Diagnosing an overcrowded emergency department from its Electronic Health Records.

Emergency department overcrowding is a complex problem that persists globally. Data of visits constitute an opportunity to understand its dynamics. However, the gap between the collected information and the real-life clinical processes, and the lack of a whole-system perspective, still constitute a relevant limitation. An analytical pipeline was developed to analyse one-year of production data following the patients that came from the ED (n = 49,938) at Uppsala University Hospital (Uppsala, Sweden) by involving clinical experts in all the steps of the analysis. The key internal issues to the ED were the high volume of generic or non-specific diagnoses from non-urgent visits, and the delayed decision regarding hospital admission caused by several imaging assessments and lack of hospital beds. Furthermore, the external pressure of high frequent re-visits of geriatric, psychiatric, and patients with unspecified diagnoses dramatically contributed to the overcrowding. Our work demonstrates that through analysis of production data of the ED patient flow and participation of clinical experts in the pipeline, it was possible to identify systemic issues and directions for solutions. A critical factor was to take a whole systems perspective, as it opened the scope to the boundary effects of inflow and outflow in the whole healthcare system.

Investigating the Connections Between Delivery of Care, Reablement, Workload, and Organizational Factors in Home Care Services: Mixed Methods Study.

BACKGROUND: Home care is facing increasing demand due to an aging population. Several challenges have been identified in the provision of home care, such as the need for support and tailoring support to individual needs. Goal-oriented interventions, such as reablement, may provide a solution to some of these challenges. The reablement approach targets adaptation to disease and relearning of everyday life skills and has been found to improve health-related quality of life while reducing service use. OBJECTIVE: The objective of this study is to characterize home care system variables (elements) and their relationships (connections) relevant to home care staff workload, home care user needs and satisfaction, and the reablement approach. This is to examine the effects of improvement and interventions, such as the person-centered reablement approach, on the delivery of home care services, workload, work-related stress, home care user experience, and other organizational factors. The main focus was on Swedish home care and tax-funded universal welfare systems. METHODS: The study used a mixed methods approach where a causal loop diagram was developed grounded in participatory methods with academic health care science research experts in nursing, occupational therapy, aging, and the reablement approach. The approach was supplemented with theoretical models and the scientific literature. The developed model was verified by the same group of experts and empirical evidence. Finally, the model was analyzed qualitatively and through simulation methods. RESULTS: The final causal loop diagram included elements and connections across the categories: stress, home care staff, home care user, organization, social support network of the home care user, and societal level. The model was able to qualitatively describe observed intervention outcomes from the literature. The analysis suggested elements to target for improvement and the potential impact of relevant studied interventions. For example, the elements "workload" and "distress" were important determinants of home care staff health, provision, and quality of care. CONCLUSIONS: The developed model may be of value for informing hypothesis formulation, study design, and discourse within the context of improvement in home care. Further work will include a broader group of stakeholders to reduce the risk of bias. Translation into a quantitative model will be explored.

Using Prior Knowledge on Systems Through PBPK to Gain Further Insight into Routine Clinical Data on Trough Concentrations: The Case of Tacrolimus in Chronic Kidney Disease.

BACKGROUND: Routine therapeutic drug monitoring (TDM) relies heavily on measuring trough drug concentrations. Trough concentrations are affected not only by drug bioavailability and clearance, but also by various patient and disease factors and the volume of distribution. This often makes interpreting differences in drug exposure from trough data challenging. This study aimed to combine the advantages of top-down analysis of therapeutic drug monitoring data with bottom-up physiologically-based pharmacokinetic (PBPK) modeling to investigate the effect of declining renal function in chronic kidney disease (CKD) on the nonrenal intrinsic metabolic clearance ( CLint ) of tacrolimus as a case example. METHODS: Data on biochemistry, demographics, and kidney function, along with 1167 tacrolimus trough concentrations for 40 renal transplant patients, were collected from the Salford Royal Hospital's database. A reduced PBPK model was developed to estimate CLint for each patient. Personalized unbound fractions, blood-to-plasma ratios, and drug affinities for various tissues were used as priors to estimate the apparent volume of distribution. Kidney function based on the estimated glomerular filtration rate ( eGFR ) was assessed as a covariate for CLint using the stochastic approximation of expectation and maximization method. RESULTS: At baseline, the median (interquartile range) eGFR was 45 (34.5-55.5) mL/min/1.73 m 2 . A significant but weak correlation was observed between tacrolimus CLint and eGFR (r = 0.2, P < 0.001). The CLint declined gradually (up to 36%) with CKD progression. Tacrolimus CLint did not differ significantly between stable and failing transplant patients. CONCLUSIONS: Kidney function deterioration in CKD can affect nonrenal CLint for drugs that undergo extensive hepatic metabolism, such as tacrolimus, with critical implications in clinical practice. This study demonstrates the advantages of combining prior system information (via PBPK) to investigate covariate effects in sparse real-world datasets.

