Pharmacokinetics Seminar and Workshop

Application of Lipid Nanoparticle Technology for mRNA Therapeutics

Messenger RNA (mRNA) has emerged as a new category of therapeutic agent to prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degradation and that allow cellular uptake and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle–mRNA vaccines are now in clinical use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In my presentation, I will highlight recent developments in the design of lipid nanoparticles for mRNA delivery and the remaining challenges for this promising technology.

PKPD Modeling and Simulation to Support Drug Development Program

Model Informed Drug Development (MIDD) approach has been accepted and promoted by regulatory agencies to support modern drug development and accelerate drug review and approval.¹ Pharmacokinetics and pharmacodynamic (PKPD) modelling and simulation is the underlying engine, in the MIDD approach, that aids the understanding of a drug’s disposition and its effectiveness in treating the disease. In this presentation, we will discuss how PKPD models and simulations were used to support early and late-phase clinical trials and inform dose selection for optimal drug development strategies. We will look at some examples of how these mathematical models were used to optimize treatment, benchmark against competitors, and support regulatory reviews and approvals.

¹ Madabushi et al. Pharmaceutical Research. 2022. 39:1669-1680

Dried Blood Spot Analysis – A state-of-the-art Approach for Pharmacokinetic and Pharmacodynamic or Disease Response Monitoring

Compared to conventional methods using plasma/serum, dried blood spot (DBS) analysis offers several advantages, including minimal invasiveness, a small blood volume requirement, reduced biohazardous risk, and improved sample stability. Numerous assays utilizing DBS for therapeutic drug monitoring (TDM) have been reported in the literature over the past decade, covering a wide range of therapeutic drugs. Several factors can affect the accuracy and reliability of the DBS sampling method, including hematocrit (HCT), blood volume, sampling paper and chromatographic effects. It is crucial to evaluate the correlation between DBS concentrations and conventional plasma/serum concentrations, as the latter has traditionally been used for clinical decisions. The feasibility of using the DBS sampling method as an option for home-based TDM is also discussed. Furthermore, DBS has also been used as a matrix for monitoring the drug or disease responses (DRM) through various approaches such as genotyping, viral load measurement, assessment of inflammatory factors, and more recently, metabolic profiling. Although this research is still in the development stage, advancements in technology are expected to lead to the identification of surrogate biomarkers for drug treatment in DBS and a better understanding of the correlation between DBS drug levels and drug responses. This will make DBS a valuable matrix for TDM and DRM, facilitating the achievement of pharmacokinetic and pharmacodynamic correlations and enabling personalized therapy.

Fractal Kinetic Implementation in Population Pharmacokinetic Modelling

Compartment modeling is a widely accepted technique in the field of pharmacokinetic analysis. However, conventional compartment modeling is performed under a homogeneity assumption that is not a naturally occurring condition. Since the assumption lacks physiological considerations, the respective modeling approach has been questioned, as novel drugs are increasingly characterized by physiological or physical features. Alternative approaches have focused on fractal kinetics, but evaluations of their application are lacking. Thus, in this study, a simulation was performed to identify desirable fractal-kinetics applications in conventional modeling. Visible changes in the profiles were then investigated. Various cases of finalized population models were collected for implementation. For model diagnosis, the objective function value (OFV), Akaike’s information criterion (AIC), and corrected Akaike’s information criterion (AICc) were used as performance metrics, and the goodness of fit (GOF), visual predictive check (VPC), and normalized prediction distribution error (NPDE) were used as visual diagnostics. In most cases, model performance was enhanced by the fractal rate, as shown in a simulation study. The necessary parameters of the fractal rate in the model varied and were successfully estimated between 0 and 1. GOF, VPC, and NPDE diagnostics show that models with the fractal rate described the data well and were robust. In the simulation study, the fractal absorption process was, therefore, chosen for testing. In the estimation study, the rate application yielded improved performance and good prediction–observation agreement in early sampling points, and did not cause a large shift in the original estimation results. Thus, the fractal rate yielded explainable parameters by setting only the heterogeneity exponent, which reflects true physiological behavior well. This approach can be expected to provide useful insights in pharmacological decision making.

