Model‐Informed Dose Optimization in Pregnancy

Chaphekar, Nupur; Caritis, Steve N.; Venkataramanan, Raman

doi:10.1002/jcph.1777

Cited by 18 publications

(25 citation statements)

References 68 publications

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“…This current fetal model structure matches the most complex fetal PBPK models focusing on prediction of maternal and fetal PK at different pregnancy stages [15,17,53,54]. Recent publications presented pregnancy PBPK models that include additional maternal tissues compartments: breast, endometrium, and myometrium [55,56]. However, these organs are not connected to the placenta and therefore should have no or limited impact on APIs transplacental maternal to fetal transfer.…”

Section: Discussionmentioning

confidence: 71%

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Kidney in Pregnant Subjects and Fetus

Szeto

Merdy

Dupont³

et al. 2021

AAPS J

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The purpose of this study was to develop a physiologically based pharmacokinetic (PBPK) model predicting the pharmacokinetics (PK) of different compounds in pregnant subjects. This model considers the differences in tissue sizes, blood flow rates, enzyme expression levels, glomerular filtration rates, plasma protein binding, and other factors affected during pregnancy in both the maternal and fetal models. The PBPKPlus™ module in GastroPlus® was used to model the PK of cefuroxime and cefazolin. For both compounds, the model was first validated against PK data in healthy non-pregnant volunteers and then applied to predict pregnant groups PK. The model accurately described the PK in both non-pregnant and pregnant groups and explained well differences in the plasma concentration due to pregnancy. The fetal plasma and amniotic fluid concentrations were also predicted reasonably well at different stages of pregnancy. This work describes 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 compounds excreted renally. The prediction for pregnant groups is also improved when the model is calibrated with postpartum or non-pregnant female group if such data are available.

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Section: Discussionmentioning

confidence: 71%

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Kidney in Pregnant Subjects and Fetus

Szeto

Merdy

Dupont³

et al. 2021

AAPS J

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“…Subsequently, using the normal population as the control group, the predicted values of critical PK parameters were compared. The age group–adjusted proposed dosage for renally impaired pediatric patients was calculated by multiplying the geometric mean ratio of AUC 0‐t of the renally impaired population to the corresponding normal population by the dose in the normal population 12,13,24,25 …”

Section: Methodsmentioning

confidence: 99%

Ceftaroline Dosage Optimized for Pediatric Patients With Renal Impairment Using Physiologically Based Pharmacokinetic Modeling

Zhou

You

Guo

et al. 2021

The Journal of Clinical Pharma

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Ceftaroline fosamil is a fifth‐generation cephalosporin approved as a treatment for adults and children with community‐acquired bacterial pneumonia and acute bacterial skin and skin structure infections. However, its pharmacokinetics have not been fully evaluated in children with renal impairment. This study aimed to propose proper ceftaroline dosages optimized for the renally impaired pediatric population using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of ceftaroline was established and verified to simulate its disposition in the healthy population and renally impaired adults and to predict the exposure in renally impaired pediatric patients. Consistency was confirmed between simulated and observed data after intravenous administration of various ceftaroline regimens; fold errors were within the 2‐fold error range. Among 6‐year‐old children, healthy subjects had 1.5‐fold, 2‐fold, and 2.6‐fold lower areas under the plasma concentration–time curve (AUCs) than the moderate, severe, and end‐stage renally impaired patient groups, respectively; among 1‐year‐old children, healthy subjects had 1.5‐fold, 2.1‐fold, and 2.5‐fold lower AUCs than the respective renally impaired patient groups; among 1‐month‐old children, healthy subjects had 1.5‐fold, 1.8‐fold, and 2.2‐fold lower AUCs than the respective renally impaired patient groups. The proposed dosage should be adjusted to 8, 6, and 5 mg/kg every 8 hours for patients aged ≥2 years to <18 years (≤33 kg) with moderate, severe, and end‐stage renal impairment, respectively; 5, 4, and 3 mg/kg every 8 hours for patients aged 2 months to <2 years with moderate, severe, and end‐stage renal impairment, respectively; 4, 3.5, and 2.5 mg/kg every 8 hours for patients 0 to <2 months of age with moderate, severe, and end‐stage renal impairment, respectively. Furthermore, pharmacodynamic investigations demonstrated that adequate antimicrobial effects were attained at the proposed doses in 3 age groups. Hence, our PBPK model can be an effective tool to support ceftaroline dosage proposals for renally impaired pediatric patients.

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“…Despite frequent and increasing drug use in pregnant women ( 1 , 2 ), little is known about placental drug transfer and pharmacokinetics in the fetus. To address this knowledge gap, numerous physiologically based pharmacokinetic (PBPK) models for pregnant women were developed over the past years and used to simulate fetal pharmacokinetics ( 3 , 4 ). Yet, adequate parameterization of placental drug transfer in these models remains challenging.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery

et al. 2021

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Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.

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Model‐Informed Dose Optimization in Pregnancy

Cited by 18 publications

References 68 publications

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Kidney in Pregnant Subjects and Fetus

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Kidney in Pregnant Subjects and Fetus

Ceftaroline Dosage Optimized for Pediatric Patients With Renal Impairment Using Physiologically Based Pharmacokinetic Modeling

Mechanistic Coupling of a Novel in silico Cotyledon Perfusion Model and a Physiologically Based Pharmacokinetic Model to Predict Fetal Acetaminophen Pharmacokinetics at Delivery

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