Physiologically-based pharmacokinetic modeling to predict the exposure and provide dosage regimens of tacrolimus in pregnant women with infection disease

Tacrolimus is extensively used for the prevention of graft rejection following solid organ transplantation in pregnant women. However, knowledge gaps in the dosage of tacrolimus for pregnant patients with different CYP3A5 genotypes and infection conditions have been identified. This study aimed to develop a pregnant physiologically based pharmacokinetic (PBPK) model to characterize the maternal and fetal pharmacokinetics of tacrolimus during pregnancy and explore and provide dosage adjustments. We developed PBPK models for nonpregnant patients and validated them via data from previous clinical studies using PK-Sim and Mobi software. To extrapolate to pregnancy, we considered anatomical, physiological, and metabolic alterations and simulated tacrolimus by adding six groups of IL-6 concentrations (0, 5, 25, 50, 500, and 5000 pg/mL). Models were verified by assessing goodness-of-fit plots and ratios of predicted-to-observed pharmacokinetic parameters. The developed PBPK models adequately describe the available clinical data; the fold errors of the predicted and observed values of the area under the curve and peak plasma concentration were between 0.59 and 1.64, and the average folding error and the absolute average folding error values for all concentration-time data points were 1.15 and 1.36, respectively. The simulation results indicated that the area under the steady-state concentration‒time curve and trough concentrations decreased from the first to the third trimester of pregnancy. The trough concentrations were not within the therapeutic range (4-11 ng/mL) in pregnant patients with the CYP3A5 genotype for most of the infection conditions and exceeded its effective concentration in all the CYP3A5 nonexpressers. Based on the model-derived dosing regimen, the tacrolimus trough concentration in pregnant patients with different CYP3A5 genotypes could fall into the therapeutic window, which provided a clinical practice reference for dosage adjustments during pregnancy.