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Pharmacotherapy during lactation often lacks reliable drug safety data, resulting in delayed treatment or early cessation of breastfeeding. tools, such as physiologically-based pharmacokinetic (PBPK) models, can help to bridge this knowledge gap. To increase the accuracy of these models, it is essential to account for the physiological changes that occur throughout the postpartum period. This study aimed to collect and analyze data on the longitudinal changes in various physiological parameters that can affect drug distribution into breast milk during lactation. Following meta-analysis of the collated data, mathematical functions were fitted to the available data for each parameter. The best-performing functions were selected through numerical and visual diagnostics. The literature search identified 230 studies, yielding a dataset of 36,689 data points from 20,801 postpartum women, covering data from immediately after childbirth to 12 months postpartum. Sufficient data were obtained to describe postpartum changes in maternal plasma volume, breast volume, cardiac output, glomerular filtration rate, haematocrit, human serum albumin, alpha-1-acid glycoprotein, milk pH, milk volume, milk fat, milk protein, milk water content, and daily infant milk intake. Although data beyond 7 months postpartum were limited for some parameters, mathematical functions were generated for all parameters. These functions can be integrated into lactation PBPK models to increase their predictive power and better inform medication efficacy and safety for breastfeeding women.

Cholestasis underlies one of the major manifestations of drug-induced liver injury. Drug-induced cholestatic liver toxicity is a complex process, as it can be triggered by a variety of factors that induce 2 types of biological responses, namely a deteriorative response, caused by bile acid accumulation, and an adaptive response, aimed at removing the accumulated bile acids. Several key events in both types of responses have been characterized in the past few years. In parallel, many efforts have focused on the development and further optimization of experimental cell culture models to predict the occurrence of drug-induced cholestatic liver toxicity in vivo. In this paper, a state-of-the-art overview of mechanisms and in vitro models of drug-induced cholestatic liver injury is provided.

Bosentan is the first approved oral medication for pulmonary arterial hypertension, yet the black‐box warning on its labeling implies a substantial risk of liver injury associated with bosentan exposure. The risk assessment of bosentan‐induced liver injury requires a thorough understanding of the underlying mechanisms, for which there is accumulating evidence. Integrating these mechanisms with clinical liver bosentan concentration would enable a more dynamic and relevant risk assessment. This study designed a workflow of physiologically−based pharmacokinetic (PBPK) model development to capture bosentan's hepatic disposition and predict the (intra)hepatic bosentan exposure. Specifically, clinical plasma and excretion data of bosentan were used to minimize the uncertainty in estimating the hepatic clearance. The model predictions were well overlapped with observations in the systemic circulation and excretion. Furthermore, the model‐derived intrinsic hepatic clearance was comparable with the one derived from a clinical study. These results reflected confidence in the model's capability to predict hepatic bosentan exposure. The model‐simulated steady‐state unbound exposure to bosentan in hepatocytes and liver tissue ranged from 1.65 to 34.1 ng/mL following twice‐daily 125‐mg oral doses. The ratio of the simulated unbound concentration between the liver matrices and systemic plasma was between 0.80 and 2.93 across the therapeutic dosing regimens. In summary, a bosentan PBPK model was successfully developed with the designed workflow and was able to predict the hepatic disposition of bosentan. The developed model can be applied to generate hepatic bosentan exposure that bridges the toxicological mechanistic findings from in vitro to in vivo, assisting in risk assessment.

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.

Introduction: Quantitative information on disposition of maternal medicines in human milk remains a major knowledge gap. This case report presents the clinical and pharmacokinetic data of a single mother-infant pair exposed to bosentan and sildenafil for the treatment of pulmonary arterial hypertension (PAH) during lactation. Case presentation: A 43-year old mother was treated with sildenafil (20 mg, 3x/day) and bosentan (125 mg, 2x/day) for PAH. Her 21-months old infant received breastfeeding in combination with adequate complementary foods. Milk samples were collected over 24 h, at day 637 and 651 after delivery. The observed average steady-state concentrations of sildenafil (2.84 μg/L) and bosentan (49.0 μg/L) in human milk were low. The Daily Infant Dosage ingested by the nursing infant through human milk was 0.02 μg/kg/day for sildenafil and 0.29 μg/kg/day for bosentan at day 637, and 0.03 μg/kg/day and 0.60 μg/kg/day at day 651. The Relative Infant Dose calculated for an exclusively breastfed infant with an estimated milk intake of 150 ml/kg/day, was 0.06% for sildenafil and 0.24% for bosentan. General health outcome of the infant, reported by the mother, was uneventful until the sampling days. Conclusion: Low medicine concentrations were found in human milk expressed 21 months after delivery after maternal intake of 20 mg sildenafil three times daily and 125 mg bosentan twice daily. General health of the nursing infant until sampling was reported as optimal by the mother.

The ConcePTION project aims at generating further knowledge about the risks related to the use of medication during breastfeeding, as this information is lacking for most commonly used drugs. Taking into consideration multiple aspects, the pig model has been considered by the consortium as the most appropriate choice. The present research was planned to develop an efficient method for the isolation and culture of porcine Mammary Epithelial Cells (pMECs) to study the mammary epithelial barrier in vitro. Mammary gland tissues were collected at a local slaughterhouse, dissociated and the selected cellular population was cultured, expanded and characterized by morphology, cell cycle analysis and immunophenotyping. Their ability to create a barrier was tested by TEER measurement and sodium fluorescein transport activity. Expression of 84 genes related to drug transporters was evaluated by a PCR array. Our results show that primary cells express epithelial cell markers: CKs, CK18, E-Cad and tight junctions molecules ZO-1 and OCL. All the three pMEC cellular lines were able to create a tight barrier, although with different strengths and kinetics, and express the main ABC and SLC drug transporters. In conclusion, in the present paper we have reported an efficient method to obtain primary pMEC lines to study epithelial barrier function in the pig model.

