Nick Holford (1), Sarapee Hirankarn (2), Erin Dombrowsky (2), Dimple Patel (2), Jeffrey S. Barrett (2)
1. University of Auckland, New Zealand, 2. Childrens Hospital of Philadelphia, USA
Objectives: High dose methotrexate (MTX) is administered on repeated occasions known as ‘cycles’. Individualization of future doses based on a target area under the curve has been shown to improve survival. BOV determines the size of the unpredictable variation in PK between cycles. In 8 previous reports only the BOV for CL was estimated (in one BOV for V1 was also reported but without correlation with CL). BOV estimates were 12%, 16.6%, 13.3%, 8.2%, 13.3%, 13.2%, 17% and 0%. The objective was to evaluate the reliability of these estimates.
Methods: Using data from 56 children with cancer three pharmacokinetic models were selected for a simulation study. The three models are a model including BSV and BOV and their covariance (Full model), a model including BOV only on CL and without any covariance (BOVCL model as used in literature reports), and a model that estimated BOV for CL, V1, Q and V2 but without covariance between BSV or BOV parameters (BOV4 model). Details of the full PK model are described elsewhere (1). The full model MTX parameters including BSV and BOV and their correlations was used to simulate 100 data sets using the same covariates and sampling times as in the original data. A parametric bootstrap was performed with each of these data sets by fitting the Full model and the two simpler models (BOVCL and BOV4).
Results: Using the full model, the estimate of BOV for CL (56%) was accurately estimated (bias 2% larger variance) but seriously underestimated when BOV in the other PK parameters was ignored (BOVCL=91% smaller variance) or if covariance in BOV was ignored (BOV4=71% smaller variance). The empirical Bayes estimate of BOV for CL was 35% when each occasion was treated as if it came from a different subject. When the BOVCL model was applied to the original data set the BOV in CL was estimated to be 16%. The residual error parameter was estimated with negligible bias with the Full model but was overestimated with the simpler BOVCL (75% larger variance) and BOV4 (49% larger variance) models.
Conclusions: We conclude that literature estimates of BOV of CL are substantial underestimates of the true BOV. The BOV values overestimate the usefulness of estimating CL during one cycle of MTX in order to predict the dose needed to achieve a target exposure in subsequent cycles.
References:
[1] Hirankarn, S., Holford, N.H.G., Dombrowsky, E., Patel, D. & Barrett, J.S. Pharmacokinetics of high-dose methotrexate in children with cancer: A mechanism-based evaluation of clearance prediction. PAGE, (2012).
Reference: PAGE 21 (2012) Abstr 2474 [www.page-meeting.org/?abstract=2474]
Poster: Covariate/Variability Model Building