p-PBPK Model Research Articles

Development of a physiologically based toxicokinetic model for lead in pregnant women: The role of bone tissue in the maternal and fetal internal exposure

Epidemiological studies have shown associations between prenatal exposure to lead (Pb) and neurodevelopmental effects in young children. Prenatal exposure is generally characterized by measuring the concentration in the umbilical cord at delivery or in the maternal blood during pregnancy. To assess internal Pb exposure during prenatal life, we developed a pregnancy physiologically based pharmacokinetic (p-PBPK) model that to simulates Pb levels in blood and target tissues in the fetus, especially during critical periods for brain development. An existing Pb PBPK model was adapted to pregnant women and fetuses. Using data from literature, both the additional maternal bone remodeling, that causes Pb release into the blood, and the Pb placental transfers were estimated by Bayesian inference. Additional maternal bone remodeling was estimated to start at 21.6 weeks. Placental transfers were estimated between 4.6 and 283 L.day−1 at delivery with high interindividual variability. Once calibrated, the p-PBPK model was used to simulate fetal exposure to Pb. Internal fetal exposure greatly varies over the pregnancy with two peaks of Pb levels in blood and brain at the end of the 1st and 3rd trimesters. Sensitivity analysis shows that the fetal blood lead levels are affected by the maternal burden of bone Pb via maternal bone remodeling and by fetal bone formation at different pregnancy stages. Coupling the p-PBPK model with an effect model such as an adverse outcome pathway could help to predict the effects on children's neurodevelopment.

Predicting fetal exposure of crizotinib during pregnancy: Combining human ex vivo placenta perfusion data with physiologically-based pharmacokinetic modeling

Commercially available physiologically-based pharmacokinetic (PBPK) modeling platforms increasingly allow estimations of fetal exposure to xenobiotics. We aimed to explore a physiology-based approach in which literature data from ex vivo placenta perfusion studies are used to parameterize Simcyp's pregnancy-PBPK (p-PBPK) model, taking crizotinib as an example. First, a physiologically-based semi-mechanistic placenta (PBMP) model was developed in MATLAB to analyze placenta perfusion data of crizotinib. Mixed-effects modeling was performed to derive intrinsic unbound clearance values across the maternal-placental barrier and fetal-placental barrier. Values were then used for parameterization of the p-PBPK model. The PBMP model adequately described the perfusion data. Clearance was estimated to be 71 mL/min and 535 mL/min for the maternal placental uptake and efflux, and 8 mL/min and 163 mL/min for fetal placental uptake and efflux, respectively. For oral dosing of 250 mg twice daily, p-PBPK modeling predicted a Cmax and AUC0-τ of 0.08 mg/L and 0.78 mg/L*h in the umbilical vein at steady-state, respectively. In placental tissue, a Cmax of 5.04 mg/L was predicted. In conclusion, PBMP model-based data analysis and the associated p-PBPK modeling approach illustrate how ex vivo placenta perfusion data may be used for fetal exposure predictions.

Evaluation of Placental Transfer and Tissue Distribution of cis- and Trans-Permethrin in Pregnant Rats and Fetuses Using a Physiological-Based Pharmacokinetic Model.

Biomonitoring studies have highlighted the exposure of pregnant women to pyrethroids based on the measurement of their metabolites in urine. Pyrethroids can cross the placental barrier and be distributed in the fetus as some pyrethroids were also measured in the meconium of newborns. Prenatal exposure to pyrethroids is suspected to alter the neurodevelopment of children, and animal studies have shown that early life exposure to permethrin, one of the most commonly used pyrethroid in household applications, can alter the brain development. This study aimed to characterize the fetal permethrin exposure throughout gestation in rats. We developed a pregnancy physiologically based pharmacokinetic (pPBPK) model that describes the maternal and fetal kinetics of the cis- and trans- isomers of permethrin during the whole gestation period. Pregnant Sprague–Dawley rats were exposed daily to permethrin (50 mg/kg) by oral route from the start of gestation to day 20. Permethrin isomers were quantified in the feces, kidney, mammary gland, fat, and placenta in dams and in both maternal and fetal blood, brain, and liver. Cis- and trans-permethrin were quantified in fetal blood and tissues, with higher concentrations for the cis-isomer. The pPBPK model was fitted to the toxicokinetic maternal and fetal data in a Bayesian framework. Several parameters were adjusted, such as hepatic clearances, partition coefficients, and intestinal absorption. Our work allowed to estimate the prenatal exposure to permethrin in rats, especially in the fetal brain, and to quantitatively estimate the placental transfer. These transfers could be extrapolated to humans and be incorporated in a human pPBPK model to estimate the fetal exposure to permethrin from biomonitoring data.

