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Physiologically Based Pharmacokinetic Modeling for Multiple Oral Administration Labetalol in Pregnant Women

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Abstract

Background

Labetalol has an irreplaceable role in treating Hypertensive disorders of pregnancy (HDP), a common disease during pregnancy with a prevalence of 5.2–8.2%. However, there were big differences in dosage regimens between various guidelines.

Purpose

A physiologically-based pharmacokinetics (PBPK) model was established and validated to evaluate the existing oral dosage regimens, and to compare the difference in plasma concentration between pregnant and non-pregnant women.

Methods

First, non-pregnant woman models with specific plasma clearance or enzymatic metabolism (UGT1A1, UGT2B7, CYP2C19) were established and validated. For CYP2C19, slow, intermediate, and rapid metabolic phenotypes were considered. Then, a pregnant model with proper structure and parameters adjustment was established and validated against the multiple oral administration data.

Results

The predicted labetalol exposure captured the experimental data well. The following simulations with criteria lowering 15 mmHg blood pressure (corresponding to around 108 ng/ml plasma labetalol) found that the maximum daily dosage in the Chinese guideline may be insufficient for some severe HDP patients. Moreover, similar predicted steady-state trough plasma concentration was found between the maximum daily dosage in the American College of Obstetricians and Gynecologists (ACOG) guideline, 800 mg Q8h and a regimen of 200 mg Q6h. Simulations comparing non-pregnant and pregnant women found that the difference in labetalol exposure highly depended on the CYP2C19 metabolic phenotype.

Conclusions

In summary, this work initially established a PBPK model for multiple oral administration of labetalol for pregnant women. This PBPK model may lead to personalized labetalol medication in the future.

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Funding

Current research is financially supported by the Macau FDCT Research Grant (0108/2021/A) and the University of Macau Research Grant (MYRG2020-00113-ICMS).

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Author notes

  1. Yudi Song and Wei Wang contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macau, China

    Yudi Song, Wei Wang, Xinyang Liu & Defang Ouyang

  2. Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China

    Jingsi Chen, Dunjin Chen & Xiaoyi Wang

  3. Key Laboratories for Major Obstetric Diseases of Guangdong Province, Guangzhou, 510150, China

    Jingsi Chen, Dunjin Chen & Xiaoyi Wang

  4. Department of Pharmacy, The Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, People’s Republic of China

    Wei Li

  5. Department of Public Health and Medicinal Administration, Faculty of Health Sciences (FHS), University of Macau, Macau, China

    Defang Ouyang

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Correspondence to Defang Ouyang.

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Song, Y., Wang, W., Liu, X. et al. Physiologically Based Pharmacokinetic Modeling for Multiple Oral Administration Labetalol in Pregnant Women. Pharm Res 40, 1765–1775 (2023). https://doi.org/10.1007/s11095-023-03523-y

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