Fetal Physiologically Based Pharmacokinetic Models: Systems Information on Fetal Blood Components and Binding Proteins

Abduljalil, Khaled; Jamei, Masoud; Johnson, Trevor N.

doi:10.1007/s40262-019-00836-3

Cited by 19 publications

(16 citation statements)

References 74 publications

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“…When calculating the fetal unbound drug fraction according to Equation ( 1 ), it was assumed that the drug binds to one protein only (namely albumin) and that the number of adult and fetal protein binding sites as well as the drug's affinity to adult and fetal plasma proteins are the same. The assumption that albumin is the exclusive protein binding partner may contribute to an underestimation of the fetal unbound fraction of a drug with mixed binding to albumin or α1-acidic glycoprotein because the relative concentration difference between fetal and adult α1-acidic glycoprotein is considerably larger than that for albumin [α1-acidic glycoprotein: 0.21 g/L in the fetus at 38 weeks of gestation vs. 0.70 g/L in non-pregnant adults; albumin: 38.6 g/L in the fetus at 38 weeks of gestation vs. 46.4 g/L in non-pregnant adults ( 20 , 29 )]. Relatively little information could be found in the scientific literature to falsify (or verify) the assumption of equal number of protein binding sites and binding affinity of adult and fetal albumin.…”

Section: Discussionmentioning

confidence: 99%

“…For drugs weakly or moderately bound to albumin (fraction unbound > ~30%), the differences in fetal/maternal protein binding can, under normal conditions, be expected to be rather low at term delivery because the difference between fetal and maternal albumin concentration diminishes toward term ( 20 , 29 ). However, they may become more relevant at earlier stages of pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…Here, f u _ nonpreg is the fraction unbound of non-pregnant adults in plasma; C prot _ nonpreg is the concentration of binding proteins in the blood plasma in non-pregnant adults; C prot _ fetus is the concentration of binding proteins in fetal blood plasma. Values for C prot _ fetus were taken from a previously published meta-analysis ( 20 ). Implicit assumptions of this equation are that the number of adult and fetal protein binding sites and the drug's affinity to adult and fetal plasma proteins are the same and that the drug exclusively binds to one plasma protein only.…”

Section: Methodsmentioning

confidence: 99%

“…Values for C prot_fetus were taken from a previously published meta-analysis (20). Implicit assumptions of this equation are that the number of adult and fetal protein binding sites and the drug's affinity to adult and fetal plasma proteins are the same and that the drug exclusively binds to one plasma protein only.…”

Section: Estimation Of Fetal Fraction Unboundmentioning

confidence: 99%

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Mechanistic Modeling of Placental Drug Transfer in Humans: How Do Differences in Maternal/Fetal Fraction of Unbound Drug and Placental Influx/Efflux Transfer Rates Affect Fetal Pharmacokinetics?

et al. 2021

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Background: While physiologically based pharmacokinetic (PBPK) models generally predict pharmacokinetics in pregnant women successfully, the confidence in predicting fetal pharmacokinetics is limited because many parameters affecting placental drug transfer have not been mechanistically accounted for.Objectives: The objectives of this study were to implement different maternal and fetal unbound drug fractions in a PBPK framework; to predict fetal pharmacokinetics of eight drugs in the third trimester; and to quantitatively investigate how alterations in various model parameters affect predicted fetal pharmacokinetics.Methods: The ordinary differential equations of previously developed pregnancy PBPK models for eight drugs (acyclovir, cefuroxime, diazepam, dolutegravir, emtricitabine, metronidazole, ondansetron, and raltegravir) were amended to account for different unbound drug fractions in mother and fetus. Local sensitivity analyses were conducted for various parameters relevant to placental drug transfer, including influx/efflux transfer clearances across the apical and basolateral membrane of the trophoblasts.Results: For the highly-protein bound drugs diazepam, dolutegravir and ondansetron, the lower fraction unbound in the fetus vs. mother affected predicted pharmacokinetics in the umbilical vein by ≥10%. Metronidazole displayed blood flow-limited distribution across the placenta. For all drugs, umbilical vein concentrations were highly sensitive to changes in the apical influx/efflux transfer clearance ratio. Additionally, transfer clearance across the basolateral membrane was a critical parameter for cefuroxime and ondansetron.Conclusion: In healthy pregnancies, differential protein binding characteristics in mother and fetus give rise to minor differences in maternal-fetal drug exposure. Further studies are needed to differentiate passive and active transfer processes across the apical and basolateral trophoblast membrane.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Estimation Of Fetal Fraction Unboundmentioning

confidence: 99%

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Mechanistic Modeling of Placental Drug Transfer in Humans: How Do Differences in Maternal/Fetal Fraction of Unbound Drug and Placental Influx/Efflux Transfer Rates Affect Fetal Pharmacokinetics?

