Towards More Robust Evaluation of the Predictive Performance of Physiologically Based Pharmacokinetic Models: Using Confidence Intervals to Support Use of Model-Informed Dosing in Clinical Care.

BACKGROUND AND OBJECTIVE: With the rise in the use of physiologically based pharmacokinetic (PBPK) modeling over the past decade, the use of PBPK modeling to underpin drug dosing for off-label use in clinical care has become an attractive option. In order to use PBPK models for high-impact decisions, thorough qualification and validation of the model is essential to gain enough confidence in model performance. Currently, there is no agreed method for model acceptance, while clinicians demand a clear measure of model performance before considering implementing PBPK model-informed dosing. We aim to bridge this gap and propose the use of a confidence interval for the predicted-to-observed geometric mean ratio with predefined boundaries. This approach is similar to currently accepted bioequivalence testing procedures and can aid in improved model credibility and acceptance. METHODS: Two different methods to construct a confidence interval are outlined, depending on whether individual observations or aggregate data are available from the clinical comparator data sets. The two testing procedures are demonstrated for an example evaluation of a midazolam PBPK model. In addition, a simulation study is performed to demonstrate the difference between the twofold criterion and our proposed method. RESULTS: Using midazolam adult pharmacokinetic data, we demonstrated that creating a confidence interval yields more robust evaluation of the model than a point estimate, such as the commonly used twofold acceptance criterion. Additionally, we showed that the use of individual predictions can reduce the number of required test subjects. Furthermore, an easy-to-implement software tool was developed and is provided to make our proposed method more accessible. CONCLUSIONS: With this method, we aim to provide a tool to further increase confidence in PBPK model performance and facilitate its use for directly informing drug dosing in clinical care.

Placental transfer of tofacitinib in the ex vivo dual-side human placenta perfusion model.

Tofacitinib is a small molecule Janus kinase (JAK) inhibitor, introduced to the European market in 2017, for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. In the treatment of women with autoimmune diseases, pregnancy is a relevant issue, as such diseases typically affect women in their reproductive years. Currently, there is limited data on the use of tofacitinib during pregnancy. To estimate the extent of placental transfer in the absence of clinical data, we conducted ex vivo dual-side perfused human placental cotyledon perfusions. Term placentas were perfused for 180 min with tofacitinib (100 nM, added to the maternal circuit) in a closed-closed configuration. At the end of the perfusions, drug concentrations in the maternal and fetal reservoirs were near equilibrium, at 35.6 ± 5.5 and 24.8 ± 4.7 nM, respectively. Transfer of tofacitinib was similar to that observed for the passive diffusion marker antipyrine (100 µg/mL, added to the maternal reservoir). Final antipyrine maternal and fetal concentrations amounted to 36.9 ± 3.0 and 36.7 ± 1.3 µg/mL, respectively. In conclusion, in the ex vivo perfused placenta tofacitinib traverses the placental barrier rapidly and extensively. This suggests that substantial fetal tofacitinib exposure will take place after maternal drug dosing.

The impact of obesity on doravirine exposure in people with HIV.

Obesity incidence is increasing among people with HIV. Doravirine is a recommended first-line antiretroviral drug in many countries with no data from people with obesity. This study investigates the exposure of doravirine 100 mg standard dose in obese versus normal weight patients using clinical data combined with physiologically based pharmacokinetic modelling. Results from both approaches showed an elevated doravirine exposure during obesity, yet within the safety range of doravirine with no need for dose modification.

Pragmatic physiologically-based pharmacokinetic modeling to support clinical implementation of optimized gentamicin dosing in term neonates and infants: proof-of-concept.

Introduction: Modeling and simulation can support dosing recommendations for clinical practice, but a simple framework is missing. In this proof-of-concept study, we aimed to develop neonatal and infant gentamicin dosing guidelines, supported by a pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach and a decision framework for implementation. Methods: An already existing PBPK model was verified with data of 87 adults, 485 children and 912 neonates, based on visual predictive checks and predicted-to-observed pharmacokinetic (PK) parameter ratios. After acceptance of the model, dosages now recommended by the Dutch Pediatric Formulary (DPF) were simulated, along with several alternative dosing scenarios, aiming for recommended peak (i.e., 8-12 mg/L for neonates and 15-20 mg/L for infants) and trough (i.e., <1 mg/L) levels. We then used a decision framework to weigh benefits and risks for implementation. Results: The PBPK model adequately described gentamicin PK. Simulations of current DPF dosages showed that the dosing interval for term neonates up to 6 weeks of age should be extended to 36-48 h to reach trough levels <1 mg/L. For infants, a 7.5 mg/kg/24 h dose will reach adequate peak levels. The benefits of these dose adaptations outweigh remaining uncertainties which can be minimized by routine drug monitoring. Conclusion: We used a PBPK model to show that current DPF dosages for gentamicin in term neonates and infants needed to be optimized. In the context of potential uncertainties, the risk-benefit analysis proved positive; the model-informed dose is ready for clinical implementation.