Physiologically Based Pharmacokinetic Modelling for Nicotine and Cotinine Clearance in Pregnant Women.

Introduction: Physiologically based pharmacokinetic (PBPK) models for the absorption, disposition, metabolism and excretion (ADME) of nicotine and its major metabolite cotinine in pregnant women (p-PBPK) are rare. The aim of this short research report is to present a p-PBPK model and its simulations for nicotine and cotinine clearance. Methods: The maternal-placental-fetal compartments of the p-PBPK model contain a total of 16 compartments representing major maternal and fetal organs and tissue groups. Qualitative and quantitative data of nicotine and cotinine disposition and clearance have been incorporated into pharmacokinetic parameters. Results: The p-PBPK model reproduced the higher clearance rates of nicotine and cotinine in pregnant women than non-pregnant women. Temporal profiles for their disposition in organs such as the brain were also simulated. Nicotine concentration reaches its maximum value within 2 min after an intravenous injection. Conclusion: The proposed p-PBPK model produces results consistent with available data sources. Further pharmacokinetic experiments are required to calibrate clearance parameters for individual organs, and for the fetus.

When special populations intersect with drug-drug interactions: Application of physiologically-based pharmacokinetic modeling in pregnant populations.

Pregnancy results in significant physiological changes that vary across trimesters and into the postpartum period, and may result in altered disposition of endogenous substances and drug pharmacokinetics. Pregnancy represents a unique special population where physiologically-based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms without subjecting pregnant women or their fetuses to extensive clinical studies. A critical review of applications of pregnancy PBPK models (pPBPK) was conducted to understand its current status for prediction of drug exposure in pregnant populations and to identify areas of further expansion. Evaluation of existing pPBPK modeling efforts highlighted improved understanding of cytochrome P450 (CYP)-mediated changes during pregnancy and identified knowledge gaps for non-CYP enzymes and the physiological changes of the postpartum period. Examples of the application of pPBPK beyond simple dose regimen recommendations are limited, particularly for prediction of drug-drug interactions (DDI) or differences between genotypes for polymorphic drug metabolizing enzymes. A raltegravir pPBPK model implementing UGT1A1 induction during the second and third trimesters of pregnancy was developed in the current work and verified against clinical data. Subsequently, the model was used to explore UGT1A1-related DDI risk with atazanavir and rifampicin along with the effect of enzyme genotype on raltegravir apparent clearance. Simulations of pregnancy-related induction of UGT1A1 either exacerbated UGT1A1 induction by rifampicin or negated atazanavir UGT1A1 inhibition. This example illustrated the advantages of pPBPK modeling for mechanistic evaluation of complex interplays of pregnancy- and drug-related effects in support of model-informed approaches in drug development.

Assessing the impacts on fetal dosimetry of the modelling of the placental transfers of xenobiotics in a pregnancy physiologically based pharmacokinetic model

The developmental origin of health and diseases theory supports the critical role of the fetal exposure to children's health. We developed a physiologically based pharmacokinetic model for human pregnancy (pPBPK) to simulate the maternal and fetal dosimetry throughout pregnancy. Four models of the placental exchanges of chemicals were assessed on ten chemicals for which maternal and fetal data were available. These models were calibrated using non-animal methods: in vitro (InV) or ex vivo (ExV) data, a semi-empirical relationship (SE), or the limitation by the placental perfusion (PL). They did not impact the maternal pharmacokinetics but provided different profiles in the fetus. The PL and InV models performed well even if the PL model overpredicted the fetal exposure for some substances. The SE and ExV models showed the lowest global performance and the SE model a tendency to underprediction. The comparison of the profiles showed that the PL model predicted an increase in the fetal exposure with the pregnancy age, whereas the ExV model predicted a decrease. For the SE and InV models, a small decrease was predicted during the second trimester. All models but the ExV one, presented the highest fetal exposure at the end of the third trimester. Global sensitivity analyses highlighted the predominant influence of the placental transfers on the fetal exposure, as well as the metabolic clearance and the fraction unbound. Finally, the four transfer models could be considered depending on the framework of the use of the pPBPK model and the availability of data or resources to inform their parametrization.