Application of Process Mining for Modelling Small Cell Lung Cancer Prognosis.

Process mining is a relatively new method that connects data science and process modelling. In the past years a series of applications with health care production data have been presented in process discovery, conformance check and system enhancement. In this paper we apply process mining on clinical oncological data with the purpose of studying survival outcomes and chemotherapy treatment decision in a real-world cohort of small cell lung cancer patients treated at Karolinska University Hospital (Stockholm, Sweden). The results highlighted the potential role of process mining in oncology to study prognosis and survival outcomes with longitudinal models directly extracted from clinical data derived from healthcare.

A novel analytical framework for risk stratification of real-world data using machine learning: A small cell lung cancer study.

In recent studies, small cell lung cancer (SCLC) treatment guidelines based on Veterans' Administration Lung Study Group limited/extensive disease staging and resulted in broad and inseparable prognostic subgroups. Evidence suggests that the eight versions of tumor, node, and metastasis (TNM) staging can play an important role to address this issue. The aim of the present study was to improve the detection of prognostic subgroups from a real-word data (RWD) cohort of patients and analyze their patterns using a development pipeline with thoracic oncologists and machine learning methods. The method detected subgroups of patients informing unsupervised learning (partition around medoids) including the impact of covariates on prognosis (Cox regression and random survival forest). An analysis was carried out using patients with SCLC (n = 636) with stage IIIA-IVB according to TNM classification. The analysis yielded k = 7 compacted and well-separated clusters of patients. Performance status (Eastern Cooperative Oncology Group-Performance Status), lactate dehydrogenase, spreading of metastasis, cancer stage, and CRP were the baselines that characterized the subgroups. The selected clustering method outperformed standard clustering techniques, which were not capable of detecting meaningful subgroups. From the analysis of cluster treatment decisions, we showed the potential of future RWD applications to understand disease, develop individualized therapies, and improve healthcare decision making.

Integration of advanced methods and models to study drug absorption and related processes: An UNGAP perspective.

This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.

Review article: time to revisit Child-Pugh score as the basis for predicting drug clearance in hepatic impairment.

BACKGROUND: Prescription information for many drugs entering the market lacks dosage guidance for hepatic impairment. Dedicated studies for assessing the fate of drugs in hepatic impairment commonly stratify patients using Child-Pugh score. Child-Pugh is a prognostic clinical score with limitations in reflecting the liver's metabolic capacity. AIMS: To demonstrate the need for better drug dosing approaches in hepatic impairment, summarise the current status, identify knowledge gaps related to drug kinetic parameters in hepatic impairment, propose solutions for predicting the liver disease impact on drug exposure and discuss barriers to dosing guidance in those patients. METHODS: Relevant reports on dosage adjustment in hepatic impairment were analysed concerning the prediction of the impairment impact on drug kinetics using physiologically-based pharmacokinetic (PBPK) modelling. RESULTS: PBPK models are suggested as a potential framework to understand drug clearance changes in hepatic impairment. Quantifying changes in abundance and activity of drug-metabolising enzymes and transporters, understanding the impact of shunting, and accounting for interindividual variations in drug absorption could help in extending the success of these models in hepatically-impaired populations. These variables might not correlate with Child-Pugh score as a whole. Therefore, new metabolic activity markers, imaging techniques and other scoring systems are proposed to either support or substitute Child-Pugh score. CONCLUSIONS: Many physiological changes in hepatic impairment determining the fate of drugs do not necessarily correlate with Child-Pugh score. Quantifying these changes in individual patients is essential in future hepatic impairment studies. Further studies assessing Child-Pugh alternatives are recommended to allow better prediction of drug exposure.

