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

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.

Assessment of ibrutinib scheduling on leukocyte, lymph node size and blood pressure dynamics in chronic lymphocytic leukemia through pharmacokinetic‐pharmacodynamic models

“…This could be because it used the daily AUC 0-24 to assess the exposure-response relationship, but if the full plasma concentration-time profile was used instead, we might have seen a slower turnover rate. 30 Moreover, for a dose of 420 mg day −1 , the median simulated Btk occupancy was 92.7% (80% CI, 56.8%-99%) at steady-state, which is close to the previously reported median target occupancy for ibrutinib (range 96%-99%) for dose levels 420 and 840 mg day −1 . 7,32 Here, ibrutinib was assumed to be able to completely inhibit both CLL cell proliferation and homing given the previously reported effective suppression of these two processes by ibrutinib.…”

“…The developed population PK‐PD models successfully quantified the relationships among ibrutinib exposure, represented by daily AUC 0‐24 , and leukocyte count along with SPD, sBP, and dBP dynamics, while considering the mechanism of action of ibrutinib. was chosen as the PK driver because it has previously been proposed as a surrogate of plasma exposure and a metric for therapeutic drug monitoring of ibrutinib owing to its short half‐life (4–13 h) 29,30 . The semi‐mechanistic PK‐SPD‐leukocyte model identified four subpopulations of CLL cells that were linked as a continuum reflecting the complexity of CLL biology and dynamics.…”

“…However, the model overestimated the turnover rate. This could be because it used the daily AUC 0‐24 to assess the exposure‐response relationship, but if the full plasma concentration‐time profile was used instead, we might have seen a slower turnover rate 30 . Moreover, for a dose of 420 mg day −1 , the median simulated Btk occupancy was 92.7% (80% CI, 56.8%–99%) at steady‐state, which is close to the previously reported median target occupancy for ibrutinib (range 96%–99%) for dose levels 420 and 840 mg day −1 7,32 …”

Limited efficacy for ibrutinib and venetoclax in T-prolymphocytic leukemia: results from a phase 2 international study

“…In this study, steady-state pre-dose plasma concentrations of both ibrutinib and venetoclax, available in 6 patients who received full dosing of both drugs, were similar to those seen in monotherapy trials, 9 and the combination did not increase exposures to either agent as previously seen for venetoclax. 10 The safety profile was consistent with that of previous venetoclax studies in R/R T-PLL, 4 and also for this combination in other disease settings.…”

Easy and reliable maximum a posteriori Bayesian estimation of pharmacokinetic parameters with the open‐source R package mapbayr

“…Data were generated in accordance with the drug administration schedules and sampling strategies used in the context of TDM with n = 1000 individuals. In addition, a variable corresponding to the routinely monitored PK outcome was computed with both NONMEM and mapbayr: last dose of a 3‐day schedule to reach a total AUC of 24 mg·min/ml for carboplatin 32 ; AUC at steady state between two doses (AUC τ,SS ) for ibrutinib 33,34 ; trough concentration at steady state for cabozantinib, 35 pazopanib, 36 and voriconazole 37 ; sum of parent drug and metabolite trough concentration for sunitinib and N‐desethyl‐sunitinib 38 ; and time to reach a concentration below 0.2 μmol/L for methotrexate 39 . A detailed description of these models and the related data are provided in Table 3.…”