Abstract
Aims:
Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole-blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics. The aim of this study was to describe tacrolimus pharmacokinetics throughout pregnancy and explain the changes by investigating covariates in a population pharmacokinetic model.
Methods:
Data of pregnant women using a twice-daily tacrolimus formulation following kidney transplantation were retrospectively collected from 6 months before conception, throughout gestation and up to 6 months postpartum. Pharmacokinetic analysis was performed using nonlinear mixed effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. The final model was evaluated using goodness-of-fit plots, visual predictive checks and a bootstrap analysis.
Results:
A total of 260 whole-blood tacrolimus predose concentrations from 14 pregnant kidney transplant recipients were included. Clearance increased during pregnancy from 34.5 to 41.7 L/h, by 15, 19 and 21% in the first, second and third trimester, respectively, compared to prior to pregnancy. This indicates a required increase in the tacrolimus dose by the same percentage to maintain the prepregnancy concentration. Haematocrit and gestational age were negatively correlated with tacrolimus clearance (P ≤ 0.01), explaining 18% of interindividual and 85% of interoccasion variability in oral clearance.
Conclusions:
Tacrolimus clearance increases during pregnancy, resulting in decreased exposure to tacrolimus, which is explained by gestational age and haematocrit. To maintain prepregnancy target whole-blood tacrolimus predose concentrations during pregnancy, increasing the dose is required.
| Original language | English |
|---|---|
| Pages (from-to) | 176-188 |
| Number of pages | 13 |
| Journal | British Journal of Clinical Pharmacology |
| Volume | 90 |
| Issue number | 1 |
| Early online date | 18 Aug 2023 |
| DOIs | |
| Publication status | Published - Jan 2024 |
Bibliographical note
Publisher Copyright:© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Funding information:
This research did not receive any specific grant
from funding agencies in the public,
commercial, or not-for-profit sectors