Physiologically Based Pharmacokinetic Modeling of Transporter-Mediated Hepatic Disposition of Imaging Biomarker Gadoxetate in Rats.

Physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development to simulate changes in both systemic and tissue exposures that arise as a result of changes in enzyme and/or transporter activity. Verification of these model-based simulations of tissue exposure is challenging in the case of transporter-mediated drug-drug interactions (tDDI), in particular as these may lead to differential effects on substrate exposure in plasma and tissues/organs of interest. Gadoxetate, a promising magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). In this study, we developed a gadoxetate PBPK model and explored the use of liver-imaging data to achieve and refine in vitro-in vivo extrapolation (IVIVE) of gadoxetate hepatic transporter kinetic data. In addition, PBPK modeling was used to investigate gadoxetate hepatic tDDI with rifampicin i.v. 10 mg/kg. In vivo dynamic contrast-enhanced (DCE) MRI data of gadoxetate in rat blood, spleen, and liver were used in this analysis. Gadoxetate in vitro uptake kinetic data were generated in plated rat hepatocytes. Mean (%CV) in vitro hepatocyte uptake unbound Michaelis-Menten constant (Km,u) of gadoxetate was 106 µM (17%) (n = 4 rats), and active saturable uptake accounted for 94% of total uptake into hepatocytes. PBPK-IVIVE of these data (bottom-up approach) captured reasonably systemic exposure, but underestimated the in vivo gadoxetate DCE-MRI profiles and elimination from the liver. Therefore, in vivo rat DCE-MRI liver data were subsequently used to refine gadoxetate transporter kinetic parameters in the PBPK model (top-down approach). Active uptake into the hepatocytes refined by the liver-imaging data was one order of magnitude higher than the one predicted by the IVIVE approach. Finally, the PBPK model was fitted to the gadoxetate DCE-MRI data (blood, spleen, and liver) obtained with and without coadministered rifampicin. Rifampicin was estimated to inhibit active uptake transport of gadoxetate into the liver by 96%. The current analysis highlighted the importance of gadoxetate liver data for PBPK model refinement, which was not feasible when using the blood data alone, as is common in PBPK modeling applications. The results of our study demonstrate the utility of organ-imaging data in evaluating and refining PBPK transporter IVIVE to support the subsequent model use for quantitative evaluation of hepatic tDDI.

A latent variable approach to account for correlated inputs in global sensitivity analysis.

In drug development decision-making is often supported through model-based methods, such as physiologically-based pharmacokinetics (PBPK). Global sensitivity analysis (GSA) is gaining use for quality assessment of model-informed inference. However, the inclusion and interpretation of correlated factors in GSA has proven an issue. Here we developed and evaluated a latent variable approach for dealing with correlated factors in GSA. An approach was developed that describes the correlation between two model inputs through the causal relationship of three independent factors: the latent variable and the unique variances of the two correlated parameters. The latent variable approach was applied to a set of algebraic models and a case from PBPK. Then, this method was compared to Sobol's GSA assuming no correlations, Sobol's GSA with groups and the Kucherenko approach. For the latent variable approach, GSA was performed with Sobol's method. By using the latent variable approach, it is possible to devise a unique and easy interpretation of the sensitivity indices while maintaining the correlation between the factors. Compared methods either consider the parameters independent, group the dependent variables into one unique factor or present difficulties in the interpretation of the sensitivity indices. In situations where GSA is called upon to support model-informed decision-making, the latent variable approach offers a practical method, in terms of ease of implementation and interpretability, for applying GSA to models with correlated inputs that does not violate the independence assumption. Prerequisites and limitations of the approach are discussed.

Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy.

Model-informed precision dosing (MIPD) has become synonymous with modern approaches for individualizing drug therapy, in which the characteristics of each patient are considered as opposed to applying a one-size-fits-all alternative. This review provides a brief account of the current knowledge, practices, and opinions on MIPD while defining an achievable vision for MIPD in clinical care based on available evidence. We begin with a historical perspective on variability in dose requirements and then discuss technical aspects of MIPD, including the need for clinical decision support tools, practical validation, and implementation of MIPD in health care. We also discuss novel ways to characterize patient variability beyond the common perceptions of genetic control. Finally, we address current debates on MIPD from the perspectives of the new drug development, health economics, and drug regulations.

Application of the Nested Enzyme-Within-Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects.

The gut wall consists of many biological elements, including enterocytes. Rapid turnover, a prominent feature of the enterocytes, has generally been ignored in the development of enterocyte-targeting drugs, although it has a comparable rate to other kinetic rates. Here, we investigated the impact of enterocyte turnover on the pharmacodynamics of enterocyte-targeting drugs by applying a model accounting for turnover of enterocytes and target proteins. Simulations showed that the pharmacodynamics depend on enterocyte lifespan when drug-target affinity is strong and half-life of target protein is long. Interindividual variability of enterocyte lifespan, which can be amplified by disease conditions, has a substantial impact on the variability of response. However, our comprehensive literature search showed that the enterocyte turnover causes a marginal impact on currently approved enterocyte-targeting drugs due to their relatively weak target affinities. This study proposes a model-informed drug development approach for selecting enterocyte-targeting drugs and their optimal dosage regimens.

IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 4: Prediction accuracy and software comparisons with improved data and modelling strategies.

Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlus™ (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project. Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters. On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.

Global Sensitivity Analysis of the Rodgers and Rowland Model for Prediction of Tissue: Plasma Partitioning Coefficients: Assessment of the Key Physiological and Physicochemical Factors That Determine Small-Molecule Tissue Distribution.

In physiologically based pharmacokinetic (PBPK) modelling, the large number of input parameters, limited amount of available data and the structural model complexity generally hinder simultaneous estimation of uncertain and/or unknown parameters. These parameters are generally subject to estimation. However, the approaches taken for parameter estimation vary widely. Global sensitivity analyses are proposed as a method to systematically determine the most influential parameters that can be subject to estimation. Herein, a global sensitivity analysis was conducted to identify the key drug and physiological parameters influencing drug disposition in PBPK models and to potentially reduce the PBPK model dimensionality. The impact of these parameters was evaluated on the tissue-to-unbound plasma partition coefficients (Kpus) predicted by the Rodgers and Rowland model using Latin hypercube sampling combined to partial rank correlation coefficients (PRCC). For most drug classes, PRCC showed that LogP and fraction unbound in plasma (fup) were generally the most influential parameters for Kpu predictions. For strong bases, blood:plasma partitioning was one of the most influential parameter. Uncertainty in tissue composition parameters had a large impact on Kpu and Vss predictions for all classes. Among tissue composition parameters, changes in Kpu outputs were especially attributed to changes in tissue acidic phospholipid concentrations and extracellular protein tissue:plasma ratio values. In conclusion, this work demonstrates that for parameter estimation involving PBPK models and dimensionality reduction purposes, less influential parameters might be assigned fixed values depending on the parameter space, while influential parameters could be subject to parameters estimation.

Accounting for inter-correlation between enzyme abundance: a simulation study to assess implications on global sensitivity analysis within physiologically-based pharmacokinetics.

