Adam S Darwich

KTH Royal Institute of Technology | KTH · School of Technology and Health

Demands for health care are becoming overwhelming for healthcare systems around the world regarding the availability of resources, particularly, in emergency departments (EDs) that are continuously open and must serve immediately any patient who comes in. Efficient management of EDs and their resources is required more than ever. This could be achi...

BACKGROUND Homecare is facing increasing demand due to an aging population. Several challenges have been identified in the provision of homecare, such as the need for support, and tailoring support to the individual needs. Goal-oriented interventions, such as reablement, may provide a solution to some of these challenges. The reablement approach ta...

In recent studies, small cell lung cancer (SCLC) treatment guidelines based on VALSG limited/extensive disease staging resulted in broad and inseparable prognostic subgroups. Evidence suggests that the eight version of TNM staging can play an important role to address this issue. The aim of the present study was to improve the detection of prognost...

PAGE 30 (2022) Abstr 10067 [www.page-meeting.org/?abstract=10067] Objectives: Stratification of patients to predict accurate prognostic outcomes and improve treatment selection is a crucial challenge in oncology [1]. Increased availability and utilization of real-world data (RWD) provides the opportunity to aid stratification from prognostic indic...

The age distribution has changed in Europe over the last decade. The group of 45 year-olds and above has increased and the median age in the EU is estimated to increase by 4.5 years during the next 3 decades reaching a median age of approximately 48.2 years according to Eurostat. A similar trend is noticeable in the United States, where the median...

A webinar series that was organised by the Academy of Pharmaceutical Sciences Biophar-maceutics focus group in 2021 focused on the challenges of developing clinically relevant dissolution specifications (CRDSs) for oral drug products. Industrial scientists, together with regulatory and academic scientists, came together through a series of six webi...

In this chapter, the authors delve deeper into the mechanisms that may affect intestinal first‐pass metabolism of modified‐release formulations as compared to immediate‐release formulations, the overall impact on a formidable barrier for limiting the bioavailability (F oral ). The most apparent contributors to the extent of gut wall metabolism are...

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...

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...

PAGE 29 (2021) Abstr 9742 [www.page-meeting.org/?abstract=9742] Introduction: Retrospective studies using clinical data from cancer patients usually are analysed using Cox Proportional Hazards CPH. [1] This approach has several limitations when it comes to evaluating effects of relevant covariates, such as lack of relative importance criterion be...

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...

Various factors influence mental well-being, and span individual, social and familial levels. These factors are connected in many ways, forming a complex web of factors and providing pathways for developing programs to improve well-being and for further research. These factors can be studied individually using traditional methods and mapped togethe...

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...

In pharmaceutical research and development decision-making related to drug candidate selection, efficacy and safety is commonly supported through modelling and simulation (M\&S). Among others, physiologically-based pharmacokinetic models are used to describe drug absorption, distribution and metabolism in human. Global sensitivity analysis (GSA) is...

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 ach...

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 en...

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 formu...

Access blocks throughout the entire healthcare system and overcrowding issues are pervasive in many emergency departments where the coordination and strategic management of resources could be supported by serious games and simulations approaches. However, existing studies have not addressed the reciprocal relation between patient inflow and working...

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 estim...

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 shifte...

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...

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 administrati...

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 desc...

Aim To investigate total serum levobupivacaine concentrations after a caudal‐epidural loading dose followed by a maintenance infusion in infants aged 3‐6 months over 48 hours. Background The local anaesthetic, levobupivacaine, is the safer enantiomer of racemic bupivacaine. Present protocols for levobupivacaine are based on studies and pharmacokin...

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...

Hepatocyte drug depletion-time assays are well established for the determination of metabolic clearance in vitro. The present study focuses on the refinement and evaluation of a "media loss" assay, an adaptation of the conventional depletion assay involving centrifugation of hepatocytes prior to sampling, allowing estimation of uptake in addition t...

