Feras Khalil

Physiologically based pharmacokinetic modeling: methodology, applications, and limitations with a focus on its role in pediatric drug development.

The concept of physiologically based pharmacokinetic (PBPK) modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”.

Physiologically Based Pharmacokinetic Models in the Prediction of Oral Drug Exposure Over the Entire Pediatric Age Range—Sotalol as a Model Drug

In recent years, the increased interest in pediatric research has enforced the role of physiologically based pharmacokinetic (PBPK) models in pediatric drug development. However, an existing lack of published examples contributes to some uncertainties about the reliability of their predictions of oral drug exposure. Developing and validating pediatric PBPK models for oral drug application shall enrich our knowledge about their limitations and lead to a better use of the generated data. This study was conducted to investigate how whole-body PBPK models describe the oral pharmacokinetics of sotalol over the entire pediatric age. Two leading software tools for whole-body PBPK modeling: Simcyp® (Simcyp Ltd, Sheffield, UK) and PK-SIM® (Bayer Technology Services GmbH, Leverkusen, Germany), were used. Each PBPK model was first validated in adults before scaling to children. Model input parameters were collected from the literature and clinical data for 80 children were used to compare predicted and observed values. The results obtained by both models were comparable and gave an adequate description of sotalol pharmacokinetics in adults and in almost all pediatric age groups. Only in neonates, the mean ratio(Obs/Pred) for any PK parameter exceeded a twofold error range, 2.56 (95% confidence interval (CI), 2.10–3.49) and 2.15 (95% CI, 1.77–2.99) for area under the plasma concentration-time curve from the first to the last concentration point and maximal concentration (Cmax) using SIMCYP® and 2.37 (95% CI, 1.76–3.25) for time to reach Cmax using PK-SIM®. The two PBPK models evaluated in this study reflected properly the age-related pharmacokinetic changes and predicted adequately the oral sotalol exposure in children of different ages, except in neonates.

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows–A Physiologically Based Pharmacokinetic Approach

Chronic heart failure (CHF) is a systemic low perfusion syndrome resulting from impairment in the pumping function of the heart. The decrease in blood supply to body organs can potentially affect the pharmacokinetics (PK) of the drugs being administered. Carvedilol is administered as a racemic mixture and undergoes extensive stereoselective first pass metabolism. For such a drug, the pathophysiological changes occurring in CHF can have a profound impact on PK, and thus the resulting pharmacodynamic response, of both enantiomers. The aim of the current work was to predict stereoselective disposition of carvedilol after incorporating the pathophysiological changes in CHF into a whole-body physiologically based PK model using Simcyp, and to scale that model to pediatric CHF patients on a physiologic basis to investigate whether the same changes in the adult model can also be adopted for children. The developed model has successfully described PK of carvedilol enantiomers in healthy adults and in patients after the incorporation of reduced organ blood flows, as seen by the visual predictive checks and the calculated observed/predicted ratios for all PK parameters of interest. In contrast to adults, pediatric patients up to 12 years of age were better described without the reductions in organ blood flow, whereas older pediatric patients were better described after incorporating organ blood flow reductions. These findings indicate that the incorporated blood flow reductions in the adult model cannot be directly adopted in pediatrics, at least for the young ones; however, to draw definite conclusions, more data are still needed.

Author’s Reply to Zheng et al.: A Physiologically Based Pharmacokinetic Drug–Disease Model to Predict Carvedilol Exposure in Adult and Paediatric Heart Failure Patients by Incorporating Pathophysiological Changes in Hepatic and Renal Blood Flows

We would like to thank Li and colleagues for showing their interest in our recently published work [1], and appreciate their constructive remarks [2], which reflect the importance of scientific collaboration in this rapidly evolving and expanding multidisciplinary field. Our previous effort focused on the changes in renal and hepatic blood flows in chronic heart failure (CHF) as these are undoubtedly the most relevant haemodynamic changes with respect to drug clearance and, hence, the total drug exposure [1]. However, we do agree that incorporation of blood flow changes to additional organs and tissues, other than the liver and the kidney, may further improve the predictive performance of the previously reported models, especially with regard to drug absorption and distribution. In light of these considerations, we additionally adopted the reported blood flow changes to the skeletal muscle, bone, skin and adipose tissue in our model as mentioned by Li et al. in the presented Table 1. The results of the resimulations showed an improved visual fit to the observed data, which can be explained by an improved prediction of drug distribution in these patients (Fig. 1). As a result, the predicted values for maximum systemic concentration (Cmax) and time to Cmax (tmax) were partly improved, whereas the predicted area under the systemic drug concentration–time curve from time zero to the last measured concentration (AUClast) and the oral clearance remained almost the same with and without these additional blood flow changes (Table 1). Although the decrease in blood flow to the small intestine may lead to impaired drug absorption, no changes were made with respect to the blood flow to the intestine due to non-stratification of intestinal blood flow data with respect to severity of CHF [3, 4]. We also appreciate the valuable discussion provided by Li and colleagues about the possible impact of the used adult values for gastric pH, bile secretion, transporters and gut fluid dynamics on the accuracy of the carvedilol model predictions in infants. Nevertheless, we still remain conservative in simply excluding any age-related impact of these factors on the predicted drug absorption, especially with regard to the effect of gastrointestinal fluid volume and composition on the solubility, and thus the absorption of a Biopharmaceutics Classification System (BCS) class II drug such as carvedilol [5]. It is true that in our previous model the volume of fluid intake was not modified according to age, but this was due to a limitation in the advanced dissolution absorption and metabolism (ADAM) model for paediatric simulations in Simcyp version 13 (Simcyp Ltd, Sheffield, UK), which will not show the effect of any change on the drug solubility and absorption anyway. Paediatric drug absorption is, however, an area of ongoing research and the absorption models in the existing specialised physiologically based pharmacokinetic (PBPK) modelling platforms are constantly being updated and equipped with more age-specific physiological data. For example, the current Simcyp version 14 includes the first b-version of the paediatric ADAM model with corrected M. F. Rasool and F. Khalil contributed equally to this work.

PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS FOR ADULT AND PAEDIATRIC CHRONIC HEART FAILURE PATIENTS USING THE EXAMPLE OF CARVEDILOL TREATED PATIENTS

Background In chronic heart failure (CHF), the changes in organ blood flows can significantly affect the metabolism of drugs with high hepatic extraction. Physiologically based pharmacokinetic modelling (PBPK) can be utilized to predict clearances of high extraction drugs like carvedilol in CHF. The adult PBPK-CHF model after its evaluation in adults, can be scaled to pediatrics using population based PBPK simulator. Methods After a literature search for model input parameters, two-PBPK models were developed which differed only on the basis of clearance as, model-1 was based on human liver and intestinal microsomes clearance and model-2 was based on cytochrome-P450 clearances. Developed models were evaluated in healthy adults and in adult CHF patients, after incorporation of reduced organ blood flows. The evaluated adult CHF models were finally scaled to pediatric CHF patients using population based simulator Simcyp®. A two-fold error range for the ratios(Obs/Pred) of the pharmacokinetic parameters was used for model evaluation. Results The prediction results from both models were within the 2-fold error range but the initial absorption phase after oral drug application was slightly over predicted with model-1 on the other hand, the model-2 efficiently captured the oral absorption phase. The CL/F ratios(Obs/Pred) were clearly improved after incorporation of reduced organ blood flows in adult CHF patients. In pediatrics CHF patients, improvement in predictions were seen only in adolescents above 17 years of age, staged with NYHA system of classification. Conclusion There was a clear link between reduced organ blood flows and reduced carvedilol clearance in adult patients with CHF. It was suggested that Ross scoring system in pediatrics was not well correlated with organ blood flow reductions as the NYHA classification system. Due to the mechanistic nature of the developed models, they can be extended to other drugs with high hepatic extraction. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA) and from the Faculty Development Program BZ University Multan, Pakistan.

SAFETY OF ACE INHIBITORS IN CHILDREN WITH HEART FAILURE

Background ACE inhibitors (ACE-I) are a cornerstone in the treatment of children with heart failure. Little is known on the pharmacokinetics (PK) and pharmacodynamics (PD) of enalapril in children. LENA trials will investigate a novel child-appropriate solid drug formulation of enalapril and obtain PK, PD and safety data. For this study clear safety cut-offs need to determined. Aim To review the literature on safety of ACE-I in paediatric heart failure. Methods We searched electronic databases and reference lists of relevant studies. Inclusion criteria were 1. Randomized Controlled Trials (RCT), Controlled trials (CT), case reports or retrospective cohorts. 2. Patients under 18 years with congestive heart failure. 3. Any kind of ACE-I 4. Outcome measures: Mortality, hypotension, renal failure, hyperkalaemia, liver enzyme rise, cough, neutropenia. Results We assessed 12 of 593 articles as relevant: 2 RCTs, 5 CTs, 3 retrospective cohort studies and 2 case reports on a total of 734 children with heart failure. Systematic analyses was hampered by the heterogeneity of the study designs. In summary, we identified renal failure, hypotension and hyperkalemia as the most important side effects. Renal failure was found in 80 patients (11%), hypotension in 33 (4,5%) and hyperkalemia in 5 (0,7%). Five studies (n= 315 children) suggest that young age and low weight increases the risk of renal failure. Conclusions Renal failure, hypotension and hyperkalemia are the most reported adverse events in children on an ACE-I for heart failure. We defined strict adjusting- and stopping rules for enalapril based on an Acute Kidney Injury scale, b. on values of systolic blood pressure and on c. serum levels potassium. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).

Modelling and Simulation to Support Neonatal Clinical Trials

Modelling and simulation are acknowledged methodologies used by industry, academia, and regulatory agencies to support and optimize clinical trials and are used as data-analysis tools during various stages of the drug-development process. Conventional modelling and simulation tools are data driven, and besides their potential in clinical applications, particularly in establishing therapeutic dosage regimens and addressing factors responsible for the observed variability in drug behaviour in a certain population, these tools are unsuitable for use beyond the experimental data, e.g., for age extrapolation to neonates. In contrast, physiology-based pharmacokinetic (PBPK) models are mechanistic models that are independent of the measured concentrations and are based instead on the known anatomy and physiology of the living organism being modelled. They can also be used as a predictive tool to explore the changes in drug behaviour a priori, e.g., for age extrapolation, and are considered to be superior to classical compartmental models in this respect. This report will explore the potential contributions of PBPK models to paediatric and neonatal clinical trials, will give a brief overview of the basic concepts of PBPK modelling and, where it is appropriate, will provide an overview of examples of such models reported in the published literature.