RESEARCH - Variable oral MTX cell concentrations in RA confound therapy

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Variable Oral Methotrexate Cell Concentrations in RA Confound Therapy

By Judith Groch, Contributing Writer, MedPage Today

Published: November 11, 2008

Reviewed by Zalman S. Agus, MD; Emeritus Professor

University of Pennsylvania School of Medicine. Earn CME/CE credit

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CHRISTCHURCH, New Zealand, Nov. 11 -- Wide variability in the way oral

methotrexate accumulates and is eliminated makes monitoring and dosing

decisions for rheumatoid arthritis patients difficult, a

pharmacokinetic study found. Action Points

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Explain to patients who ask that this study suggests that dosing of

oral methotrexate in rheumatoid arthritis patients is difficult

because of the wide variability in the way the drug accumulates in

cells and is eventually eliminated.

The time needed for the drug to reach steady-state concentrations in

red blood cells ranged from six to 140 weeks, K. Stamp, Ph.D., of

the University of Otago here, and colleagues reported in the November

issue of Arthritis Care & Research.

And it took from 4.5 to six weeks before methotrexate became

undetectable in red blood cells, they said.

Methotrexate is the first-line agent for the treatment of rheumatoid

arthritis and is suggested to be the " anchor " drug in rheumatoid

arthritis therapy, they said.

Joint damage occurs early in the course of the disease and once

present is largely irreversible. Thus, the primary goal of therapy is

to achieve rapid, effective disease control to prevent long-term

damage to joint structure and function.

But the methotrexate dose required for individual patients varies and

is largely unpredictable. Correlations have been both positive and

negative in various studies.

Thus knowledge of the pharmacokinetics of methotrexate and its

glutamate moieties (Glu 1-5) is required for the optimal timing of

blood sampling.

These include the time required to achieve adequate concentrations in

patients starting treatment as well as the time to elimination from

red blood cells, the researchers said.

The aims of this study were two-fold: first to determine the time to

steady state and the half-life of accumulation of red blood cell (RBC)

methotrexate Glu 1-5 in patients starting oral methotrexate.

Second, to determine the time it took for methotrexate glutamates to

become undetectable in red blood cells as well as the half-life of

elimination of RBC methotrexate in patients ceasing treatment with the

oral drug.

The study included 10 patients beginning treatment and 10 patients

stopping treatment after at least three months with low-dose oral

methotrexate stable for at least a month. Patients were recruited from

October 2005 to October 2007.

Blood samples were initially collected weekly, with gradual extension

to monthly collection over the study period. Patients were seen at

eight, 16, and 24 weeks.

RBC methotrexate Glu 1-5 concentrations were assayed by

high-performance liquid chromatography and analyzed with a first-order

exponential method.

The median times to reach steady state in red blood cells (90% of the

maximum concentration) for methotrexate glutamates 1 thru 5 were 6.2,

10.6, 41.2, 149, and 139.8 weeks, respectively.

The median half-life of accumulation for RBC methotrexate Glu1-5

ranged from 1.9 weeks to 45.2 weeks.

The median times for methotrexate glutamates 1 thru 5 to become

undetectable in red blood cells were 4.5, 5.5, 10, six, and four

weeks, respectively.

The median half-life of elimination for RBC methotrexate glutamates

ranged from 1.2 weeks to 4.3 weeks.

Drugs that accumulate and are eliminated by simple first-order

pharmacokinetic mechanisms usually accumulate and are eliminated at

approximately the same rate, the researchers said.

The data from this study, however, suggest that the median rate of

elimination is more rapid than the median rate of accumulation. This

may be related to the lifespan of the red blood cells.

The gradual loss of red blood cells from the circulation, combined

with the ongoing production of new cells, provides a " dilutional

effect " when methotrexate dosing ceases. The red blood cell lifespan

may also contribute to the delay in achieving steady state, although

this is less clear from the data presented here, they said.

There was significant inter-patient variability in the measured red

blood cell concentrations of the drug. This variation was not

explained by age.

Also, the study suggested a correlation between renal impairment and

an increased drug concentration, but further study in a larger

population is required to substantiate this finding, they said.

Study limitations included its small size and the fact that

participants stopping methotrexate should have been included only

after receiving a stable drug dose for six months.

In addition the concentration-time profiles for accumulation and

elimination of the drug suggest the need for a more complex analysis.

All told, they said, the variability in time till RBC methotrexate

concentrations reach steady state after initiation and dose adjustment

may limit the use of RBC methotrexate glutamates as a therapeutic

monitoring tool in clinical practice.

These data, they added, also suggest that after a dose change, more

than six months are required for RBC methotrexate polyglutamate to

reach a steady state.

Such delays in achieving a steady state suggest that more rapid oral

dose escalation or subcutaneous administration from the onset of

treatment should be considered.

This study was supported by the Health Research Council of New

Zealand, the New Zealand Pharmacy and Education Research Foundation,

Arthritis New Zealand, and the Canterbury Rheumatology and Immunology

Research Trust.

The authors made no statements on conflicts of interest.

Primary source: Arthritis Care & Research

Source reference:

Dalrymple JM, et al " Pharmacokinetics of Oral Methotrexate in Patients

With Rheumatoid Arthritis " Arthritis Care & Research 2008; 59:

3299-3308.

http://www.medpagetoday.com/Rheumatology/Arthritis/11737

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