Pharmacokinetic modeling study on methotrexate and its active metabolites in rheumatoid arthritis patients

Abstract

Abstract: AIM: To quantitatively investigate the pharmacokinetics of Methotrexate (MTX) and its active metabolites (MTXPG_n) in plasma, red blood cells, and synovial fluid of rheumatoid arthritis (RA) patients using modeling approach.METHODS: Concentration values of MTX and MTXPG_n in plasma, red blood cells, and synovial fluid of rheumatoid arthritis patients after orally, intravenously, and intra-synovial fluid dosing of MTX were digitized from 4 published literatures. ADAPT5 was utilized to conduct nonlinear regression analysis using maximum likelihood algorism for fitting these pharmacokinetic data using semi-physiologically-based PK model simultaneously.RESULTS: A semi-physiologically-based PK model was developed. This model could capture pharmacokinetic characteristics of MTX in plasma and synovial fluid using standard two compartment model separately, where MTX in central compartment system and synovial fluid could be distributed to each other. The PK model also could capture MTXPG_1-5 concentrations using 5 compartments with first order distribution constant from system central compartment to red blood cell compartment, where MTXPG_1-5 could be transformed to each other and be eliminated in same elimination rate constant. The physiological value of red blood cell was used as red blood cell compartment volume. Estimated parameters were close to physiological and pathological value, which were reasonable. The precision expressed in CV% of all parameters were less than 50% except for distribution clearance in synovial fluid (56.7%), which showed the estimation is robust.CONCLUSION: This study developed pharmacokinetic model of MTX and MTXPG_n in RA patients, which could improve quantitative understanding on pharmacokinetics of MTX and MTXPG_n in circulation and synovial fluid of RA patients.

Key words: methotrexate, poly-glutamate methotrexate, rheumatoid arthritis, pharmacokinetic model

CLC Number:

R969.1

LIU Dong-yang, SU Jing-mei, SONG Han-lin, CHEN Jia, LIU Yang, YAO Xue-ting, SONG Lin, JIANG Ji, HU Pei. Pharmacokinetic modeling study on methotrexate and its active metabolites in rheumatoid arthritis patients[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(5): 571-577.

References

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