Sildenafil for Antenatal Treatment of Congenital Diaphragmatic Hernia: From Bench to Bedside.

Persistent pulmonary hypertension (PPH) is one of the main causes of mortality and morbidity in infants affected by congenital diaphragmatic hernia (CDH). Since the structural changes that lead to PPH take place already in utero, a treatment starting in the prenatal phase may prevent the occurrence of this complication. To summarize the development process of antenatal sildenafil for CDH. The pharmacokinetics and efficacy of sildenafil have been assessed in the rat and the rabbit model. The transfer of the drug through the human placenta has been measured with the ex-vivo placenta perfusion model. Results from this experiment are being incorporated in a pregnancy-physiologically based pharmacokinetic (p- PBPK) model. A phase I-IIb placental transfer and safety study is ongoing. Sildenafil administration to pregnant rats and rabbits led to therapeutic foetal drug levels without maternal and foetal toxicity, although it was associated with impaired vascular development in foetuses with nonhypoplastic lungs. Peak concentrations and 24-hour exposure were higher in pregnant rabbits compared to nonpregnant ones. In rat and rabbit foetuses with CDH, sildenafil rescued the lung vascular anomalies and partially improved parenchymal development. Sildenafil crossed the human placenta at a high rate ex-vivo, independently from the initial maternal concentration. There is preclinical evidence that maternally administered sildenafil prevents the vascular changes that lead to PPH in CDH newborns. The phase I/IIb clinical study together with the p-PBPK model will define the maternal dose needed for a therapeutic effect in the foetus. Foetal safety will be investigated both in the clinical study and in the sheep. The final step will be a multicentre, randomized, placebo-controlled trial.

Physiologically-based pharmacokinetics of ziprasidone in pregnant women.

Pregnancy is associated with physiological changes that alter the pharmacokinetics (PK) of drugs. The aim of this study was to predict the PK of ziprasidone in pregnant women. A full physiologically-based pharmacokinetic (PBPK) model of ziprasidone was developed and validated for the non-pregnant population (healthy adults, paediatrics, geriatrics), and this was extended to the pregnant state to assess the change in PK profile of ziprasidone throughout pregnancy. The PBPK model successfully predicted the ziprasidone disposition in healthy adult volunteers, wherein the predicted and observed AUC, Cmax and tmax were within the fold-difference of 0.94-1.09, 0.89-1.40 and 0.80-1.08, respectively. The paediatric and geriatric population, also showed predicted AUC, Cmax and tmax within a two-fold range of the observed values. The simulated exposure in pregnant women using a p-PBPK model showed no significant difference when compared to non-pregnant women. The PBPK model predicted the impact of physiological changes during pregnancy on PK and exposure of ziprasidone, suggesting that dose adjustment is not necessary in this special population.

O-1 Dosing for two: placental transfer and fetal darunavir exposure

Background Fetal drug exposure during pregnancy can be a determinant of fetal drug toxicity or efficacy. Fetal exposure is usually derived from the cord-to-maternal (ctm) concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship. Pregnancy physiologically-based pharmacokinetic (p-PB-PK) modelling could provide a solution, although incor-poration of placental transfer remains challenging. Here, we aimed to include placental transfer parameters de-rived from an ex vivo human cotyledon perfusion model into a p-PBPK model, to quantitatively simulate fetal ex-posure to the antiretroviral agent darunavir, co-adminis-tered with ritonavir, at term. Methods An existing and validated p-PBPK model of ma-ternal darunavir/ritonavir exposure was coded in Berkeley Madonna syntax to allow expansion with a feto-placental unit. Bidirectional placental transport of darunavir at term was included. In order to parameterize the model, we determined maternal-to-fetal (mtf) and fetal-to-maternal (ftm) darunavir/ritonavir placental clearances with an ex vivo human cotyledon perfusion model. Simulated ma-ternal PK profiles were compared with observed clinical data to verify the validity of the maternal model aspect. Next, population fetal PK profiles were simulated for different darunavir/ritonavir dosing regimens. These profiles were compared with available cord blood concen-trations in vivo . Additionally, we explored the influence of different DRV/r dosing regimens on fetal exposure and antiviral effects. Results An average (±SD) mtf cotyledon clearance of 0.91±0.11 mL/min and ftm of 1.6±0.3 mL/min was de-termined (n=6 perfusions). Scaled placental transfer was included into a feto-placental unit and integrated in the p-PBPK model. For darunavir 600/100 mg twice daily, the simulated fetal plasma Cmax, Ctrough, Tmax and T1/2 at steady state were; 1.1 mg/L, 0.57 mg/L, 3 hours, and 21 hours, respectively. This indicates that the fetal population Ctrough is above the protein-adjusted EC90 for inhibit-ing the replication of wild type (0.20 mg/L) and around the EC90 for resistant virus (0.55 mg/L). The simulated ftm plasma concentration ratio (range) over a dosing interval was 0.30 (0.16–0.37), compared to a median (range) ratio for observed darunavir ctm plasma ratio of 0.18 (0–0.82; 0 reported if cord blood concentrations were below the lower limit of quantification [ Conclusion A p-PBPK model for maternal darunavir exposure was extended with a feto-placental unit. The simulated fetal darunavir plasma concentrations were in the range of observed cord blood concentrations. This advanced model provides a valuable tool in assessing the implications of new dosing regimens, optimising the safety of maternal pharmacotherapy and fetal antiretro-viral treatment.

Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models.

Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively. Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models. Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo. The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.

A pregnancy physiologically based pharmacokinetic (p‐PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4

Pregnant women are usually not part of the traditional drug development programme. Pregnancy is associated with major biological and physiological changes that alter the pharmacokinetics (PK) of drugs. Prediction of the changes to drug exposure in this group of patients may help to prevent under- or overtreatment. We have used a pregnancy physiologically based pharmacokinetic (p-PBPK) model to assess the likely impact of pregnancy on three model compounds, namely caffeine, metoprolol and midazolam, based on the knowledge of their disposition in nonpregnant women and information from in vitro studies. A perfusion-limited form of a 13-compartment full-PBPK model (Simcyp® Simulator) was used for the nonpregnant women, and this was extended to the pregnant state by applying known changes to all model components (including the gestational related activity of specific cytochrome P450 enzymes) and through the addition of an extra compartment to represent the fetoplacental unit. The uterus and the mammary glands were grouped into the muscle compartment. The model was implemented in Matlab Simulink and validated using clinical observations. The p-PBPK model predicted the PK changes of three model compounds (namely caffeine, metoprolol and midazolam) for CYP1A2, CYP2D6 and CYP3A4 during pregnancy within twofold of observed values. The changes during the third trimester were predicted to be a 100% increase, a 30% decrease and a 35% decrease in the exposure of caffeine, metoprolol and midazolam, respectively, compared with the nonpregnant women. In the absence of clinical data, the in silico prediction of PK behaviour during pregnancy can provide a valuable aid to dose adjustment in pregnant women. The performance of the model for drugs metabolized by a single enzyme to different degrees (high and low extraction) and for drugs that are eliminated by several different routes warrants further study.

Resurgence in the use of physiologically based pharmacokinetic models in pediatric clinical pharmacology: parallel shift in incorporating the knowledge of biological elements and increased applicability to drug development and clinical practice

(i) To describe an example of the development work required for building a 'pediatric physiologically based pharmacokinetic' (P-PBPK) model (Simcyp Pediatric ADME Simulator), (ii) to replicate pediatric clinical studies and undertake theoretical studies to show the potential applications of mechanistic PBPK in pediatric drug clinical investigation and practice, with emphasis on pediatric anesthesia. PBPK models draw together the physiological and biochemical information that determine drug absorption, distribution, metabolism, and excretion and then link them in a physiologically realistic 'systems' model. Incorporating the emerging additional information on developmental physiology and biochemistry has resulted in the creation of P-PBPK. There has been a renewed interest in the application of such modeling by the pharmaceutical industry to improve the efficiency of drug development, especially in populations where designing and conducting clinical studies is more challenging, such as pediatric patients. P-PBPK was used to simulate a number of published clinical studies and clinical case scenarios with the aim of highlighting the potential applications. Changing the P-PBPK model parameters in a number of 'what if' simulations were used to explore the likely underlying reasons for observed pharmacokinetic (PK) behavior of drugs in critically ill children. In addition, the use of P-PBPK models to predict complex drug-drug interactions (DDI) highlighted disparities with adult populations. The examples highlight the use of prior knowledge of in vitro drug attributes and biology of the system (human body) to simulate PK and multiple DDI scenarios not infrequently encountered in critically ill pediatric patients.