Last updated 17 June 2024
Methotrexate
is the pioneering example of the use of target concentration intervention (TCI)
to substantially improve clinical outcome. In 1998 Evans and his team of
pharmacists and medical doctors revealed the results of a clinical trial of TCI
showing the 5 year survival of children with acute lymphoblastic leukaemia (ALL) was extended from 66% to 76% simply by
individualizing the dose to achieve a target exposure of methotrexate (Evans, Relling
et al. 1998). This improvement in outcome is
arguably bigger than any new medicine tested since then for ALL.
The
acceptable range for methotrexate used by Evans et al. was an AUC of 580 to 950
micromol/L*h. AUC was effectively integrated from 0
to infinity because doses were administered weekly. The target AUC was 800 micromol/L*h. Methotrexate clearance was estimated using
concentrations measured at 1 and 6 h after the dose with a 2 compartment
Bayesian model. The individual clearance was then used to predict future doses.
The individualized dosing approach was not strictly TCI because it had a TDM
element. If the estimated AUC was within the acceptable range
then the dose was not changed. An individualized dose was only used if the
estimated AUC was outside the acceptable range.
The
pharmacokinetic model was developed in a group of children administered high
dose methotrexate for the treatment of a variety of cancers (Hirankarn,
Holford et al. 2012). Theory based allometry was used to
develop a two compartment model with first-order
elimination after intravenous infusions of methotrexate of known duration.
Total body weight was the best predictor of clearance and central and
peripheral volumes. Intercompartmental clearance was more closely associated
with fat free mass. Maturation of clearance was not identifiable because the majority of children were older than 2 years. Although
methotrexate is known to be renally eliminated the use of creatinine clearance
to predict renal function accounted for only 20% of total clearance and
explained 3% of the population parameter variability of clearance. This is
explicable by the narrow distribution of renal function in this group of
children. Both between subject and between occasion variability were important
to describe unpredictable differences in PK. In addition, it was essential to
account for the covariance of the random effects in order to accurately
estimate between occasion variability of clearance (Holford,
Hirankarn et al. 2012).
Evans, W. E., M. V. Relling, J. H. Rodman, W. R. Crom, J. M. Boyett and
C. H. Pui (1998). "Conventional compared with individualized chemotherapy
for childhood acute lymphoblastic leukemia." N Engl J Med 338(8): 499-505.
Hirankarn,
S., N. H. G. Holford, E. Dombrowsky, D. Patel and J. S. Barrett (2012).
"Pharmacokinetics of high-dose methotrexate in children with cancer: A
mechanism-based evaluation of clearance prediction." PAGANZ https://www.paganz.org/abstracts/pharmacokinetics-of-high-dose-methotrexate-in-children-with-cancer-a-mechanism-based-evaluation-of-clearance-prediction/.
Holford, N.
H. G., S. Hirankarn, E. Dombrowsky, D. Patel and J. S. Barrett (2012).
"What is the between cycle variability in methotrexate clearance?" PAGE
21 (Abstr 2474): [www.page-meeting.org/?abstract=2474].
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Holford 2012-2024