Yun Seob Jung (1,2), Dong Woo Chae (1,2), Kyungsoo Park (1,2)
(1) Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea (2) Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea
Introduction: Methotrexate is a drug for treatment of cancers and autoimmune diseases. To our knowledge, several population pharmacokinetic models have been built in Chinese [1] and Western people [2] but there was no model developed in Korean people. Furthermore, current dosing regimen of methotrexate has a limitation because it was only based on body size such as body surface area (BSA) and was not individualized based on other factors such as age.
Objective:
- Develop a population PK model of methotrexate in Korean people
- Develop new dosing regimen of methotrexate for Korean people
Methods: PK data were acquired from electronic medical records in Yonsei Severance Hospital from 2005 January to 2016 January. We excluded data with sampling time more than 120 hr, intrathecal injection and no duration information. The total number of subjects and samples used for analysis were 188 and 1544, respectively. Subjects had diseases including leukemia and non-Hodgkin’s lymphoma. Inter-occasional variabilities were considered in modeling. Theory-based allometry was assumed in incorporating weight into PK parameters [3]. After developing a basic structural model, we explored possible covariate-parameter relationships and developed a covariate model. In continuous covariates, those were centered to median values. Then, multivariate covariate seletion was performed using stepwise covariate modeling with likelihood ratio test at significance level of p < 0.01 for forward addition and p < 0.001 for backward deletion. Data exploration and model building was carried out using R ver 3.3.3 and NONMEM ver 7.3.
Results: A two compartment model with 1st order elimination was chosen for the basic structural model. Based on that structural model, we chose and developed the covariate model. Significant covariates were age on peripheral volume of distribution, age and serum creatinine on clearance. The structural parameter estimates were 36.39L for central volume of distribution, 26.27L for peripheral volume of distribution, 16.6 for clearance and 0.831 for intercompartmental clearance. The coefficients about covariate-parameter relationships were -0.241, -0.008 and -0.317 in age on peripheral volume of distribution, age on clearance and serum creatinine on clearance, respectively. The inter-individual variabilities (CV%) were 27.2% in peripheral volume of distribution and 31.0% in clearance. The inter-occasional variabilites (CV%) were 92.1% in central volume of distribution, 193.0% in peripheral volume of distribution, 84.2% in clearance and 182.8% in intercompartmental clearance. The proportional residual error (CV%) was estimated to be 41.9%. Standard errors about parameters were all less than 30%. Based on the finally developed covariate model, periphreal volume of distribution decreases by age and clearance decreases by age or serum creatinine. The model adequately described the time course of observed concentrations.
Conclusions: We successfully built a population PK model of methotrexate in Korean people. By a population PK model, we can develop new dosing regimen for Korean patients with hematologic malignancy according to characteristics of a patients.
References:
[1] Zhang C, Zhai S, Yang L, Wu H, Zhang J, Ke X. Population pharmacokinetic study of methotrexate in children with acute lymphoblastic leukemia. Int J Clin Pharmacol Ther. 2010 Jan;48(1):11-21
[2] Godfrey C, Sweeney K, Miller K, Hamilton R, Kremer J. The population pharmacokinetics of long-term methotrexate in rheumatoid arthritis. Br J Clin Pharmacol. 1998 Oct;46(4):369-376
[3] Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol, 2008;48:303-332.
Reference: PAGE 27 (2018) Abstr 8435 [www.page-meeting.org/?abstract=8435]
Poster: Drug/Disease Modelling - Oncology