Pharmacokinetic Considerations for Combining Antiretroviral Therapy, Direct‐Acting Antiviral Agents for Hepatitis C Virus, and Addiction Treatment Medications

Abstract

There are many factors that can affect the pharmacokinetics (PK) of drugs. Pathophysiological changes from disease states can alter the mechanisms that control the PK of antiretrovirals (ARVs), direct-acting antivirals (DAAs) and addiction treatment medications. Drug-drug interaction pathways of certain ARVs and DAAs can be very complex, with agents being substrates, inhibitors or inducers of multiple metabolic and transporter pathways. Buprenorphine and methadone may be used in HIV and hepatitis C virus (HCV) - infected patients, and may also be affected by drug interactions. Current research is focused on novel PK analyses, which aim to describe the PK of agents within the organs that host the infection of interest, such as within hepatocytes during treatment for HCV. Modeling techniques allow for the prediction of drug PK in specific organs and the plasma compartment. This review will provide a summary of these areas while exploring PK considerations for ARVs, DAAs, and addiction treatment medications.

Efavirenz reduces renal excretion of lamivudine in rats by inhibiting organic cation transporters (OCT, Oct) and multidrug and toxin extrusion proteins (MATE, Mate)

“…Experiments on the uptake of metformin in HEK 293-cells mediated by MATE2-K were performed as previously described [ 5 ]. The number of cells per well was 7.0x10 5 for HEK-MATE2-K cells and 3.5x10 5 for HEK-Co cells to compensate for differences in protein concentration in the two lines.…”

“…The drug itself has several side effects, and presents a risk of even greater toxicity when co-administered with other drugs because of potential drug-drug interactions (DDI). Renal toxicity and impairments in hepatic function are among the most common cART-associated adverse effects [ 3 , 4 ], and can be made more severe by pharmacokinetic DDI affecting the elimination rate of co-administered antiretrovirals and/or their accumulation in excretory organs [ 5 ].…”

Drug–Drug Interactions and Diagnostics for Drug Users With HIV and HIV/HCV Coinfections: Introduction

“…Morse evaluated the influence of HIV infection on the design and interpretation of DDI studies on ARV pharmacokinetics including issues such as reduced gastric pH, cytokine patterns, and renal function. He pointed out that many factors, such as pathological changes from disease states, can affect the pharmacokinetics of ARTs, DAAs, and medications used for treatment of substance use disorders.…”

“…Juluru described novel radiologic applications such as specialized MR imaging techniques to measure liver function in diseased states and also presented results from his current research on the performance of intracellular uptake and other pharmacokinetic parameters in the diagnosis of fibrosis stage. Juluru et al conducted an eloquent study of dynamic Gd‐EOB‐DTPA‐enhanced MRI imaging performed in patients with varying stages of hepatic fibrosis; they also measured PK parameters derived from the whole liver and from three fixed regions of interest in all patients.…”