Physiologically-Based Pharmacokinetic Modeling for Drug Dosing in Pediatric Patients: A Tutorial for a Pragmatic Approach in Clinical Care.

It is well-accepted that off-label drug dosing recommendations for pediatric patients should be based on the best available evidence. However, the available traditional evidence is often low. To bridge this gap, physiologically-based pharmacokinetic (PBPK) modeling is a scientifically well-founded tool that can be used to enable model-informed dosing (MID) recommendations in children in clinical practice. In this tutorial, we provide a pragmatic, PBPK-based pediatric modeling workflow. For this approach to be successfully implemented in pediatric clinical practice, a thorough understanding of the model assumptions and limitations is required. More importantly, careful evaluation of an MID approach within the context of overall benefits and the potential risks is crucial. The tutorial is aimed to help modelers, researchers, and clinicians, to effectively use PBPK simulations to support pediatric drug dosing.

Physiologically Based Pharmacokinetic (PBPK) Model-Informed Dosing Guidelines for Pediatric Clinical Care: A Pragmatic Approach for a Special Population.

Physiologically based pharmacokinetic (PBPK) modeling can be an attractive tool to increase the evidence base of pediatric drug dosing recommendations by making optimal use of existing pharmacokinetic (PK) data. A pragmatic approach of combining available compound models with a virtual pediatric physiology model can be a rational solution to predict PK and hence support dosing guidelines for children in real-life clinical care, when it can also be employed by individuals with little experience in PBPK modeling. This comes within reach as user-friendly PBPK modeling platforms exist and, for many drugs and populations, models are ready for use. We have identified a list of drugs that can serve as a starting point for pragmatic PBPK modeling to address current clinical dosing needs.

Feasibility of a Pragmatic PBPK Modeling Approach: Towards Model-Informed Dosing in Pediatric Clinical Care.

BACKGROUND AND OBJECTIVE: More than half of all drugs are still prescribed off-label to children. Pharmacokinetic (PK) data are needed to support off-label dosing, however for many drugs such data are either sparse or not representative. Physiologically-based pharmacokinetic (PBPK) models are increasingly used to study PK and guide dosing decisions. Building compound models to study PK requires expertise and is time-consuming. Therefore, in this paper, we studied the feasibility of predicting pediatric exposure by pragmatically combining existing compound models, developed e.g. for studies in adults, with a pediatric and preterm physiology model. METHODS: Seven drugs, with various PK characteristics, were selected (meropenem, ceftazidime, azithromycin, propofol, midazolam, lorazepam, and caffeine) as a proof of concept. Simcyp® v20 was used to predict exposure in adults, children, and (pre)term neonates, by combining an existing compound model with relevant virtual physiology models. Predictive performance was evaluated by calculating the ratios of predicted-to-observed PK parameter values (0.5- to 2-fold acceptance range) and by visual predictive checks with prediction error values. RESULTS: Overall, model predicted PK in infants, children and adolescents capture clinical data. Confidence in PBPK model performance was therefore considered high. Predictive performance tends to decrease when predicting PK in the (pre)term neonatal population. CONCLUSION: Pragmatic PBPK modeling in pediatrics, based on compound models verified with adult data, is feasible. A thorough understanding of the model assumptions and limitations is required, before model-informed doses can be recommended for clinical use.

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.

Ex vivo dual perfusion of an isolated human placenta cotyledon: Towards protocol standardization and improved inter-centre comparability.