Physiologically based pharmacokinetic (PBPK) models often include several sets of correlated parameters, such as organ volumes and blood flows. Because of recent advances in proteomics, it has been demonstrated that correlations are also present between abundances of drug-metabolising enzymes in the liver. As the focus of population PBPK has shifted the emphasis from the average individual to theoretically conceivable extremes, reliable estimation of the extreme cases has become paramount. We performed a simulation study to assess the impact of the correlation between the abundances of two enzymes on the pharmacokinetics of drugs that are substrate of both, under assumptions of presence or lack of such correlations. We considered three semi-physiological models representing the cases of: (1) intravenously administered drugs metabolised by two enzymes expressed in the liver; (2) orally administered drugs metabolised by CYP3A4 expressed in the liver and gut wall; (3) intravenously administered drugs that are substrates of CYP3A4 and OATP1B1 in the liver. Finally, the impact of considering or ignoring correlation between enzymatic abundances on global sensitivity analysis (GSA) was investigated using variance based GSA on a reduced PBPK model for repaglinide, substrate of CYP3A4 and CYP2C8. Implementing such correlations can increase the confidence interval for population pharmacokinetic parameters (e.g., AUC, bioavailability) and impact the GSA results. Ignoring these correlations could lead to the generation of implausible parameters combinations and to an incorrect estimation of pharmacokinetic related parameters. Thus, known correlations should always be considered in building population PBPK models.

The nested enzyme-within-enterocyte (NEWE) turnover model for predicting dynamic drug and disease effects on the gut wall.

Physiologically-based pharmacokinetic (PBPK) models provide a framework for in vitro-in vivo extrapolation of metabolic drug clearance. Many of the concepts in PBPK can have consequential impact on more mechanistic systems pharmacology models. In the gut wall, turnover of enzymes and enterocytes are typically lumped into one rate constant that describes the time dependent enzyme activity. This assumption may influence predictability of any sustained and dynamic effects such as mechanism-based inhibition (MBI), particularly when considering translation from healthy to gut disease. A novel multi-level systems PBPK model was developed. This model comprised a 'nested enzyme-within enterocyte' (NEWE) turnover model to describe levels of drug-metabolising enzymes. The ability of the model to predict gut metabolism following MBI and gut disease was investigated and compared to the conventional modelling approach. For MBI, the default NEWE model performed comparably to the conventional model. However, when drug-specific spatial crypt-villous absorption was considered, up to approximately 50% lower impact of MBI was simulated for substrates highly metabolised by cytochrome P450 (CYP) 3A4, interacting with potent inhibitors. Further, the model showed potential in predicting the disease effect of gastrointestinal mucositis and untreated coeliac disease when compared to indirect clinical pharmacokinetic parameters. Considering the added complexity of the NEWE model, it does not provide an attractive solution for improving upon MBI predictions in healthy individuals. However, nesting turnover may enable extrapolation to gut disease-drug interactions. The principle detailed herein may be useful for modelling drug interactions with cellular targets where turnover is significant enough to affect this process.

What Does it Take to Make Model-Informed Precision Dosing Common Practice? Report from the 1st Asian Symposium on Precision Dosing.

Model-informed precision dosing (MIPD) is modeling and simulation in healthcare to predict the drug dose for a given patient based on their individual characteristics that is most likely to improve efficacy and/or lower toxicity in comparison to traditional dosing. This paper describes the background and status of MIPD and the activities at the 1st Asian Symposium of Precision Dosing. The theme of the meeting was the question, "What does it take to make MIPD common practice?" Formal presentations highlighted the distinction between genetic and non-genetic sources of variability in drug exposure and response, the use of modeling and simulation as decision support tools, and the facilitators to MIPD implementation. A panel discussion addressed the types of models used for MIPD, how the pharmaceutical industry views MIPD, ways to upscale MIPD beyond academic hospital centers, and the essential role of healthcare professional education as a way to progress. The meeting concluded with an ongoing commitment to use MIPD to improve patient care.

Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance.