Background/Objectives: Hydroxyurea is currently the standard disease-modifying therapy for reducing sickle cell disease (SCD) complications; however, drug labels currently advise discontinuation of breastfeeding during hydroxyurea therapy due to limited human data on the risk of hydroxyurea exposure in breastfed neonates. Methods: A physiologically based pharmacokinetic (PBPK) model for hydroxyurea was built and verified with data from non-lactating adult patients with SCD. The model was then extended to predict hydroxyurea in nursing and in paediatric populations. Predictions were compared to the observed data. Results: The PBPK model predictions for hydroxyurea pharmacokinetics described the observed data in both adult and paediatric subjects with SCD. Observed concentration profiles were within the 5th–95th prediction intervals, and predicted PK parameters were within 2-fold of the observed values. The predicted milk-to-plasma ratio was 0.8. Neonatal exposure to hydroxyurea via breast milk as a percentage of maternal exposure increased from 0.6% at 1 day to 10% at the 4th week postpartum before declining to 5%, 3%, and 2% at 6, 9, and 12 months postpartum, respectively. Conclusions: About 56% of total milk hydroxyurea exposure is within the first 3 h of post-maternal dose. Disposal of this early milk would reduce the exposure of breastfed children. The reduction in exposure is especially pronounced around the first 1 month postpartum. Lactation PBPK models offer a physiological approach to assess real-life scenarios that are difficult to investigate in clinical studies and provide useful results for future clinical study design and clinical recommendations. This was exemplified with hydroxyurea in the current work.

PurposeColistin is an antibiotic which is increasingly used as a last-resort therapy in critically-ill patients with multidrug resistant Gram-negative infections. The purpose of this study was to evaluate the mechanisms underlying colistin’s pharmacokinetic (PK) behavior and to characterize its hepatic metabolism.MethodsIn vitro incubations were performed using colistin sulfate with rat liver microsomes (RLM) and with rat and human hepatocytes (RH and HH) in suspension. The uptake of colistin in RH/HH and thefraction of unbound colistin in HH (fu,hep) was determined. In vitro to in vivo extrapolation (IVIVE) was employed to predict the hepatic clearance (CLh) of colistin.ResultsSlow metabolism was detected in RH/HH, with intrinsic clearance (CLint) values of 9.34± 0.50 and 3.25 ± 0.27 mL/min/kg, respectively. Assuming the well-stirred model for hepatic drug elimination, the predicted rat CLh was 3.64± 0.22 mL/min/kg which could explain almost 70% of the reported non-renal in vivo clearance. The predicted human CLh was 91.5 ± 8.83 mL/min, which was within two-fold of the reported plasma clearance in healthy volunteers. When colistin was incubated together with the multidrug resistance-associated protein (MRP/Mrp) inhibitor benzbromarone, the intracellular accumulation of colistin in RH/HH increased significantly.ConclusionThese findings indicate the major role of hepatic metabolism in the non-renal clearance of colistin, while MRP/Mrp-mediated efflux is involved in the hepatic disposition of colistin. Our data provide detailed quantitative insights into the hereto unknown mechanisms responsible for non-renal elimination of colistin.

Bile salts are biosurfactants released into the intestinal lumen which play an important role in the solubilisation of fats and certain drugs. Their concentrations vary along the gastrointestinal tract (GIT). This is significant for implementation in physiologically based pharmacokinetic (PBPK) modelling to mechanistically capture drug absorption. The aims of this meta-analysis were to collate all appropriate data on intestinal bile salt concentrations in healthy adults across all GIT segments in fasted and fed states for the purpose of PBPK modelling. Terms relating to bile composition were searched in PubMed and Google Scholar from inception to May 2024. Selected studies included aspirated intestinal fluid collected via gastric tubes or colonoscopy. Results showed high variability across studies and a time-dependency for the fed state. Data were rich for the duodenum, which showed a two-fold increase for the fed state versus the fasted state within multiple studies. Peaks and troughs in bile salt concentrations along the GIT were observed for both fasted and fed states, likely due to segmental water absorption differences. The highest between subject variability was observed for the duodenum in the fasted and fed state and the fed proximal jejunum, distal ileum, and colon. The findings from this meta-analysis can be used for the purpose of PBPK modelling to capture segmental drug solubilisation and absorption in fasted and fed states. However, data are lacking under different fed conditions, especially following low-fat meals, so the impact of different fat content associated with different meals on bile salt concentrations cannot be discerned. Graphical Abstract Gastrointestinal bile salt concentrations in healthy subjects A meta-analysis has been conducted to collate fasted and fed gastrointestinal bile salt concentrations in healthy subjects for the purpose of physiologically-based pharmacokinetic (PBPK) modelling within the Simcyp and other PBPK simulators. Values are presented as weighted means with coefficient of variability for each segment. These data will help improve mechanistic models of oral drug absorption.

Background Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. Objectives The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. Methods The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO ( AL lopurinol in addition to TH for hypoxic-ischemic B rain I njury on N eurocognitive O utcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. Results Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). Conclusions Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. Trial Registration ClinicalTrials.gov identifier NCT03162653.