Since the full development of the ex vivo dual perfusion model of the human placenta cotyledon, the technique has provided essential insight into how nutrients, lipids, gases, immunoglobulins, endocrine agents, pharmaceuticals, chemicals, nanoparticles, micro-organisms and parasites might traverse the maternofetal barrier. Additionally, the model has been instrumental in gaining a better understanding of the regulation of vascular tone, endocrinology and metabolism within this organ. The human placenta is unique amongst species in its anatomy and transfer modalities. This orthologous diversity therefore requires an appropriate consideration of placental transfer rates of compounds, particles and micro-organisms specific to humans. Different research centres have adapted this model with a wide variation in perfusion parameters, including in the establishment of perfusion, perfusate composition, gassing regime, cannulation method, flow rates, perfused tissue mass, and also in the application of quality control measures. The requirement to harmonise and standardise perfusion practice between centres is largely driven by the need to obtain consistency in our understanding of placental function, but also in the qualification of the model for acceptance by regulatory agencies in drug and toxicology testing. A pilot study is proposed, aiming to describe how existing inter-centre variation in perfusion methodology affects placental metabolism, protein synthesis, oxygen consumption, the materno-fetal transfer of key molecular markers, and placental structure.

Non-clinical considerations for supporting accelerated inclusion of pregnant women in pre-licensure clinical trials with anti-HIV agents.

INTRODUCTION: To allow the continued participation of women enrolled in pre-licensure clinical trials who become pregnant, and to potentially enrol pregnant women in clinical trials, non-clinical developmental and reproductive toxicology studies (DART) are essential. Generally during pharmaceutical development, DART studies are conducted late during clinical development, leading to the exclusion of pregnant women from enrolment and withdrawal of women becoming pregnant during pre-licensure trials. DISCUSSION: Completing all DART studies prior to or early during the conduct of phase 3 trials (i.e. earlier than current common practice) can accelerate and facilitate the inclusion of women who become pregnant during pre-licensure trials to remain on study drug and to potentially enrol pregnant women more rapidly. Promoting complementary strategies, such as alternative combinations of DART study designs and physiologically based pharmacokinetic modelling, could better inform drug dosing and safety in pregnancy at an earlier stage in drug development. The interpretation of the results of non-clinical DART studies is often complex. Institutional review boards/ethics committees should have access to relevant expertise for interpretation and application of results of non-clinical developmental and reproductive toxicity studies. Clear communication and thorough understanding of non-clinical findings and the overall benefit-risk profile of the product are critical to review protocols and determine if women who become pregnant during a clinical trial could continue on study drug and/or to enrol pregnant women in the trial. The informed consent document should be well written so that participants can make an informed decision to stay on study drug or participate in a trial during pregnancy. Ultimately, the decision to allow women who become pregnant during pre-licensure trials to remain on study will depend on the totality of the evidence and benefit-risk considerations. CONCLUSIONS: We propose that industry completes non-clinical reproductive toxicity studies prior to or early during the conduct of phase 3 trials in HIV drug development, especially for priority agents, and potentially uses alternative DART study design strategies to achieve this goal.

Effects of tumor necrosis factor on undifferentiated and syncytialized placental choriocarcinoma BeWo cells.

Tumor necrosis factor (TNF) regulates trophoblast turnover during the formation of the placental syncytium and can be a potentially relevant target for adverse effects of xenobiotics. We mimicked syncytialization in vitro by stimulating BeWo cells with 50 µM forskolin. Undifferentiated and syncytialized BeWo cells were exposed to TNF (10 pg/mL-10 ng/mL) for 48 h after which cell viability, progesterone release and gene expression of a selected set of markers representative for placental function were assessed. In undifferentiated BeWo cells, high TNF levels (1-10 ng/mL) increased gene expression of TNF, NF-κB, and TNFRSF1B to maximally 99 ± 17, 2.2 ± 0.2, and 3.0 ± 0.4 of control values, respectively (p < 0.001). These effects were also found in syncytialized BeWo cells but less pronounced. Additionally, TNF may induce syncytialization in BeWo cells as it upregulated ERVW-1 expression by 1.55 ± 0.14-fold (p < 0.05). On the contrary, TNF levels of 10 and 100 pg/mL did not affect gene expression in both undifferentiated and syncytialized BeWo cells, but did enhance cell viability in syncytialised BeWo cells (p < 0.001). In conclusion, we found that high TNF levels (1-10 ng/mL) increased gene expression of TNF, NF-κB, and TNFRSF1B especially in undifferentiated BeWo cells, while physiological TNF concentrations positively affected cell viability and while there was no effect on any of the investigated functional markers.

Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling.

Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.

Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.

Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 µg/mL, while C5-eculizumab levels were 22 and 26 µg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 µg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 µg/g, and of C5 20 ± 3 and 30 ± 2 µg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.

Toxicity of anticancer drugs in human placental tissue explants and trophoblast cell lines.

The application of anticancer drugs during pregnancy is associated with placenta-related adverse pregnancy outcomes. Therefore, it is important to study placental toxicity of anticancer drugs. The aim of this study was to compare effects on viability and steroidogenesis in placental tissue explants and trophoblast cell lines. Third trimester placental tissue explants were exposed for 72 h (culture day 4-7) to a concentration range of doxorubicin, paclitaxel, cisplatin, carboplatin, crizotinib, gefitinib, imatinib, or sunitinib. JEG-3, undifferentiated BeWo, and syncytialised BeWo cells were exposed for 48 h to the same drugs and concentrations. After exposure, tissue and cell viability were assessed and progesterone and estrone levels were quantified in culture medium. Apart from paclitaxel, all compounds affected both cell and tissue viability at clinically relevant concentrations. Paclitaxel affected explant viability moderately, while it reduced cell viability by 50% or more in all cell lines, at 3-10 nM. Doxorubicin (1 µM) reduced viability in explants to 83 ± 7% of control values, whereas it fully inhibited viability in all cell types. Interference with steroid release in explants was difficult to study due to large variability in measurements, but syncytialised BeWo cells proved suitable for this purpose. We found that 1 µM sunitinib reduced progesterone release to 76 ± 6% of control values, without affecting cell viability. While we observed differences between the models for paclitaxel and doxorubicin, most anticancer drugs affected viability significantly in both placental explants and trophoblast cell lines. Taken together, the placenta should be recognized as a potential target organ for toxicity of anticancer drugs.

[Black particles in plasma and carcinogenic pills]. / Zwarte deeltjes in plasma en kankerverwekkende pillen.

Recently in a national newspaper presumed large hazards in care were described. Visible black particles were seen in blood plasma and a cancerogenic substance was found in paracetamol. Every year 300.000 bags of plasma are produced. The black particles were found in 11 bags of plasma. Possibly one of these was administered. During administration 175 micron filters are used. Presumably remaining particles will be degraded by the mononuclear-phagocytic system. In paracetamol 6 ppm of para-chloroaniline was found. Depending of the limit used by either the ICH or the EFSA this means for patients using lifelong 6 grams of paracetamol a risk off respectively 1: 200.000 or 1:20.000. This risk is neglectable compared of the life time risks of cancer in the population (1:3). Journalists should realize that this exaggerated commentary can lead to real serious risks (taking NSAID's instead of paracetamol) and mistrust in regular care.

Assessment of Placental Disposition of Infliximab and Etanercept in Women With Autoimmune Diseases and in the Ex Vivo Perfused Placenta.

Tumor necrosis factor (TNF) inhibitors are increasingly applied during pregnancy without clear knowledge of the impact on placenta and fetus. We assessed placental transfer and exposure to infliximab (n = 3) and etanercept (n = 3) in women with autoimmune diseases. Furthermore, we perfused healthy term placentas for 6 hours with 100 µg/mL infliximab (n = 4) or etanercept (n = 5). In pregnant women, infliximab transferred into cord blood but also entered the placenta (cord-to-maternal ratio of 1.6 ± 0.4, placenta-to-maternal ratio of 0.3 ± 0.1, n = 3). For etanercept, a cord-to-maternal ratio of 0.04 and placenta-to-maternal ratio of 0.03 was observed in one patient only. In ex vivo placenta perfusions, the extent of placental transfer did not differ between the drugs. Final concentrations in the fetal compartment for infliximab and etanercept were 0.3 ± 0.3 and 0.2 ± 0.2 µg/mL, respectively. However, in placental tissue, infliximab levels exceeded those of etanercept (19 ± 6 vs. 1 ± 3 µg/g, P < 0.001). In conclusion, tissue exposure to infliximab is higher than that of etanercept both in vivo as well as in ex vivo perfused placentas. However, initial placental transfer, as observed ex vivo, does not differ between infliximab and etanercept when administered in equal amounts. The difference in placental tissue exposure to infliximab and etanercept may be of clinical relevance and warrants further investigation. More specifically, we suggest that future studies should look into the occurrence of placental TNF inhibition and possible consequences thereof.

Impact of gastrointestinal physiology on drug absorption in special populations--An UNGAP review.

