Quantification of Fetal Renal Function Using Fetal Urine Production Rate and Its Reflection on the Amniotic and Fetal Creatinine Levels During Pregnancy

Ezuruike, Udoamaka; Blenkinsop, Alexander; Pansari, Amita; Abduljalil, Khaled

doi:10.3389/fped.2022.841495

Cited by 13 publications

(13 citation statements)

References 65 publications

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“…This was due to lack of curation of gestational age-dependent fetal and placental physiological parameters (eg, gestational agedependent tissue blood flow) and lack of availability of the abundance of drug transporters and metabolizing enzymes that determine drug CL MP , CL PM , CL p0 , and CL f0 . However, we 6,22,79,90,91 and others [92][93][94][95][96][97][98] have begun to fill these gaps in knowledge by generating/curating relevant physiological data (eg, blood flow, organ sizes, plasma protein concentrations) and describing their gestational age-dependent changes with models that allow interpolation for any gestational age. In addition, we have quantified the abundance of placental transporters at various gestational ages.…”

Section: S102mentioning

confidence: 99%

Predicting Human Fetal Drug Exposure Through Maternal‐Fetal PBPK Modeling and In Vitro or Ex Vivo Studies

Balhara

Kumar

Unadkat

2022

The Journal of Clinical Pharma

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Medication (drug) use in human pregnancy is prevalent. Determining fetal safety and efficacy of drugs is logistically challenging. However, predicting (not measuring) fetal drug exposure (systemic and tissue) throughout pregnancy is possible through maternal‐fetal physiologically based pharmacokinetic (PBPK) modeling and simulation. Such prediction can inform fetal drug safety and efficacy. Fetal drug exposure can be quantified in 2 complementary ways. First, the ratio of the steady‐state unbound plasma concentration in the fetal plasma (or area under the plasma concentration–time curve) to the corresponding maternal plasma concentration (ie, Kp,uu). Second, the maximum unbound peak (Cu,max,ss,f) and trough (Cu,min,ss,f) fetal steady‐state plasma concentrations. We (and others) have developed a maternal‐fetal PBPK model that can successfully predict maternal drug exposure. To predict fetal drug exposure, the model needs to be populated with drug specific parameters, of which transplacental clearances (active and/or passive) and placental/fetal metabolism of the drug are critical. Herein, we describe in vitro studies in cells/tissue fractions or the perfused human placenta that can be used to determine these drug‐specific parameters. In addition, we provide examples whereby this approach has successfully predicted systemic fetal exposure to drugs that passively or actively cross the placenta. Apart from maternal‐fetal PBPK models, animal studies also have the potential to estimate fetal drug exposure by allometric scaling. Whether such scaling will be successful is yet to be determined. Here, we review the above approaches to predict fetal drug exposure, outline gaps in our knowledge to make such predictions and map out future research directions that could fill these gaps.

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Section: S102mentioning

confidence: 99%

Predicting Human Fetal Drug Exposure Through Maternal‐Fetal PBPK Modeling and In Vitro or Ex Vivo Studies

Balhara

Kumar

Unadkat

2022

The Journal of Clinical Pharma

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“…Although beyond the scope of this work, evaluation of medicine use in pregnant women is further complicated by the concern on drug effect to the fetuses PBPK model may be potentially be used to predict fetal exposure to drugs. [40][41][42][43][44] Zhang and Unadkat 43 have developed a maternal-fetal PBPK model to predict fetal exposure for drugs that passively diffuse across the placenta. Other authors 44 showed that the use of perfused placenta technique could be used to enrich PBPK modeling; that is, data from ex vivo experiments could be integrated into PBPK models to study maternal and fetal exposure to drugs used during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Use of Pregnancy Physiologically Based Pharmacokinetic Modeling for Renally Cleared Drugs

