Considerations for Tacrolimus in Pregnant Patients with a History of Organ Transplantation

Introduction

Pregnancies in patients with a history of organ transplantation are considered high-risk, but current literature continues to endorse their safety and success.^1–7 With growth in the number of female transplant patients of child-bearing age comes an expanded responsibility for clinicians to adequately prepare and support these patients through future pregnancies; this includes ensuring the safety of the allograft, mother, fetus, and future neonate.^8,9 Pregnancy itself initiates widespread physiologic changes, potentially leading to significant challenges with immunosuppressant medications. Tacrolimus (Envarsus XR; Veloxis) is the most widely prescribed of these medications, and the clinical ambiguity in tacrolimus dosing during pregnancy should be explored.

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An Overview of Tacrolimus

Tacrolimus is a selective calcineurin inhibitor that exerts inhibitory effects on T-cell proliferation. The limited bioavailability of tacrolimus is due to factors including premature metabolism via bowel mucosal enzymes or first-pass hepatic metabolism, as well as P-glycoprotein (P-gp) activity that effluxes drug into the gut lumen for both systemic reabsorption and excretion. Tacrolimus extensively distributes throughout the body and is highly bound to erythrocytes (RBCs) in the blood before slowly equilibrating with plasma, where it is extensively bound to albumin and α-1-acid glycoprotein (AAG). Cytochrome P450 (CYP) isoforms, specifically 3A4 and 3A5, exclusively metabolize tacrolimus and excrete via fecal elimination, primarily mediated through the bile. Whole-blood trough levels are the standard monitoring for dose adjustments because of the significant intra- and inter-patient variability, as well as a narrow therapeutic index associated with tacrolimus. Unbound tacrolimus concentrations in the plasma are most representative of active drug in the body, but these are not attainable due to the complicated methodology required of plasma assays.^10–18

Physiologic Changes in Pregnancy Related to Tacrolimus

Physiologic changes during pregnancy believed to significantly impact tacrolimus disposition and kinetics include hemodilutional changes in binding-capacity, increased CYP3A isoform activity, and increased Pg-p expression. Increases in maternal blood volume by 40% to 50% lead to a hemodilutional decrease in blood RBC counts and plasma protein concentrations alongside increased albuminuria. Additional literature suggests that CYP3A isoform activity increases by 25% to 100% during gestation, regardless of potential polymorphisms that may be present in patients.

Finally, renal P-gp expression is known to increase during pregnancy (activity doubles), so researchers hypothesize that intestinal P-gp expression may change as well, which would be more relevant to tacrolimus. Considering the binding, metabolic, and absorptive properties of tacrolimus, these pregnancy-induced changes have significant effects.^19–22

Pharmacokinetic Alterations to Tacrolimus During Gestation

The only study characterizing pregnancy-related pharmacokinetic alterations to tacrolimus, by Zheng et al, specifically aimed to account for issues limiting previously available literature. This includes differences in non-specific methodologies and little attention towards changes in RBC counts and plasma protein concentrations.^21,22 The authors conducted pharmacokinetic studies among 10 pregnant transplant recipients on steady-state oral tacrolimus dosages at multiple points during early, mid-, and late pregnancy, then 3 months postpartum for reference. Not all subjects were able to participate in every pharmacokinetic study, so a mixed-effect linear model was employed to analyze and compare data across the groups.²²

The study presented differences between the blood and plasma pharmacokinetic characteristics during gestation with key observations: the tacrolimus fraction unbound doubled (averaging 112% higher than postpartum) despite whole-blood tacrolimus troughs decreasing as expected with drug binding changes. They observed numerical and statistically significant decreased clearance of unbound tacrolimus in the whole-blood and plasma, respectively.²² These findings endorse that without a significant change in unbound tacrolimus clearance, decrements in plasma protein binding and RBC counts should result in whole-blood trough decreases, without a decrease in unbound tacrolimus concentrations.

The investigators additionally evaluated unbound tacrolimus concentrations in patients who experienced dose titrations reactive to decreased whole-blood trough levels. Unbound tacrolimus concentrations almost doubled in these patients, further displaying a lack of change in clearance of unbound tacrolimus.²² Figure 1²² outlines key takeaways from Zheng et al.

Figure 1.²² Key takeaways from Zheng et al.

This study was the first of its kind but remains limited by the small patient sample size and inability to continuously follow every patient throughout their pregnancy and postpartum. The analysis relied on the use of extrapolated and averaged data from various time points in different patients to reach conclusions.²² Both factors are difficult to avoid with this unique patient population, yet the findings of this piece remain significant.

Evidence-Guided Approaches to Tacrolimus Dosing and Monitoring During Pregnancy

Despite many pregnancy-induced pharmacokinetic differences in tacrolimus, therapeutic approaches themselves may not require proactive modifications as per Zheng et al. Dose-normalized, whole-blood tacrolimus troughs decrease during pregnancy compared to pre- and postpartum levels and will continue to fall if dose adjustments are not made. This reflects changes in RBC and plasma protein binding, as well as increased clearance of oral tacrolimus in whole blood. Once again, unbound tacrolimus levels and clearance in the blood are proposed to remain unchanged, which is why some literature suggests that titrations by whole-blood target trough attainment may double unbound tacrolimus levels in the blood, increasing maternal and fetal risks for toxicity.^21,22

Clinicians must continue to take an individualized approach to treatment, factoring in patient-specific characteristics such as medical history, concomitant medications, and additional factors enhancing pharmacokinetic variability. The studies illustrating pregnancy-initiated pharmacokinetic alterations in tacrolimus excluded subjects with concerns in these specified areas, so the 2 proposed treatment approaches are suggested for patients of a similar profile.

Providers can first opt to maintain whole-blood tacrolimus concentrations in the recommended therapeutic range until signs and symptoms of toxicity develop. This commonly presents as acute renal failure, but tremors, electrolyte disturbances, and headaches may also indicate toxicity. Clinicians must closely monitor renal function while keeping respective changes during pregnancy in mind. Glomerular filtration and urine output expectedly increase during pregnancy, and serum creatinine should decrease. In the event of suspected toxicity, dosages should be reduced.²¹

Alternatively, stable prepartum tacrolimus doses can be maintained and only increased when drug trough concentrations fall by more than 50% or below the lower limit of the assay. Some may be hesitant of this methodology due to risks of insufficient immunosuppression, but Jain et al. employed this approach with no episodes of rejection occurring despite decreased whole-blood trough concentrations that were left unaddressed.^21–23

Regardless of the approach taken, it is important to consider that significant changes will occur in the clearance of whole-blood tacrolimus when RBC counts are below 3.5 million/μL and albumin concentrations fall below 3.0 g/dL to the point that the percent unbound may also change. Thus, clinical interpretation of these trough levels should include an evaluation of RBC and albumin laboratory results.²¹ Clinicians should individualize treatment and assess the risks vs benefits of either method through the lens of each patient and collaboration between an interdisciplinary team to determine the best treatment approach.

Conclusions

Tacrolimus dosing is challenging, regardless of the alterations observed during pregnancy. Tacrolimus appears safe and effective throughout gestation, but treatment approaches remain variable. Both proposed methods come with risks of either allograft rejection from insufficient immunosuppression or toxicity attributed to correction of whole-blood tacrolimus levels. Clinicians must further individualize tacrolimus therapy in pregnancy, considering patient risk factors, physiological changes, and pharmacokinetic variability.

References

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