In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CLR) using the physiologically based kidney models can provide mechanistic insight into the interplay of multiple processes occurring in the renal tubule; however, the ability of these models to capture quantitatively the impact of perturbed conditions (e.g., urine flow, urine pH changes) on CLR has not been fully evaluated. In this work, we aimed to assess the predictability of the effect of urine flow and urine pH on CLR and tubular drug concentrations (selected examples). Passive diffusion clearance across the nephron tubule membrane was scaled from in vitro human epithelial cell line Caco-2 permeability data by nephron tubular surface area to predict the fraction reabsorbed and the CLR of caffeine, chloramphenicol, creatinine, dextroamphetamine, nicotine, sulfamethoxazole, and theophylline. CLR values predicted using mechanistic kidney model at a urinary pH of 6.2 and 7.4 resulted in prediction bias of 2.87- and 3.62-fold, respectively. Model simulations captured urine flow-dependent CLR, albeit with minor underprediction of the observed magnitude of change. The relationship between drug solubility, urine flow, and urine pH, illustrated in simulated intratubular concentrations of acyclovir and sulfamethoxazole, agreed with clinical data on tubular precipitation and crystal-induced acute kidney injury. This study represents the first systematic evaluation of the ability of the mechanistic kidney model to capture the impact of urine flow and urine pH on CLR and drug tubular concentrations with the aim of facilitating refinement of IVIVE-based mechanistic prediction of renal excretion.

A study of the dosage and duration for levobupivacaine infusion by the caudal-epidural route in infants aged 3-6 months.

BACKGROUND: The local anesthetic, levobupivacaine, is the safer enantiomer of racemic bupivacaine. Present protocols for levobupivacaine are based on studies and pharmacokinetic modeling with racemic bupivacaine. AIMS: The aim is to investigate total serum levobupivacaine concentrations after a caudalepidural loading dose followed by a maintenance infusion over 48 hours in infants aged 3-6 months. METHODS: The clinical trial was conducted in eight infants aged 3-6 months, undergoing bladder exstrophy repair. Pharmacokinetic modeling allowed optimization of clinical sampling to measure total levobupivacaine and α1 -acid glycoprotein and prediction of the effect of α1 -acid glycoprotein on levobupivacaine plasma protein binding. RESULTS: The observed median total levobupivacaine serum concentration was 0.30 mg/L (range: 0.20-0.70 mg/L) at 1 hour after the loading dose of 2 mg/kg. The median total levobupivacaine concentration after 47 hours of infusion, at 0.2 mg/kg/h, was 1.21 mg/L (0.07-1.85 mg/L). Concentrations of α1 -acid glycoprotein were found to rise throughout the study period. Pharmacokinetic modeling suggested that unbound levobupivacaine quickly reached steady state at a concentration of approximately 0.03 mg/L. CONCLUSION: The study allows the development of a pharmacokinetic model, combining levobupivacaine and α1 -acid glycoprotein data. Modeling indicates that unbound levobupivacaine quickly reaches steady state once the infusion is started. Simulations suggest that it may be possible to continue the infusion beyond 48 hours.

Variance based global sensitivity analysis of physiologically based pharmacokinetic absorption models for BCS I-IV drugs.

Regulatory agencies have a strong interest in sensitivity analysis for the evaluation of physiologically-based pharmacokinetic (PBPK) models used in pharmaceutical research and drug development and regulatory submissions. One of the applications of PBPK is the prediction of fraction absorbed and bioavailability for drugs following oral administration. In this context, we performed a variance based global sensitivity analysis (GSA) on in-house PBPK models for drug absorption, with the aim of identifying key parameters that influence the predictions of the fraction absorbed and the bioavailability for neutral, acidic and basic compounds. This analysis was done for four different classes of drugs, defined according to the Biopharmaceutics Classification System, differentiating compounds by permeability and solubility. For class I compounds (highly permeable, highly soluble), the parameters that mainly influence the fraction absorbed are related to the formulation properties, for class II compounds (highly permeable, lowly soluble) to the dissolution process, for class III (lowly permeable, highly soluble) to both absorption process and formulation properties and for class IV (lowly permeable, lowly soluble) to both absorption and dissolution processes. Considering the bioavailability, the results are similar to those for the fraction absorbed, with the addition that parameters related to gut wall and liver clearance influence as well the predictions. This work aimed to give a demonstration of the GSA methodology and highlight its importance in improving our understanding of PBPK absorption models and in guiding the choice of parameters that can safely be assumed, estimated or require data generation to allow informed model prediction.