Simulation of Imatinib Pharmacokinetics in pregnant women with chronic myeloid leukemia in the third trimester.

Purpose To simulate different dosing regimens of imatinib in third trimester pregnant women with CML that could meet plasma exposure targets for efficacy (C≥1000 ng/mL) without compromising on fetal safety risk. Methods An initial physiologically-based pharmacokinetic (PBPK) model from Loer et al. was verified with routine non-pregnant PK data from a single center and then scaled to pregnancy by implementing pregnancy physiological and enzymatic changes relevant to imatinib PK. The pregnancy model was evaluated by comparing predictions with PK data observed in pregnant women receiving imatinib 400 mg once daily (QD). Simulations explored different dosing regimens that would meet C≥1000 ng/mL without meaningfully higher AUC. Results Predictions for imatinib PK in the third trimester were well aligned with the observed data. Simulations indicate that 14.4% of third trimester pregnant women would achieve plasma C≥1000 ng/mL at 400 mg QD, compared to 51.7% of non-pregnant female comparators receiving the same dose. Conclusions While dividing 400 mg QD into 200 mg twice daily (BID) could modestly improve PK target attainment for third trimester pregnant women (28.5%), a dose of 300 mg BID could be needed to match C target attainment (54.2%) and AUCwith expectations for a non-pregnant population receiving 400 mg QD. However, given the potential for increased fetal exposure, this approach requires careful risk-benefit assessment, and further research is warranted to establish the safest and most effective strategy.