Pharmacokinetics 101

This interactive lecture delves into the essential concepts of pharmacokinetics and the therapeutic window in pharmacology before clinical use. Participants will learn to analyze drug concentration profiles, understand the relationship between drug concentrations and target/off-target effects, and calculate key pharmacokinetic parameters such as AUC, Cmax, Tmax, and half-life. Through interactive discussions and practical exercises, attendees will gain insights into optimizing drug efficacy and safety by identifying the ideal therapeutic range. This workshop is designed to equip participants with the knowledge and skills needed to make informed decisions in drug development, dosing regimens, and patient care, ultimately improving clinical outcomes and ensuring effective medication administration.

Pharmacokinetics and Safety Evaluation of Gene and Cell Therapy: Challenges and Opportunities

Gene and cell therapy as a new modality of medicine has far-reaching impacts on various hard-to-treat diseases including inherited genetic diseases and malignant cancer. Before bringing the new modalities to the patients, a comprehensive assessment of the pharmacokinetics of the new modalities and associated safety evaluation in the pre-clinical and clinical settings are key to the ultimate success of gene and cell medicine. In this seminar, I will share with the audience two major topics: the current trend of gene and cell therapy in pharma investment; and the considerations of PK, immunogenicity, and pharmacodynamics as a holistic safety evaluation of a gene and cell medicine in the pharma’s perspective. Moreover, I will open the window to discuss the challenges and opportunities in discovering and developing complex gene and cell therapy medicine.

Targeting the Colon through Oral Route: Drug Delivery Systems and Pharmacokinetic Insights for Effective Therapy

The human colon presents a unique challenge for drug delivery due to its complex anatomy and physiological characteristics. Following oral ingestion, drug delivery systems pass through diverse microenvironments of the upper gastrointestinal tract before arriving in the colon. After arriving in the colon, several factors in the colon's microenvironment (e.g., pH, pressure, enzymes, and microbial composition) significantly influence drug release behaviour from the delivery system and its efficacy. In this session, the presenter will discuss the approaches that have been explored for colon-specific drug release as well as their pros and cons. Furthermore, the presenter will delve into the pharmacokinetic insights of colon-specific drug delivery systems. Finally, the presenter will discuss future prospects and potential directions for further research and development in colon-targeted drug delivery systems.

Understanding and Applying PKPD Modelling and Simulation in Clinical Practice

Understanding the relationship between dose, concentration, and effect is a fundamental aspect of clinical pharmacology. Interpreting data related to this relationship requires the use of mathematical models. Drug models describe the relationship between exposure (or pharmacokinetics), response (or pharmacodynamics) for both desired and undesired effects, and individual patient characteristics. It is important to note that the application of PKPD concepts extends beyond drug development. These concepts help in determining appropriate off-label dosing for special populations, personalizing dosages based on measured biomarkers (personalized medicine), and evaluating whether lack of efficacy or unexpected toxicity can be addressed by adjusting the dose rather than changing the drug. In this talk, we will review fundamental PKPD principles and provide some real-world examples of PKPD use in clinical practice and applied clinical research.

Metabolic Activation of Piceatannol: Promise to Human Health

To assess the potential health benefits of piceatannol (trans-3,5,3',4'-tetrahydroxystilbene), a dietary derivative of resveratrol, we conducted biotransformation studies using human and rat hepatic microsomes and cytosols. Additionally, we examined the pharmacokinetic profiles of piceatannol in Sprague-Dawley rats. In hepatic microsomes, we observed limited phase I metabolism of piceatannol. However, in cytosols, piceatannol underwent rapid conversion to two pharmacologically active metabolites: rhapontigenin and isorhapontigenin. This biotransformation process was found to be mediated by catechol-O-methyltransferase (COMT), as it was completely blocked by the COMT inhibitor, entacapone. Furthermore, we identified piceatannol as a substrate inhibitor of COMT, indicating its potential therapeutic benefits in Alzheimer's disease. Due to extensive phase II metabolism, including glucuronidation, sulfation, and O-methylation, piceatannol exhibited rapid clearance in rats. After intravenous administration, approximately 4.02 ± 0.61% and 17.70 ± 0.91% of piceatannol were converted to rhapontigenin and isorhapontigenin, respectively. Similar results were observed upon oral administration, where piceatannol served as an effective precursor of isorhapontigenin. Considering the pleiotropic health-promoting activities of piceatannol and its metabolites, it emerges as a promising nutraceutical candidate for further development. This study also highlights the importance of in vivo testing in nutritional research, as active metabolites may not be present in in vitro systems. The findings underscore the potential health benefits of piceatannol and its role in enhancing our understanding of dietary compounds with therapeutic potential.