et al. 2021

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“…The pregnancy PBPK model can be more complex if the aim is to investigate the transplacental passage of drugs known to be affected by placental transports or metabolizing enzymes and in PBPK terms this model requires permeability-limited models where (saturated or unsaturated) kinetics can be evaluated [36]. The complexity of the model can be further increased if the model is developed to assess the fetal systemic or organ exposure, where detailed physiological parameters are required for describing the growth of fetal organs, their blood perfusions and compositions [37][38][39]. Differences in the structure of the basline (non-pregnant) and dynamic (pregnant) PBPK models have been reviewed [40,41].…”

Section: Current Status Of Pregnancy Pbpk Applicationsmentioning

confidence: 99%

Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Abduljalil

Badhan

2020

J Pharmacokinet Pharmacodyn

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Drugs can have harmful effects on the embryo or fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of nonpregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester.This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions.For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Three examples were described to show how pregnancy PBPK can facilitate and guide dose assessment throughout gestation.

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Successful Prediction of Fetal Exposure to Dual BCRP/P‐gp Drug Substrates Using the Efflux Ratio‐Relative Expression Factor Approach and PBPK M&S

Balhara,

Yin,

Unadkat

2024

Clin Pharma and Therapeutics

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To inform fetal drug safety, it is important to determine or predict fetal drug exposure throughout pregnancy. The former is not possible in the 1st or 2nd trimester. In contrast, at the time of birth, fetal drug exposure, relative to maternal exposure, can be estimated as Kp,uu (unbound fetal umbilical venous [UV] plasma AUC/unbound maternal plasma [MP] AUC), provided the observed UV/MP values, spanning the dosing interval, are available from multiple maternal‐fetal dyads. However, this fetal Kp,uu cannot be extrapolated to other drugs. To overcome the above limitations, we have used an efflux ratio‐relative expression factor (ER‐REF) approach to successfully predict the fetal Kp,uu of P‐gp substrates. Since many drugs taken by pregnant people are also BCRP substrates, here we extend this approach to drugs that are effluxed by both placental BCRP and P‐gp or P‐gp alone. To verify our predictions, we chose drugs for which UV/MP data were available at term: glyburide and imatinib (both BCRP and P‐gp substrates) and nelfinavir (only P‐gp substrate). First, the ER of the drugs was determined using Transwells and MDCKII cells expressing either BCRP or P‐gp. Then, the ER was scaled using the proteomics‐informed REF value to predict the fetal Kp,uu of the drug at term. The ER‐REF predicted fetal Kp,uu of glyburide (0.43), imatinib (0.42) and nelfinavir (0.40) fell within 2‐fold of the corresponding in vivo fetal Kp,uu (0.44, 0.37 and 0.46, respectively). These data confirm that the ER‐REF can successfully predict fetal drug exposure to BCRP/P‐gp and P‐gp substrates, at term.

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Fetal Physiologically Based Pharmacokinetic Models: Systems Information on Fetal Blood Components and Binding Proteins

Cited by 19 publications

References 74 publications

Mechanistic Modeling of Placental Drug Transfer in Humans: How Do Differences in Maternal/Fetal Fraction of Unbound Drug and Placental Influx/Efflux Transfer Rates Affect Fetal Pharmacokinetics?

Mechanistic Modeling of Placental Drug Transfer in Humans: How Do Differences in Maternal/Fetal Fraction of Unbound Drug and Placental Influx/Efflux Transfer Rates Affect Fetal Pharmacokinetics?

Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Successful Prediction of Fetal Exposure to Dual BCRP/P‐gp Drug Substrates Using the Efflux Ratio‐Relative Expression Factor Approach and PBPK M&S

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