Inflammation and pharmacokinetics: potential implications for HIV-infection

ABSTRACT

Introduction: The physiological changes accompanying inflammation may alter the pharmacokinetics (PK) of certain medications. Individuals infected with HIV have chronically elevated inflammatory markers despite viral suppression following effective antiretroviral therapy (ART), as well as age-related inflammation. Understanding the potential clinical implications of inflammation on the PK of medications is important for understanding dose-response relationships and necessitates future research.

Areas covered: An extensive literature search was carried out using PubMed and associated bibliographies to summarize the current state of knowledge regarding altered PK in response to inflammation and its application to the field of HIV.

Expert opinion: Preclinical and clinical studies show that inflammation leads to a downregulation of certain drug metabolizing enzymes and both up and down regulation of transporters depending on the transporter and cell type. Decreased gastric acidity, fluid shifts, and plasma protein alterations also occur with inflammation, leading to potential absorption, distribution, and clearance changes. More research is needed including controlled PK studies to address the clinical relevance of these observations, especially in the aging HIV-infected population. Results from future studies will enable us to better predict drug concentrations in individuals with inflammation, in line with efforts to provide personalized pharmacotherapy in our healthcare system.

KEYWORDS:

• HIV
• inflammation
• pharmacokinetics
• antiretrovirals

Article highlights

• Inflammation appears to cause a downregulation of drug metabolizing enzymes, up- and down- regulation of transporters, altered levels of plasma proteins, volume changes, and decreased gut acidity, which may alter the pharmacokinetics of medications

• Chronic immune activation and inflammation are hallmarks of HIV infection despite the use of effective antiretroviral therapy and pharmacokinetic changes caused by inflammation may have significant clinical implications, but studies are needed to evaluate inflammation-pharmacokinetic relationships

• The additive effects of inflammation and aging may lead to unpredictable pharmacokinetics of medications susceptible to inflammation-induced changes, shifts in body composition (decreased lean muscle, increased fat mass), and declines in function of relevant elimination organs

• The clinical relevance of inflammation on pharmacokinetics remains largely unknown and requires future research to determine if, and when, therapeutic drug monitoring and/or dose modifications of medications should be carried out, especially for drugs with narrow therapeutic indices

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was funded through the National Institutes of Health on behalf of the Colorado HIV Research Training Program (grant number 5 T32 AI 7447-23)