Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Apr;42(4):160-177.
doi: 10.1002/bdd.2272. Epub 2021 Apr 26.

When special populations intersect with drug-drug interactions: Application of physiologically-based pharmacokinetic modeling in pregnant populations

Caroline Sychterz  1 , Aleksandra Galetin  2 , Kunal S Taskar  3
Affiliations
Review

When special populations intersect with drug-drug interactions: Application of physiologically-based pharmacokinetic modeling in pregnant populations

Caroline Sychterz et al. Biopharm Drug Dispos. 2021 Apr.

Abstract

Pregnancy results in significant physiological changes that vary across trimesters and into the postpartum period, and may result in altered disposition of endogenous substances and drug pharmacokinetics. Pregnancy represents a unique special population where physiologically-based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms without subjecting pregnant women or their fetuses to extensive clinical studies. A critical review of applications of pregnancy PBPK models (pPBPK) was conducted to understand its current status for prediction of drug exposure in pregnant populations and to identify areas of further expansion. Evaluation of existing pPBPK modeling efforts highlighted improved understanding of cytochrome P450 (CYP)-mediated changes during pregnancy and identified knowledge gaps for non-CYP enzymes and the physiological changes of the postpartum period. Examples of the application of pPBPK beyond simple dose regimen recommendations are limited, particularly for prediction of drug-drug interactions (DDI) or differences between genotypes for polymorphic drug metabolizing enzymes. A raltegravir pPBPK model implementing UGT1A1 induction during the second and third trimesters of pregnancy was developed in the current work and verified against clinical data. Subsequently, the model was used to explore UGT1A1-related DDI risk with atazanavir and rifampicin along with the effect of enzyme genotype on raltegravir apparent clearance. Simulations of pregnancy-related induction of UGT1A1 either exacerbated UGT1A1 induction by rifampicin or negated atazanavir UGT1A1 inhibition. This example illustrated the advantages of pPBPK modeling for mechanistic evaluation of complex interplays of pregnancy- and drug-related effects in support of model-informed approaches in drug development.

Keywords: PBPK; UGT1A1; drug-drug interaction; pregnancy; raltegravir.

PubMed Disclaimer

References

REFERENCES

    1. Abduljalil, K., Furness, P., Johnson, T. N., Rostami-Hodjegan, A., & Soltani, H. (2012). Anatomical, physiological and metabolic changes with gestational age during normal pregnancy. Clinical Pharmacokinetics, 51(6), 365-396. https://doi.org/10.2165/11597440-000000000-00000
    1. Almurjan, A., Macfarlane, H., & Badhan, R. K. S. (2020). Precision dosing-based optimisation of paroxetine during pregnancy for poor and ultrarapid CYP2D6 metabolisers: A virtual clinical trial pharmacokinetics study. The Journal of Pharmacy and Pharmacology, 72(8), 1049-1060. https://doi.org/10.1111/jphp.13281
    1. Alqahtani, S., & Kaddoumi, A. (2015). Development of physiologically based pharmacokinetic/pharmacodynamic model for indomethacin disposition in pregnancy. PLoS One, 10(10), e0139762. https://doi.org/10.1371/journal.pone.0139762
    1. Anderson, G. D. (2005). Pregnancy-induced changes in pharmacokinetics. Clinical Pharmacokinetics, 44(10), 989-1008. https://doi.org/10.2165/00003088-200544100-00001
    1. Annas, G. J., & Elias, S. (1999). Thalidomide and the Titanic: Reconstructing the technology tragedies of the twentieth century. American Journal of Public Health, 89(1), 98-101. https://doi.org/10.2105/AJPH.89.1.98