Susan Cole1, Dr Mary Malamatari1, Dr Andrew Butler1, Yiyang Yeo2, Dr Essam Kerwash1
1Medicine and Healthcare Products Regulatory Agency, 2University College London
Introduction Tacrolimus, a potent immunosuppressant commonly used to prevent organ transplant rejection, presents challenges in dosing due to its narrow therapeutic index and significant high variability in drug exposure. Ensuring appropriate blood concentrations through dose adjustments is particularly critical for special populations, such as pregnant and lactating women, where clinical data on the safety and efficacy are limited [1,2]. The use of physiologically-based pharmacokinetic (PBPK) models to predict exposure in pregnant and breastfeeding women is of increasing interest and we have previously investigated the qualification of these models in pregnancy [3-6]. Objectives: •Optimise the previously developed PBPK model of tacrolimus to address previous limitations around clearance, distribution, and absorption. •Evaluate the predictive performance of the drug model for its ability to inform the drug exposure in non-pregnant women. •Evaluate the predictive performance of the drug model for its ability to inform the drug exposure in pregnant women. •Evaluate the predictive performance of the drug model for its ability to inform the drug exposure in breastfeeding women and utilise this to estimate dosage via the breastmilk in breastfed infants. •Highlight the implications for dosing in these populations. Methodology A previously developed PBPK model [5] was optimised using the SIMCYP software V23 by incorporating a more mechanistic (ADAM) absorption model describing the low solubility, and associated phenomena, for the molecule. Clearance pathways were also optimised using Km and Vmax parameters for CYP3A4 and CYP3A5 enzyme pathways to support extrapolation across populations. Refining tacrolimus distribution process was also found to be required to adequately capture the profile. The predictive performance of the model was evaluated by graphical comparison against a population prediction and consideration of PK parameters: AUC and Cmax, with the calculation of average fold errors. Results A fully mechanistic model of absorption was developed which includes solubility, dissolution and considers super-saturation and precipitation. This model shows an improved fit to absorption data from clinical studies. Clearance is adequately captured using the equations to describe metabolism. The extensive blood partitioning was included. A higher lipophilicity value for the molecule than that predicted by its measure LogD was required to adequately capture the distribution, this value is consistent with the calculated LogP value. The simulations showed an improved fit to clinical blood concentration data for total and free drug for both non-pregnant and pregnant populations. Exposure in blood versus dose was also adequately captured. AUC and Cmax values were 1.23- and 1.1-fold, respectively, of the clinical data collected in the second and third trimester of pregnancy [7]. Calculated free concentrations in late pregnancy were somewhat unpredicted by ~2 fold, 0.54 and 0.46 respectively. The modelling supports the clinical finding of a decrease in exposure to total in blood during pregnancy compared to post-partum (64% of exposure) but a reduced effect on free (89% of exposure) [8]. This suggests that dose adjustment may not be necessary in this population. Predicted milk plasma ratio using the Atkinson and Begg model [10] in the software was 2.0, which was lower than the observed value of 2.89. Simulations for tacrolimus in breast milk were thus made using the observed value. Comparison with clinical data following a 2 mg dose given to breastfeeding women showed a reasonable predicted Cmax and AUC values in milk of 1.43 and 0.82 fold of the observed data, respectively [9]. The predicted infant daily dose is 400ng/kg/day, much lower than the recommended dose in adults and children. The mechanistic absorption model improves the prediction of exposure in women and can be used with more confidence to support tacrolimus exposure in pregnant and breastfed infants. Some misprediction is still evident, however, which may be due to the exclusion of additional enzymes and transporters involved in the disposition and elimination. In addition, there is further work required on prediction of milk/plasma ratios. Conclusion PBPK modelling can be used to support the safer and more effective use of tacrolimus in these special populations however some gaps in the knowledge still exist.
1. Caritis S., Venkataramanan R. (2021) Obstetrical, fetal, and lactation pharmacology—a crisis that can no longer be ignored. American Journal of Obstetrics and Gynaecology. 10- 20. 2. Bahmanyar E.R., Out H.J., Van Duin M. (2021) Women and babies are dying from inertia: a collaborative framework for obstetrical drug development is urgently needed. American Journal of obstetrics and Gynaecology, 44- 50 3. Coppola P., Kerwash E., Cole S. (2021). Physiologically Based Pharmacokinetics Model in Pregnancy: A Regulatory Perspective on Model Evaluation. Front Pediatr 23:9: 687978. doi: 10.3389/fped.2021.687978. 4. Coppola P., Kerwash E., Cole S. (2023) Use of Physiologically Based Pharmacokinetic Modeling for Hepatically Cleared Drugs in Pregnancy: Regulatory Perspective. Journal of Clinical Pharmacology. https://doi.org/10.1002/jcph.2266 5. Coppola P., Kerwash E., Cole S. (2023). The Use of Pregnancy Physiologically Based Pharmacokinetic Modeling for Renally Cleared Drugs. Journal of Clinical Pharmacology. https://doi.org/10.1002/jcph.2110 6. Cole S., Malamatari M., Butler A., Arshad M., Kerwash E. (2024) Investigation of a fully mechanistic physiologically based pharmacokinetics model of absorption to support predictions of milk concentrations in breastfeeding women and the exposure of infants: A case study for albendazole. CPT/PSP. Volume13, Issue11. 1990-200 https://doi.org/10.1002/psp4.13260 7. Zheng, S., Easterling, T.R., Umans, J.G., Miodovnik, M., Calamia, J.C., Thummel, K.E., Shen, D.D., Davis, C.L., Hebert, M.F. (2012) Pharmacokinetics of tacrolimus during pregnancy. Ther. Drug Monit. 34, 660–670. 8. Coppola P, Butler A, Cole S , Kerwash E. (2023) Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy. Pharmaceutics. 15(10):2455. doi: 10.3390/pharmaceutics15102455. 9. Zheng, S.; Easterling, T.R.; Hays, K.; Umans, J.G.; Miodovnik, M.; Clark, S. (2013) Tacrolimus placental transfer at delivery and neonatal exposure through breast milk. Br. J. Clin. Pharmacol. 76, 988–996. 10. Begg E, Atkinson H.C. (1993) Modelling of the passage of drugs into milk. Pharmacology & Therapeutics Volume 59, Issue 3, Pages 301-310 https://doi.org/10.1016/0163-7258(93)90072-L
Reference: PAGE 33 (2025) Abstr 11380 [www.page-meeting.org/?abstract=11380]
Poster: Drug/Disease Modelling - Absorption & PBPK