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Clinical Trial
. 2002 Nov;54(5):463-71.
doi: 10.1046/j.1365-2125.2002.01684.x.

Development and validation of limited sampling strategies for prediction of the systemic exposure to the novel anticancer agent E7070 (N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide)

Charlotte van Kesteren  1 , R A A Mathôt, E Raymond, J P Armand, P Fumoleau, C Punt, M Ravic, J Wanders, J H Beijnen, J H M Schellens; Early Clinical Studies Group of the EORTC and NDDO Oncology
Affiliations
Clinical Trial

Development and validation of limited sampling strategies for prediction of the systemic exposure to the novel anticancer agent E7070 (N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide)

Charlotte van Kesteren et al. Br J Clin Pharmacol. 2002 Nov.

Abstract

Aims: E7070 is a novel, sulphonamide anticancer agent currently under clinical development for the treatment of solid tumours. The aim of this study was to develop and validate limited sampling strategies for the prediction of E7070 exposure in two different treatment schedules for phase II studies using the Bayesian estimation approach.

Methods: Data from two phase I dose finding studies were used in which E7070 was administered either as a single 1 h infusion or as a daily 1 h infusion for 5 days. Plasma concentration-time data from 75 patients were randomly divided into an index data set, used for the development of the strategies, and a validation data set. Population pharmacokinetic parameters were derived on the basis of the index data set. The D-optimality algorithm was used for the selection of optimal time points for both treatment schedules. The developed strategies were compared by assessment of their predictive performance of exposure, expressed as AUC (area under the plasma concentration vs time curve), in the validation data set.

Results: The developed population pharmacokinetic model comprised three compartments, with saturable distribution to one peripheral compartment and both linear and saturable elimination from the central compartment. For the 1 h infusion, a four sample strategy was selected which resulted in unbiased and accurate predictions of AUC (bias 0.74%, precision 13%). A five sample strategy was generated for the daily times five schedule yielding unbiased (bias 3.2%) and precise (12% precision) predictions of AUC.

Conclusions: Optimal sampling strategies were developed and validated for estimation of E7070 exposure in two different treatment schedules. Both schedules enabled accurate and unbiased predictions of AUC.

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Figures

Figure 1
Figure 1
Typical plasma concentration time profiles in patients treated with E7070 in a single1 h infusion and a 1 h infusion daily for 5 days at 700 mg m−2 (♦) and 160 mg m−2 day−1 (▪), respectively.
Figure 2
Figure 2
Population pharmacokinetic model for E7070.
Figure 3
Figure 3
Predicted values of AUC using the optimal sampling strategies vs reference values of AUC for after a single 1 h infusion schedule (panel a) and after a 1 h infusion daily for 5 days (panel b). The solid line represents the line of identity.
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References

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