Aims: Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolising enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 inter-correlation on the predicted inter-individual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically-based pharmacoki...

Background: Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolising enzymes [1]. Current population-based physiologically-based pharmacokinetic (PBPK) models do not consider inter-correlations between the abundances of different enzymes when using Monte Carlo simulations to generate virtual indivi...

The prospect of precision dosing in oncology is attractive for several reasons. Many anticancer drugs display narrow therapeutic indices, where suboptimal therapy may lead to severe patient outcomes. Clinical study participant recruitment is seldom extended beyond the intended patient population, leading to difficulties in patient recruitment in de...

Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulation more than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on...

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patie...

Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop...

Orally administered drugs are subject to a number of barriers impacting bioavailability (Foral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of thre...

Objectives: The aim of this study was (1) to determine how closely physiologically based pharmacokinetic (PBPK) models can predict oral bioavailability using a priori knowledge of drug-specific properties and (2) to examine the influence of the biopharmaceutics classification system class on the simulation success. Methods: Simcyp Simulator, Gas...

Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp® Simulator, and GastroPlus™) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded “bottom-up” anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics p...

This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1-OH-midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in th...

Supporting Information

Supporting Information

Supporting Information

In vitro-in vivo correlations (IVIVCs) play an important role in formulation development and drug approval. At the heart of IVIVC is deconvolution, the method of deriving an in vivo "dissolution profile" for comparison with in vitro dissolution data. IVIVCs are generally believed to be possible for highly permeable and highly soluble compounds with...

Bariatric surgery is nowadays commonly applied as treatment for morbid obesity (BMI > 40 kg/m(2)). As information about the effects of this procedure on a drug's pharmacokinetics is limited, we aimed to evaluate the pharmacokinetics of CYP3A probe substrate midazolam after oral and intravenous administration in a cohort of morbidly obese patients t...

AIMSTo evaluate the disposition of metoprolol after oral administration of an immediate and controlled release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically-based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB.METHODSA single-dose pharm...

Population differences in active hepatic transport caused by polymorphism may provide answers to some of the interindividual variability in toxicokinetics of xenobiotics. In vitro assays coupled with in silico methods, such as physiologically based pharmacokinetic (PBPK) modeling, can, through in vitro–in vivo extrapolation, provide high-throughput...

Controlled release (CR) formulations are usually designed to achieve similar exposure (AUC) levels as the marketed immediate release (IR) formulation. However, the AUC is often lower following CR compared to IR formulations. There are a few exceptions when the CR formulations have shown higher AUC. This study investigated the impact of CR formulati...

Due to the rapid turnover of the small intestinal epithelia, the rate at which enterocyte renewal occurs plays an important role in determining the level of drug metabolising enzymes in the gut-wall. Current physiologically-based pharmacokinetic (PBPK) models consider enzyme and enterocyte recovery as a lumped first-order rate. An assessment of ent...

An increasing prevalence of morbid obesity has led to dramatic increases in the number of bariatric surgeries performed. Altered gastrointestinal physiology following surgery can be associated with modified oral drug bioavailability (Foral). In the absence of clinical data, an indication of changes to Foral via systems pharmacology models would be...

Due to the multi-factorial physiological implications of bariatric surgery, attempts to explain trends in oral bioavailability following bariatric surgery using singular attributes of drugs or simplified categorisations such as the biopharmaceutics classification system have been unsuccessful. So we have attempted to use mechanistic models to asses...

What is already known about this subject: Changes to oral drug bioavailability have been observed post bariatric surgery. However, the magnitude and the direction of changes have not been assessed systematically to provide insights into the parameters governing the observed trends. Understanding these can help with dose adjustments. What this stu...

External control of tissues and cells, by hormones, nerves, and other stimuli, involves the transduction of signals from ligand-activated receptors to control of rate-limiting enzymes or proteins that affect key steps in metabolism, gene transcription or other processes within the cells. The signal transduction is carried out by a network of intera...

Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gu...