Organ impairment (OI) can significantly affect drug pharmacokinetics (PK). Renal impairment (RI) is a multifaceted disease characterized by a spectrum of pathophysiological and biological alterations, manifested by reduced functional nephrons, impaired glomerular filtration and/or tubular secretion, as well as hypoalbuminemia in some patients. Hepatic impairment (HI) is caused by multiple diseases/conditions (e.g., viral infection, alcohol abuse, NAFLD) which destroy the liver parenchyma, ultimately leading to hepatic and biliary cirrhosis, and is characterized by a decline in hepatic blood flow, hematocrit, AAG, albumin, functional hepatocytes, and biliary excretion. Moreover, there are alterations in expression and activity of hepatic transporters and metabolizing enzymes as well as reduced duodenal CYP3A expression and activity. Due to these pronounced changes in physiology, both RI and HI can lead to alterations in absorption, distribution, metabolism, and excretion of drugs, hence significantly increasing the drug exposure in systemic circulation. Such high exposures could further cause adverse events and safety concerns; hence a dose reduction may be warranted to ensure the safety and efficacy of drug in patients with OI.

The goals of this Research Topic are as follows:

● Optimizing Trial Design: Explore the application of quantitative modeling and simulation techniques, including mechanistic Physiologically-Based Pharmacokinetic (PBPK) modeling and population PK modeling, to enhance trial design efficiency. Dedicated OI PK studies typically enroll healthy controls and patients with varying degrees of organ impairment, creating high cost and enrollment challenges as well as burden on study participants. By minimizing the need for extensive patient enrollment, these methodologies aim to streamline the evaluation of drug exposure in OI populations.

● Overcoming Study Challenges: Address the inherent difficulties in conducting dedicated OI PK studies. For example, enrolling patients with OI who meet the inclusion criteria can be time consuming, and enrolling healthy subjects for matching can raise ethical concerns. Additionally, OI studies are typically not powered to support significance testing. Therefore, novel study design and technologies to inform and guide the assessment of OI on the PK of an investigational drug should be considered.

● Navigating Regulatory Perspectives: Discuss regulatory considerations and guidelines pertaining to pharmacokinetic studies in organ impairment. Highlight the regulatory landscape, challenges, and best practices in obtaining approvals for clinical trials involving OI populations. Provide Insights into meeting regulatory requirements and ensuring study validity in diverse patient cohorts.

We invite original research papers, reviews, and methodological studies that contribute to understanding and mitigating the impact of organ impairment on drug pharmacokinetics. Topics of interest include, but are not limited to:

● Mechanistic insights into altered drug absorption, distribution, metabolism, and excretion in RI and HI.

● Application of PBPK modeling and population PK approaches in predicting drug exposure in OI populations.

● Novel trial designs and technologies to optimize the assessment of PK parameters in OI patients.

● Ethical considerations and regulatory perspectives in designing clinical trials involving OI populations.

● Case studies illustrating successful implementation of quantitative modeling in OI PK studies.

Are you interested in contributing a manuscript to this Research Topic?

Pharmacokinetic Studies in Organ Impairment: Overcoming Barriers and Optimizing Trial Design