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. 2021 Feb 18;14(2):162.
doi: 10.3390/ph14020162.

Limited Sampling Strategy for Determination of Ibrutinib Plasma Exposure: Joint Analyses with Metabolite Data

Félicien Le Louedec  1   2   3 , Fanny Gallais  2   3 , Fabienne Thomas  1   2   3 , Mélanie White-Koning  2   3 , Ben Allal  1   2 , Caroline Protin  4 , Loïc Ysebaert  2   3   4 , Étienne Chatelut  1   2   3 , Florent Puisset  2   3   5
Affiliations

Limited Sampling Strategy for Determination of Ibrutinib Plasma Exposure: Joint Analyses with Metabolite Data

Félicien Le Louedec et al. Pharmaceuticals (Basel). .

Abstract

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUCIBRU) instead of trough concentration (Cmin,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUCIBRU associated with Bayesian estimation. The actual AUCIBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUCIBRU were derived considering combinations of one to four sampling times. The T0-1-2-4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUCIBRU and Cmin,ss was poor (r2 = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUCIBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.

Keywords: Bayesian analysis; ibrutinib; metabolite; pharmacokinetics; therapeutic drug monitoring.

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Conflict of interest statement

L.Y. is member of the advisory boards of Abbvie, AstraZeneca, Janssen and Roche. F.L.L., F.G., F.T., M.W.-K., B.A., C.P., É.C. and F.P. declare no conflict of interest.

Figures

Figure 1
Figure 1
Ibrutinib actual area under the curve (AUC) vs. observed steady-state trough concentration. Solid line: linear regression (n = 85 patients).
Figure 2
Figure 2
Comparison of the estimation of ibrutinib AUC using ibrutinib concentrations only (left) or both ibrutinib and dihydrodiol-ibrutinib (right), as a function of the number of points used for estimation (seven values with a bias > 10% are out of bounds). MPE: mean percentage error; RMSE: Root-Mean-Square Error.
Figure 3
Figure 3
Comparison of the performance of several sampling strategies to predict ibrutinib AUC in the development (top) and validation (bottom) dataset. Crosses (+) are out of bound values censored to the maximal bound of the y-axis (i.e., +/−60%).
Figure 4
Figure 4
Distribution of the AUCANTI-BTK / free AUCIBRU ratio (dashed lines: +/−25% interval around the median).
See this image and copyright information in PMC

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