Pharmacokinetics of Tacrolimus During Pregnancy

Abstract

Background Information on the pharmacokinetics of tacrolimus during pregnancy is limited to case reports despite the increasing number of pregnant women being prescribed tacrolimus for immunosuppression. Methods Blood, plasma and urine samples were collected over one steady-state dosing interval from women treated with oral tacrolimus during early to late pregnancy (n = 10) and postpartum (n = 5). Total and unbound tacrolimus as well as metabolite concentrations in blood and plasma were assayed by a validated LC/MS/MS method. A mixed effect linear model was used for comparison across gestational age and using postpartum as the reference group. Results The mean oral clearance (CL/F) based on whole blood tacrolimus concentration was 39% higher during mid- and late-pregnancy compared to postpartum (47.4 ± 12.6 vs. 34.2 ± 14.8 L/h, P < 0.03). Tacrolimus free fraction increased by 91% in plasma (fP) and by 100% in blood (fB) during pregnancy (P = 0.0007 and 0.002, respectively). Increased fP was inversely associated with serum albumin concentration (r = − 0.7, P = 0.003), which decreased by 27% during pregnancy. Pregnancy related changes in fP and fB contributed significantly to the observed gestational increase in tacrolimus whole blood CL/F (r2 = 0.36 and 0.47 respectively, P < 0.01). In addition, tacrolimus whole blood CL/F was inversely correlated with both hematocrit and red blood cell counts, suggesting that binding of tacrolimus to erythrocytes restricts its availability for metabolism. Treating physicians increased tacrolimus dosages in study participants during pregnancy by an average of 45% in order to maintain tacrolimus whole blood trough concentrations in the therapeutic range. This led to striking increases in unbound tacrolimus trough concentrations and unbound AUC, by 112% and 173%, respectively during pregnancy (P = 0.02 and 0.03, respectively). Conclusions Tacrolimus pharmacokinetics are altered during pregnancy. Dose adjustment to maintain whole blood tacrolimus concentration in the usual therapeutic range during pregnancy increases circulating free drug concentrations, which may impact clinical outcomes.

Pregnancy After Kidney Transplantation: Outcomes, Tacrolimus Doses, and Trough Levels

“…Tacrolimus is a highly protein-bound drug and is bound to both albumin and alpha 1 acid glycoprotein (AAG) in plasma. During pregnancy, the decrease in RBC, albumin, and AAG levels will alter tacrolimus binding [11,12]. Whole blood tacrolimus level also may decrease because of decreased bounded fraction, while unbounded fraction is stable [10].…”

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

“…Another recently described example of altered drug pharmacokinetics during pregnancy involves the immunosuppressant drug tacrolimus (Zheng et al, 2012). In this case, the mean oral clearance of tacrolimus was found to be 39% higher during mid-and late pregnancy, compared with postpartum, which could result in suboptimal blood levels without dose adjustment.…”

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

“…103 During pregnancy, the pharmacokinetics properties of CNIs may vary from the nonpregnant state, so drug levels should be closely monitored during pregnancy, with dose adjustment when necessary. 46 Similar considerations may apply during intercurrent illness. 108,109 In renal transplantation, IPV in immunosuppressive drug exposure is now recognized as a predictor of poor clinical outcome.…”

“…45 Sexual health is also important, and patients should be advised about the teratogenicity of some immunosuppressive agents and the need to consider the impact of pregnancy both on the risk of rejection and the pharmacokinetic changes of drug metabolism. [46][47][48] We have also not made recommendations on the frequency of follow-up after the first year because this will depend on many factors, including the clinical status of the patient, comorbidities, and graft function. If the patient is stable and with good graft function and over 1 year posttransplant, then most centers recommend assessing the patient every 3 months.…”