Coppola¹,

Kerwash²,

Cole³

2022

The Journal of Clinical Pharma

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Physiologically based pharmacokinetic modeling (PBPK) could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations where there are currently no available clinical data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by the kidney. Models were evaluated for ceftazidime, cefuroxime, metformin, oseltamivir, and amoxicillin. Because the passive renal process contributes significantly to the renal elimination of these drugs and changes of the process during pregnancy have been implemented in existing pregnancy physiology models, simulations using these models can reasonably describe the pharmacokinetics of ceftazidime changes during pregnancy and appears to generally capture the changes in the other medicines; however, there are insufficient data on drugs solely passively cleared to fully qualify the models. In addition, in many cases, active transport processes are involved in a drug's renal clearance. Knowledge of changes in renal transport functions during pregnancy is emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is a work in progress. Filling this gap is expected to further enhance predictive performance of the models and increase the confidence in predicting pharmacokinetic changes in pregnant women for other renally cleared drugs.

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“…This CL PD of 0.0071 L/h/g tissue was used as a model input parameter to parametrize the passive diffusion clearances on both sides of the placenta assuming a placental density of 1 g/ml. In addition, to predict the amniotic exposure of theophylline, the fetal renal clearance ( fetal CL R ) was calculated based on fetal GFR of 4.9 ml/min ( 43 ) with reference to a typical adult GFR value of 121 mL/min ( 44 ) and the adult theophylline renal clearance of 0.31 L/h (see Supplementary Table 1 ) according to the following equation…”

Section: Methodsmentioning

confidence: 99%

Application of a Physiologically Based Pharmacokinetic Approach to Predict Theophylline Pharmacokinetics Using Virtual Non-Pregnant, Pregnant, Fetal, Breast-Feeding, and Neonatal Populations

2022

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Perinatal pharmacology is influenced by a myriad of physiological variables that are changing dynamically. The influence of these covariates has not been assessed systemically. The objective of this work was to use theophylline as a model drug and to predict its pharmacokinetics before, during (including prediction of the umbilical cord level), and after pregnancy as well as in milk (after single and multiple doses) and in neonates using a physiological-based pharmacokinetic (PBPK) model. Neonatal theophylline exposure from milk consumption was projected in both normal term and preterm subjects. Predicted infant daily doses were calculated using theophylline average and maximum concentration in the milk as well as an estimate of milk consumption. Predicted concentrations and parameters from the PBPK model were compared to the observed data. PBPK predicted theophylline concentrations in non-pregnant and pregnant populations at 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 PBPK model predicted an average cord-to-maternal plasma ratio of 1.0, which also agrees well with experimental observations. Predicted postpartum theophylline concentration profiles in milk were also in good agreement with observations with a predicted milk-to-plasma ratio of 0.68. For an infant of 2 kg consuming 150 ml of milk per day, the lactation model predicted a relative infant dose (RID) of 12 and 17% using predicted average (Cavg,ss) and maximum (Cmax,ss) concentration in milk at steady state. The maximum RID of 17% corresponds to an absolute infant daily dose of 1.4 ± 0.5 mg/kg/day. This dose, when administered as 0.233 mg/kg every 4 h, to resemble breastfeeding frequency, resulted in plasma concentrations as high as 3.9 (1.9–6.8) mg/L and 2.8 (1.3–5.3) (5th−95th percentiles) on day 7 in preterm (32 GW) and full-term neonatal populations.

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Quantification of Fetal Renal Function Using Fetal Urine Production Rate and Its Reflection on the Amniotic and Fetal Creatinine Levels During Pregnancy

Cited by 13 publications

References 65 publications

Predicting Human Fetal Drug Exposure Through Maternal‐Fetal PBPK Modeling and In Vitro or Ex Vivo Studies

Predicting Human Fetal Drug Exposure Through Maternal‐Fetal PBPK Modeling and In Vitro or Ex Vivo Studies

The Use of Pregnancy Physiologically Based Pharmacokinetic Modeling for Renally Cleared Drugs

Application of a Physiologically Based Pharmacokinetic Approach to Predict Theophylline Pharmacokinetics Using Virtual Non-Pregnant, Pregnant, Fetal, Breast-Feeding, and Neonatal Populations

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