A Population Pharmacokinetic Model for Low-Dose Methotrexate and its Polyglutamated Metabolites in Red Blood Cells

Korell, Julia; Stamp, Lisa K.; Barclay, Murray L.; Dalrymple, Judith M.; Drake, Jill; Zhang, Mei; Duffull, Stephen B.

doi:10.1007/s40262-013-0052-y

Cited by 20 publications

(25 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Wide inter-patient variability in the accumulation and elimination of oral methotrexate from red blood cells has been observed in rheumatoid arthritis patients, with the half-life of elimination ranging from approximately one week to more than 13 weeks [Dalrymple et al, 2008]. Similarly, a recently developed population pharmacokinetic model of low-dose methotrexate and corresponding red blood cell metabolites, specifically polyglutamated metabolites MTXGlu 2–5, highlights the complex and variable nature of methotrexate metabolism [Korell et al, 2013]. Polyglutamated forms of methotrexate have been shown to persist long term within cells of the liver and have also been associated with a reduction in folate stores [Kremer et al, 1986].…”

Section: Discussionmentioning

confidence: 99%

Maternal exposure to methotrexate and birth defects: A population‐based study

Dawson

Riehle‐Colarusso

Reefhuis

et al. 2014

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Methotrexate is an anti-folate medication that is associated with increased risk of multiple birth defects. Using data from the National Birth Defects Prevention Study, a case-control study of major birth defects in the United States, we examined mothers exposed to methotrexate. The study population included mothers of live-born infants without major birth defects (controls) and mothers of fetuses or infants with a major birth defect (cases), with expected dates of delivery between October 1997 and December 2009. Mothers of cases and controls were asked detailed questions concerning pregnancy history, demographic information, and exposures in a telephone interview. Approximately 0.06% (n=16/27,623) of case and 0.04% (n=4/10,113) of control mothers reported exposure to methotrexate between three months prior to conception through the end of pregnancy. Of the 16 case infants, 11 (68.8%) had a congenital heart defect (CHD). The observed CHDs included atrial septal defects, tetralogy of Fallot, valvar pulmonary stenosis, ventricular septal defects (VSDs), and total anomalous pulmonary venous return. One case infant had microtia in addition to a VSD and another had VACTER association. Exposed cases without a CHD had one of the following birth defects: cleft palate, hypospadias, congenital diaphragmatic hernia, or craniosynostosis. Based on a limited number of methotrexate-exposed mothers, our findings support recent case reports suggesting an association between early pregnancy exposure to methotrexate and CHDs. Because of the rarity of maternal periconceptional exposure to methotrexate, long-term, population-based case-control studies are needed to confirm these findings and better evaluate the association between methotrexate and birth defects.

show abstract

Section: Discussionmentioning

confidence: 99%

Maternal exposure to methotrexate and birth defects: A population‐based study

Dawson

Riehle‐Colarusso

Reefhuis

et al. 2014

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…The previously constructed RBC PK model Figure 1 shows the RBC PK model for MTXGlun developed previously [6]. The plasma PK of MTXGlu1 is described by a two compartment model.…”

Section: Methodsmentioning

confidence: 99%

“…Structure ofthe parent-metabolite pharmacokinetic model for MTXGlun in RBCs (adapted from [6]). ka,oral and ka,s.c.…”

Section: Figurementioning

confidence: 99%

“…Structure of the WBC PK model published by Panetta et al [10], adapted to include the dosing seen in the RBC MTX PK study [6]. Parameters in the plasma PK model are defined as in Figure 1.…”

Section: Figurementioning

confidence: 99%

“…Previously, we developed a population pharmacokinetic (PK) model for MTXGlun measured in RBCs [6]. The objective of the current work was to assess whether RBC kinetics of MTX are comparable with the kinetics observed in other cell lines such as human breast cancer cells (HBCCs) or WBCs.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Comparison of intracellular methotrexate kinetics in red blood cells with the kinetics in other cell types

