subjects and showed multiple peaks. Thus, A771726 PK modeling was conducted incorporating allometry scaling and enterohepatic circulation (EHC). For dose optimization, simulating a set of 1000 virtual subjects from the developed model and dividing the subjects into 5 groups with WT of 50, 60, 70, 80, 90 kg, respectively, the optimal dose was explored that achieves the drug concentration most similar to the target, which was defined as the concentration for the 70 kg subject treated with the current standard dosage regimen (the loading dose of 100 mg QD for 3 days, followed by the maintenance dose of 20 mg QD)., Results: The data were best described by a two compartment model with first order absorption incorporating EHC with the bile released into the intestine. None of the covariates tested was found to be significant other than WT used in allometry. Simulation showed that the optimal loading dose increased by 15 mg for every 10 kg increment in WT while the optimal maintenance dose was 15 and 25 mg for 50 and 90 kg groups, respectively, and the same (= 20 mg) for the others. Large concentration differences from the target observed in low and high WT groups disappeared when optimal doses were given., Conclusions: This work demonstrates the importance of a population PK model-based dose optimization approach in maintaining drug therapeutic concentrations in leflunomide treatment., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Valproic acid (VPA) is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC) administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500 mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125 mg were administered three times daily for 7 days and then a single dose of VPA was administered. Blood samples were collected up to 48 hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0 h·mg/L vs 889.6 h·mg/L; C max, 52.1 mg/L vs 53.0 mg/L). There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI]) of AUClast and C max (95.7 [85.9-106.5] and 98.3 [91.6-105.6], respectively). Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary.