Physiologically-Based Pharmacokinetic Modeling in Pregnancy, Lactation, and in Neonates: Achievements, Challenges and Future Directions

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 17616

Special Issue Editors


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Guest Editor
Pharmacometrics/Modeling and Simulation, Research and Development, Pharmaceuticals, Bayer AG, 51373 Leverkusen, Germany
Interests: PBPK; pregnancy; lactation; maternal–fetal; neonates

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Guest Editor
1. Department of Development and Regeneration, KU Leuven, Leuven, Belgium
2. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
3. Department of Clinical Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands
Interests: perinatal pharmacology; neonatal clinical pharmacology; PBPK in special populations; newborn; infant; lactation
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
1. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA
2. Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Interests: obstetric pharmacology; pediatric pharmacology; PBPK; pharmacometrics; maternal-fetal; special populations; translational informatics

Special Issue Information

Dear Colleagues,

Obstetric patients represent a special population in drug therapy. During pregnancy and in the postpartum period, various anatomical and physiological changes give rise to altered drug pharmacokinetics in both the mother and fetus or neonate, yet pregnant and lactating women and their infants are underrepresented in clinical trials, leading to a dearth of in-depth information on the drug pharmacokinetics in these populations. Consequently, dosing regimens are often simply extrapolated from non-pregnant to pregnant women or allometrically scaled from adults to neonates, entailing in both cases considerable risks of sub-therapeutic or toxic drug effects for the mother, fetus, and/or neonate.

In recent years, tremendous efforts have been directed towards investigating drug pharmacokinetics in obstetric populations or infants through various approaches, including physiologically based pharmacokinetic (PBPK) models. This reflects an increased awareness of the necessity to better understand clinical pharmacology and ultimately improve pharmacotherapy in this vulnerable patient population.

The goal of this Special Issue is to showcase strong examples of a successful application of PBPK modeling approaches in the obstetric population as well as to present the status quo and an outlook on future perspectives of this technology in the field of obstetric pharmacology.

We invite articles on all aspects of PBPK modeling in pregnant, lactating, or neonatal populations for this Special Issue.

Dr. André Dallmann
Prof. Dr. Karel Allegaert
Dr. Sara Quinney
Guest Editors

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Keywords

  • PBPK modeling
  • modeling and simulation
  • pharmacokinetics
  • pregnancy
  • maternal–fetal
  • lactation
  • neonates
  • infants

Published Papers (13 papers)

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Editorial

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7 pages, 405 KiB  
Editorial
Physiologically Based Pharmacokinetic Modeling in Pregnancy, during Lactation and in Neonates: Achievements, Challenges and Future Directions
by Karel Allegaert, Sara K. Quinney and André Dallmann
Pharmaceutics 2024, 16(4), 500; https://doi.org/10.3390/pharmaceutics16040500 - 05 Apr 2024
Viewed by 373
Abstract
Obstetric subjects represent a special population in pharmacology [...] Full article
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Research

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20 pages, 4477 KiB  
Article
An Application of a Physiologically Based Pharmacokinetic Approach to Predict Ceftazidime Pharmacokinetics in a Pregnant Population
by Khaled Abduljalil, Iain Gardner and Masoud Jamei
Pharmaceutics 2024, 16(4), 474; https://doi.org/10.3390/pharmaceutics16040474 - 28 Mar 2024
Viewed by 447
Abstract
Physiological changes during pregnancy can alter maternal and fetal drug exposure. The objective of this work was to predict maternal and umbilical ceftazidime pharmacokinetics during pregnancy. Ceftazidime transplacental permeability was predicted from its physicochemical properties and incorporated into the model. Predicted concentrations and [...] Read more.
Physiological changes during pregnancy can alter maternal and fetal drug exposure. The objective of this work was to predict maternal and umbilical ceftazidime pharmacokinetics during pregnancy. Ceftazidime transplacental permeability was predicted from its physicochemical properties and incorporated into the model. Predicted concentrations and parameters from the PBPK model were compared to the observed data. PBPK predicted ceftazidime concentrations in non-pregnant and pregnant subjects of different gestational weeks were within 2-fold of the observations, and the observed concentrations fell within the 5th–95th prediction interval from the PBPK simulations. The calculated transplacental clearance (0.00137 L/h/mL of placenta volume) predicted an average umbilical cord-to-maternal plasma ratio of 0.7 after the first dose, increasing to about 1.0 at a steady state, which also agrees well with clinical observations. The developed maternal PBPK model adequately predicted the observed exposure and kinetics of ceftazidime in the pregnant population. Using a verified population-based PBPK model provides valuable insights into the disposition of drug concentrations in special individuals that are otherwise difficult to study and, in addition, offers the possibility of supplementing sparse samples obtained in vulnerable populations with additional knowledge, informing the dosing adjustment and study design, and improving the efficacy and safety of drugs in target populations. Full article
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16 pages, 4819 KiB  
Article
Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling
by Matthijs W. van Hoogdalem, Ryota Tanaka, Khaled Abduljalil, Trevor N. Johnson, Scott L. Wexelblatt, Henry T. Akinbi, Alexander A. Vinks and Tomoyuki Mizuno
Pharmaceutics 2024, 16(3), 375; https://doi.org/10.3390/pharmaceutics16030375 - 08 Mar 2024
Viewed by 735
Abstract
Buprenorphine readily crosses the placenta, and with greater prenatal exposure, neonatal opioid withdrawal syndrome (NOWS) likely grows more severe. Current dosing strategies can be further improved by tailoring doses to expected NOWS severity. To allow the conceptualization of fetal buprenorphine exposure, a maternal–fetal [...] Read more.
Buprenorphine readily crosses the placenta, and with greater prenatal exposure, neonatal opioid withdrawal syndrome (NOWS) likely grows more severe. Current dosing strategies can be further improved by tailoring doses to expected NOWS severity. To allow the conceptualization of fetal buprenorphine exposure, a maternal–fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0). Buprenorphine transplacental passage was predicted from its physicochemical properties. The maternal–fetal PBPK model integrated reduced transmucosal absorption driven by lower salivary pH and induced metabolism observed during pregnancy. Maternal pharmacokinetics was adequately predicted in the second trimester, third trimester, and postpartum period, with the simulated area under the curve from 0 to 12 h, apparent clearance, and peak concentration falling within the 1.25-fold prediction error range. Following post hoc adjustment of the likely degree of individual maternal sublingual absorption, umbilical cord blood concentrations at delivery (n = 21) were adequately predicted, with a geometric mean ratio between predicted and observed fetal concentrations of 1.15 and with 95.2% falling within the 2-fold prediction error range. The maternal–fetal PBPK model developed in this study can be used to forecast fetal buprenorphine exposure and would be valuable to investigate its correlation to NOWS severity. Full article
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16 pages, 2521 KiB  
Article
PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses
by Maxime Le Merdy, Ke Xu Szeto, Jeremy Perrier, Michael B. Bolger and Viera Lukacova
Pharmaceutics 2024, 16(1), 96; https://doi.org/10.3390/pharmaceutics16010096 - 10 Jan 2024
Viewed by 1198
Abstract
This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds’ pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma protein binding, and other [...] Read more.
This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds’ pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma protein binding, and other physiological factors affecting the drugs’ PK in both the pregnant woman and the fetus. The PBPKPlus™ module in GastroPlus® was used to model the PK of metoprolol, midazolam, and metronidazole for both non-pregnant and pregnant groups. For each of the three compounds, the model was first developed and validated against PK data in healthy non-pregnant volunteers and then applied to predict the PK in the pregnant groups. The model accurately described the PK in both the non-pregnant and pregnant groups and explained well the differences in the plasma concentration due to pregnancy. When available, the fetal plasma concentration, placenta, and fetal tissue concentrations were also predicted reasonably well at different stages of pregnancy. The work described the use of a PBPK approach for drug development and demonstrates the ability to predict differences in PK in pregnant subjects and fetal exposure for metabolically cleared compounds. Full article
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17 pages, 5212 KiB  
Article
Utility of Physiologically Based Pharmacokinetic Modeling to Investigate the Impact of Physiological Changes of Pregnancy and Cancer on Oncology Drug Pharmacokinetics
by Xinxin Yang, Manuela Grimstein, Michelle Pressly, Elimika Pfuma Fletcher, Stacy Shord and Ruby Leong
Pharmaceutics 2023, 15(12), 2727; https://doi.org/10.3390/pharmaceutics15122727 - 04 Dec 2023
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Abstract
Background: The treatment of cancer during pregnancy remains challenging with knowledge gaps in drug dosage, safety, and efficacy due to the under-representation of this population in clinical trials. Our aim was to investigate physiological changes reported in both pregnancy and cancer populations into [...] Read more.
Background: The treatment of cancer during pregnancy remains challenging with knowledge gaps in drug dosage, safety, and efficacy due to the under-representation of this population in clinical trials. Our aim was to investigate physiological changes reported in both pregnancy and cancer populations into a PBPK modeling framework that allows for a more accurate estimation of PK changes in pregnant patients with cancer. Methods: Paclitaxel and docetaxel were selected to validate a population model using clinical data from pregnant patients with cancer. The validated population model was subsequently used to predict the PK of acalabrutinib in pregnant patients with cancer. Results: The Simcyp pregnancy population model reasonably predicted the PK of docetaxel in pregnant patients with cancer, while a modified model that included a 2.5-fold increase in CYP2C8 abundance, consistent with the increased expression during pregnancy, was needed to reasonably predict the PK of paclitaxel in pregnant patients with cancer. Changes in protein binding levels of patients with cancer had a minimal impact on the predicted clearance of paclitaxel and docetaxel. PBPK modeling predicted approximately 60% lower AUC and Cmax for acalabrutinib in pregnant versus non-pregnant patients with cancer. Conclusions: Our results suggest that PBPK modeling is a promising approach to investigate the effects of pregnancy and cancer on the PK of oncology drugs and potentially inform dosing for pregnant patients with cancer. Further evaluation and refinement of the population model are needed for pregnant patients with cancer with additional compounds and clinical PK data. Full article
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28 pages, 12506 KiB  
Article
Predicting Maternal and Infant Tetrahydrocannabinol Exposure in Lactating Cannabis Users: A Physiologically Based Pharmacokinetic Modeling Approach
by Babajide Shenkoya, Venkata Yellepeddi, Katrina Mark and Mathangi Gopalakrishnan
Pharmaceutics 2023, 15(10), 2467; https://doi.org/10.3390/pharmaceutics15102467 - 14 Oct 2023
Cited by 3 | Viewed by 1329
Abstract
A knowledge gap exists in infant tetrahydrocannabinol (THC) data to guide breastfeeding recommendations for mothers who use cannabis. In the present study, a paired lactation and infant physiologically based pharmacokinetic (PBPK) model was developed and verified. The verified model was used to simulate [...] Read more.
A knowledge gap exists in infant tetrahydrocannabinol (THC) data to guide breastfeeding recommendations for mothers who use cannabis. In the present study, a paired lactation and infant physiologically based pharmacokinetic (PBPK) model was developed and verified. The verified model was used to simulate one hundred virtual lactating mothers (mean age: 28 years, body weight: 78 kg) who smoked 0.32 g of cannabis containing 14.14% THC, either once or multiple times. The simulated breastfeeding conditions included one-hour post smoking and subsequently every three hours. The mean peak concentration (Cmax) and area under the concentration–time curve (AUC(0–24 h)) for breastmilk were higher than in plasma (Cmax: 155 vs. 69.9 ng/mL; AUC(0–24 h): 924.9 vs. 273.4 ng·hr/mL) with a milk-to-plasma AUC ratio of 3.3. The predicted relative infant dose ranged from 0.34% to 0.88% for infants consuming THC-containing breastmilk between birth and 12 months. However, the mother-to-infant plasma AUC(0–24 h) ratio increased up to three-fold (3.4–3.6) with increased maternal cannabis smoking up to six times. Our study demonstrated the successful development and application of a lactation and infant PBPK model for exploring THC exposure in infants, and the results can potentially inform breastfeeding recommendations. Full article
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18 pages, 2264 KiB  
Article
Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling
by Pieter-Jan De Sutter, Phebe Rossignol, Lien Breëns, Elke Gasthuys and An Vermeulen
Pharmaceutics 2023, 15(9), 2348; https://doi.org/10.3390/pharmaceutics15092348 - 19 Sep 2023
Cited by 2 | Viewed by 1199
Abstract
The volume of distribution at steady state (Vss) in neonates is still often estimated through isometric scaling from adult values, disregarding developmental changes beyond body weight. This study aimed to compare the accuracy of two physiologically based pharmacokinetic (PBPK) Vss prediction methods in [...] Read more.
The volume of distribution at steady state (Vss) in neonates is still often estimated through isometric scaling from adult values, disregarding developmental changes beyond body weight. This study aimed to compare the accuracy of two physiologically based pharmacokinetic (PBPK) Vss prediction methods in neonates (Poulin & Theil with Berezhkovskiy correction (P&T+) and Rodgers & Rowland (R&R)) with isometrical scaling. PBPK models were developed for 24 drugs using in-vitro and in-silico data. Simulations were done in Simcyp (V22) using predefined populations. Clinical data from 86 studies in neonates (including preterms) were used for comparison, and accuracy was assessed using (absolute) average fold errors ((A)AFEs). Isometric scaling resulted in underestimated Vss values in neonates (AFE: 0.61), and both PBPK methods reduced the magnitude of underprediction (AFE: 0.82–0.83). The P&T+ method demonstrated superior overall accuracy compared to isometric scaling (AAFE of 1.68 and 1.77, respectively), while the R&R method exhibited lower overall accuracy (AAFE: 2.03). Drug characteristics (LogP and ionization type) and inclusion of preterm neonates did not significantly impact the magnitude of error associated with isometric scaling or PBPK modeling. These results highlight both the limitations and the applicability of PBPK methods for the prediction of Vss in the absence of clinical data. Full article
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24 pages, 7697 KiB  
Article
Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling—A Contribution from the ConcePTION Project
by Nina Nauwelaerts, Julia Macente, Neel Deferm, Rodolfo Hernandes Bonan, Miao-Chan Huang, Martje Van Neste, David Bibi, Justine Badee, Frederico S. Martins, Anne Smits, Karel Allegaert, Thomas Bouillon and Pieter Annaert
Pharmaceutics 2023, 15(5), 1469; https://doi.org/10.3390/pharmaceutics15051469 - 11 May 2023
Cited by 4 | Viewed by 2635
Abstract
Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten [...] Read more.
Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for “non-lactating” adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage. Full article
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Review

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37 pages, 1610 KiB  
Review
Physiologically Based Pharmacokinetic Modeling in Neonates: Current Status and Future Perspectives
by Wei Zhang, Qian Zhang, Zhihai Cao, Liang Zheng and Wei Hu
Pharmaceutics 2023, 15(12), 2765; https://doi.org/10.3390/pharmaceutics15122765 - 12 Dec 2023
Viewed by 1635
Abstract
Rational drug use in special populations is a clinical problem that doctors and pharma-cists must consider seriously. Neonates are the most physiologically immature and vulnerable to drug dosing. There is a pronounced difference in the anatomical and physiological profiles be-tween neonates and older [...] Read more.
Rational drug use in special populations is a clinical problem that doctors and pharma-cists must consider seriously. Neonates are the most physiologically immature and vulnerable to drug dosing. There is a pronounced difference in the anatomical and physiological profiles be-tween neonates and older people, affecting the absorption, distribution, metabolism, and excretion of drugs in vivo, ultimately leading to changes in drug concentration. Thus, dose adjustments in neonates are necessary to achieve adequate therapeutic concentrations and avoid drug toxicity. Over the past few decades, modeling and simulation techniques, especially physiologically based pharmacokinetic (PBPK) modeling, have been increasingly used in pediatric drug development and clinical therapy. This rigorously designed and verified model can effectively compensate for the deficiencies of clinical trials in neonates, provide a valuable reference for clinical research design, and even replace some clinical trials to predict drug plasma concentrations in newborns. This review introduces previous findings regarding age-dependent physiological changes and pathological factors affecting neonatal pharmacokinetics, along with their research means. The application of PBPK modeling in neonatal pharmacokinetic studies of various medications is also reviewed. Based on this, we propose future perspectives on neonatal PBPK modeling and hope for its broader application. Full article
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22 pages, 1251 KiB  
Review
A Literature Review of Changes in Phase II Drug-Metabolizing Enzyme and Drug Transporter Expression during Pregnancy
by Christine Gong, Lynn N. Bertagnolli, David W. Boulton and Paola Coppola
Pharmaceutics 2023, 15(11), 2624; https://doi.org/10.3390/pharmaceutics15112624 - 15 Nov 2023
Cited by 1 | Viewed by 2025
Abstract
The purpose of this literature review is to comprehensively summarize changes in the expression of phase II drug-metabolizing enzymes and drug transporters in both the pregnant woman and the placenta. Using PubMed®, a systematic search was conducted to identify literature relevant [...] Read more.
The purpose of this literature review is to comprehensively summarize changes in the expression of phase II drug-metabolizing enzymes and drug transporters in both the pregnant woman and the placenta. Using PubMed®, a systematic search was conducted to identify literature relevant to drug metabolism and transport in pregnancy. PubMed was searched with pre-specified terms during the period of 26 May 2023 to 10 July 2023. The final dataset of 142 manuscripts was evaluated for evidence regarding the effect of gestational age and hormonal regulation on the expression of phase II enzymes (n = 16) and drug transporters (n = 38) in the pregnant woman and in the placenta. This comprehensive review exposes gaps in current knowledge of phase II enzyme and drug transporter localization, expression, and regulation during pregnancy, which emphasizes the need for further research. Moreover, the information collected in this review regarding phase II drug-metabolizing enzyme and drug transporter changes will aid in optimizing pregnancy physiologically based pharmacokinetic (PBPK) models to inform dose selection in the pregnant population. Full article
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14 pages, 489 KiB  
Review
Challenges Related to Acquisition of Physiological Data for Physiologically Based Pharmacokinetic (PBPK) Models in Postpartum, Lactating Women and Breastfed Infants—A Contribution from the ConcePTION Project
by Martje Van Neste, Annick Bogaerts, Nina Nauwelaerts, Julia Macente, Anne Smits, Pieter Annaert and Karel Allegaert
Pharmaceutics 2023, 15(11), 2618; https://doi.org/10.3390/pharmaceutics15112618 - 12 Nov 2023
Cited by 1 | Viewed by 1454
Abstract
Physiologically based pharmacokinetic (PBPK) modelling is a bottom-up approach to predict pharmacokinetics in specific populations based on population-specific and medicine-specific data. Using an illustrative approach, this review aims to highlight the challenges of incorporating physiological data to develop postpartum, lactating women and breastfed [...] Read more.
Physiologically based pharmacokinetic (PBPK) modelling is a bottom-up approach to predict pharmacokinetics in specific populations based on population-specific and medicine-specific data. Using an illustrative approach, this review aims to highlight the challenges of incorporating physiological data to develop postpartum, lactating women and breastfed infant PBPK models. For instance, most women retain pregnancy weight during the postpartum period, especially after excessive gestational weight gain, while breastfeeding might be associated with lower postpartum weight retention and long-term weight control. Based on a structured search, an equation for human milk intake reported the maximum intake of 153 mL/kg/day in exclusively breastfed infants at 20 days, which correlates with a high risk for medicine reactions at 2–4 weeks in breastfed infants. Furthermore, the changing composition of human milk and its enzymatic activities could affect pharmacokinetics in breastfed infants. Growth in breastfed infants is slower and gastric emptying faster than in formula-fed infants, while a slower maturation of specific metabolizing enzymes in breastfed infants has been described. The currently available PBPK models for these populations lack structured systematic acquisition of population-specific data. Future directions include systematic searches to fully identify physiological data. Following data integration as mathematical equations, this holds the promise to improve postpartum, lactation and infant PBPK models. Full article
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21 pages, 950 KiB  
Review
Physiologically Based Pharmacokinetics Modeling in the Neonatal Population—Current Advances, Challenges, and Opportunities
by Jean Dinh, Trevor N. Johnson, Manuela Grimstein and Tamorah Lewis
Pharmaceutics 2023, 15(11), 2579; https://doi.org/10.3390/pharmaceutics15112579 - 03 Nov 2023
Viewed by 1154
Abstract
Physiologically based pharmacokinetic (PBPK) modeling is an approach to predicting drug pharmacokinetics, using knowledge of the human physiology involved and drug physiochemical properties. This approach is useful when predicting drug pharmacokinetics in under-studied populations, such as pediatrics. PBPK modeling is a particularly important [...] Read more.
Physiologically based pharmacokinetic (PBPK) modeling is an approach to predicting drug pharmacokinetics, using knowledge of the human physiology involved and drug physiochemical properties. This approach is useful when predicting drug pharmacokinetics in under-studied populations, such as pediatrics. PBPK modeling is a particularly important tool for dose optimization for the neonatal population, given that clinical trials rarely include this patient population. However, important knowledge gaps exist for neonates, resulting in uncertainty with the model predictions. This review aims to outline the sources of variability that should be considered with developing a neonatal PBPK model, the data that are currently available for the neonatal ontogeny, and lastly to highlight the data gaps where further research would be needed. Full article
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Other

14 pages, 1042 KiB  
Perspective
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
by Paola Coppola, Andrew Butler, Susan Cole and Essam Kerwash
Pharmaceutics 2023, 15(10), 2455; https://doi.org/10.3390/pharmaceutics15102455 - 13 Oct 2023
Cited by 1 | Viewed by 1021
Abstract
Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased [...] Read more.
Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions. Full article
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