The release and absorption profile of an oral medication is influenced by the physicochemical properties of the drug and its formulation, as well as by the anatomy and physiology of the gastrointestinal (GI) tract. During drug development the bioavailability of a new drug is typically assessed in early clinical studies in a healthy adult population. However, many disease conditions are associated with an alteration of the anatomy and/or physiology of the GI tract. The same holds true for some subpopulations, such as paediatric or elderly patients, or populations with different ethnicity. The variation in GI tract conditions compared to healthy adults can directly affect the kinetics of drug absorption, and thus, safety and efficacy of an oral medication. This review provides an overview of GI tract properties in special populations compared to healthy adults and discusses how drug absorption is affected by these conditions. Particular focus is directed towards non-disease dependent conditions (age, sex, ethnicity, genetic factors, obesity, pregnancy), GI diseases (ulcerative colitis and Crohn's disease, celiac disease, cancer in the GI tract, Roux-en-Y gastric bypass, lactose intolerance, Helicobacter pylori infection, and infectious diseases of the GI tract), as well as systemic diseases that change the GI tract conditions (cystic fibrosis, diabetes, Parkinson's disease, HIV enteropathy, and critical illness). The current knowledge about GI conditions in special populations and their impact on drug absorption is still limited. Further research is required to improve confidence in pharmacokinetic predictions and dosing recommendations in the targeted patient population, and thus to ensure safe and effective drug therapies.

A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease.

BACKGROUND: Distal diuretics are considered less effective than loop diuretics in CKD. However, data to support this perception are limited. METHODS: To investigate whether distal diuretics are noninferior to dietary sodium restriction in reducing BP in patients with CKD stage G3 or G4 and hypertension, we conducted a 6-week, randomized, open-label crossover trial comparing amiloride/hydrochlorothiazide (5 mg/50 mg daily) with dietary sodium restriction (60 mmol per day). Antihypertension medication was discontinued for a 2-week period before randomization. We analyzed effects on BP, kidney function, and fluid balance and related this to renal clearance of diuretics. RESULTS: A total of 26 patients (with a mean eGFR of 39 ml/min per 1.73 m2) completed both treatments. Dietary sodium restriction reduced sodium excretion from 160 to 64 mmol per day. Diuretics produced a greater reduction in 24-hour systolic BP (SBP; from 138 to 124 mm Hg) compared with sodium restriction (from 134 to 129 mm Hg), as well as a significantly greater effect on extracellular water, eGFR, plasma renin, and aldosterone. Both interventions resulted in a similar decrease in body weight and NT-proBNP. Neither approaches decreased albuminuria significantly, whereas diuretics did significantly reduce urinary angiotensinogen and ß2-microglobulin excretion. Although lower eGFR and higher plasma indoxyl sulfate correlated with lower diuretic clearance, the diuretic effects on body weight and BP at lower eGFR were maintained. During diuretic treatment, higher PGE2 excretion correlated with lower free water clearance, and four patients developed mild hyponatremia. CONCLUSIONS: Distal diuretics are noninferior to dietary sodium restriction in reducing BP and extracellular volume in CKD. Diuretic sensitivity in CKD is maintained despite lower diuretic clearance. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: DD-study: Diet or Diuretics for Salt-sensitivity in Chronic Kidney Disease (DD), NCT02875886.

Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically-Based Pharmacokinetic Modeling.

Antiretroviral therapy during pregnancy reduces the risk of vertical HIV-1 transmission. However, drug dosing is challenging as pharmacokinetics (PK) may be altered during pregnancy. We combined a pregnancy physiologically-based pharmacokinetic (PBPK) modeling approach with data on placental drug transfer to simulate maternal and fetal exposure to dolutegravir (DTG). First, a PBPK model for DTG exposure in healthy volunteers was established based on physiological and DTG PK data. Next, the model was extended with a fetoplacental unit using transplacental kinetics obtained by performing ex vivo dual-side human cotyledon perfusion experiments. Simulations of fetal exposure after maternal dosing in the third trimester were in accordance with clinically observed DTG cord blood data. Furthermore, the predicted fetal trough plasma concentration (Ctrough ) following 50 mg q.d. dosing remained above the concentration that results in 90% of viral inhibition. Our integrated approach enables simulation of maternal and fetal DTG exposure, illustrating this to be a promising way to assess DTG PK during pregnancy.