Drug Interaction Potential of Pro-Inflammatory Conditions

Conditions studied

Diabetes Mellitus, Type 2, End Stage Renal Disease, Irritable Bowel Syndrome

About this study

Pro-inflammatory cytokines, which are elevated in pro-inflammatory disease states (e.g., type II diabetes mellitus \[T2DM\], irritable bowel diseases \[IBD\], and end stage renal disease \[ESRD\]) have been shown to inhibit hepatic drug-metabolizing enzymes, including members of the cytochrome P450 (CYP) family, and drug transporters; resultantly, pro-inflammatory diseases have been demonstrated to increase the exposure and potential for adverse drug events with co-administered CYP and drug transporter substrates. However, the clinical relevance of pro-inflammatory disease-drug interactions has not been systematically evaluated. The long-term goal of this research is to establish clinical strategies to mitigate pro-inflammatory disease-drug interactions and associated adverse drug events. The specific objective of this study is to determine the clinical relevance of pro-inflammatory disease-drug interactions, including establishment of the effect of pro-inflammatory diseases on drug disposition throughout disease trajectories (i.e., determining the differential effects on drug disposition based on the severity of disease). Towards this objective, this study will investigate the extent of increases in inflammation in patients with varying severities of pro-inflammatory diseases and estimate the resulting effects on drug disposition. Cytokine/chemokine concentrations and immune cell profiles will be assayed from blood samples of adult and pediatric patients with differing severities of pro-inflammatory diseases, using established disease monitoring parameters (e.g., glycosylated hemoglobin \[HbA1C\] for T2DM, C-reactive protein \[CRP\] for IBD, proteinuria for ESRD). The effect of changes in inflammation during differing severities of these pro-inflammatory diseases on drug disposition will then be estimated using established pharmacokinetic modeling approaches (e.g., physiologically-based pharmacokinetic modeling \[PBPK\]).

Interventions

• Other: None (Observational) — This observational study will not involve any interventions. Instead, the study will collect blood samples at one or multiple time points.

Primary outcomes

• Quantification of Plasma Cytokine Concentrations (Through study completion, up to 2 years post enrollment)
• Phenotyping of Patient Immune Cells (Through study completion, up to 2 years post enrollment)
• Quantification of the Plasma Concentrations of Endogenous Biomarkers of Drug Metabolism and Transport (Through study completion, up to 2 years post enrollment)
• Measures of Inflammatory Disease Severity (Through study completion, up to 2 years post enrollment)
• Development of Adverse Events Attributable to CYP/Transporter Substrate Medications (Through study completion, up to 2 years post enrollment)

Eligibility information

Study locations

• Indiana University Hospital, Indianapolis, Indiana 46202 United States