Korell

Duffull

Dalrymple

et al. 2014

Br J Clin Pharmacol

Self Cite

View full text Add to dashboard Cite

AIMTo assess the similarities in intracellular pharmacokinetics (PK) of methotrexate (MTX) in red blood cells (RBCs) and other cell lines. METHODSThree previously published PK models for intracellular MTX and MTX polyglutamate (MTXGlu2-5) concentrations were used: (i) a model for the kinetics in RBCs, (ii) a model for the kinetics in human breast cancer cells (HBCCs) and (iii) a model for the kinetics in various white blood cell (WBC) lines. All three models were used to simulate the response in a typical individual receiving 10 mg oral MTX once weekly and the predicted steady-state concentrations (Css) and time to Css (tss) were compared. RESULTSThe HBCC model showed a lower Css for MTXGlu2 and 3 and higher Css for MTXGlu 4 and 5 compared with the RBC PK model, while tss and overall intracellular MTX exposure appeared similar. The WBC PK model showed much lower Css for the parent MTXGlu1 and of tss for all MTXGlun, as well as a much lower cumulative Css for MTXGlu2-7 for the majority of the WBC cell lines.

show abstract

Methotrexate Polyglutamates Exposure – Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate

Hebing

Bartelink

Gosselt

et al. 2023

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Methotrexate polyglutamates (MTX‐PG) concentrations in red blood cells (RBCs) have been suggested as a biomarker of response in patients with rheumatoid arthritis (RA) receiving low‐dose MTX therapy. We investigated the association and interpatient variability between RBC‐MTX‐PG3‐5‐exposure and response in patients with RA starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score in 28 joints (DAS28) was analyzed using a population pharmacokinetic‐pharmacodynamic model. Relevant covariates were tested using full covariate modeling and backward elimination. From 395 patients, 3,401 MTX‐PG concentrations and 1,337 DAS28 measurements were available between 0 and 300 days after MTX treatment onset. The developed model adequately described the time course of MTX‐PG3‐5 and DAS28. The median MTX‐PG3‐5 level at month 1 was 30.9 nmol/L (interquartile range (IQR): 23.6–43.7; n = 41) and at month 3: 69.3 nmol/L (IQR: 17.9–41.2; n = 351). Clearance of MTX‐PG3‐5 from RBCs was 28% lower (95% confidence interval (CI): 23.6–32.8%) in a woman and 10% lower (95% CI: 7.7–12.4%) in a 65‐year‐old compared with a 35‐year‐old patient. MTX‐PG3‐5 concentrations associated with DAS28: half‐maximal effective concentration (EC50) was 9.14 nmol/L (95% CI: 4.2 nmol/L‐14.1 nmol/L). EF at 80% (EC80) above 47 nmol/L was regarded as the optimal response. Independent of the MTX‐PG 3–5 – response association, co‐administration of disease‐modifying antirheumatic drugs and corticosteroids improved response (additive effect on maximum effect (Emax)), whereas smoking, high body mass index and low albumin decreased Emax. In patients with RA starting MTX, RBC‐MTX‐PG3‐5 was associated with clinical response. A dose increase is suggested when MTX‐PG3‐5 at month 1 is below 9.15 nmol/L, continued with the same dose when the concentration is above 47 nmol/L, and consider other treatment options above 78 nmol/L from 3 months onwards.

show abstract

A Population Pharmacokinetic Model for Low-Dose Methotrexate and its Polyglutamated Metabolites in Red Blood Cells

Abstract: The developed model enabled acceptable description of the intracellular kinetics of MTX and MTXGlu(2-5) in RBCs. In the future it can form the basis of a full pharmacokinetic-pharmacodynamic model to assess the time-RBC concentration-effect relationship of low-dose MTX treatment in RA.

Cited by 20 publications

References 17 publications

Maternal exposure to methotrexate and birth defects: A population‐based study

Maternal exposure to methotrexate and birth defects: A population‐based study

Comparison of intracellular methotrexate kinetics in red blood cells with the kinetics in other cell types

Methotrexate Polyglutamates Exposure – Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate

Contact Info

Product

Resources

About