Mechanisms and Consequences of Drug‐Drug Interactions

Abstract

Medications used to treat human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections present a special challenge with respect to the management of potential and actual drug-drug interactions (DDIs). The HIV and HCV treatments may interact with each other, and also interact with drugs of abuse and/or with medications used to treat substance abuse. Possible mechanisms of these DDIs generally include induction or inhibition of activity/expression of human cytochromes P450, glucuronosyl transferases, or energy-dependent transport proteins. These DDIs can be complex and time-dependent in nature. Because time and resources available for new drug development are necessarily limited, not all potential DDIs can be evaluated via clinical pharmacokinetic studies in the course of development of HIV, HCV, and substance abuse treatments. Strategies are needed to refine existing in vitro models and screening techniques to allow more efficient targeting of resources to those clinical studies having the highest impact in terms of enhancing medication effectiveness and patient safety.

Drug interaction at hERG channel: In vitro assessment of the electrophysiological consequences of drug combinations and comparison against theoretical models

“…At the same time, it is clear that in a real clinical situation, multiple drugs are taken. In populations receiving multiple medications, the clinical consequences of potential DDIs are of major concern (Greenblatt, ). DDIs can be observed at the PK level, occurring due to alterations in drug absorption, metabolism, disposition or excretion and the PD level (e.g., binding to the same target).…”

Resveratrol glucuronidation in vitro: potential implications of inhibition by probenecid

“…[58,59] The concept of pharmacokinetic augmentation or 'boosting' refers to the use of a coadministered inhibitor of metabolism and/or transport to reduce presystemic extraction of a specific substrate drug and increase its systemic exposure. [60][61][62] Boosting is commonly applied to the treatment of HIV and hepatitis infection, whereby a boosting agent such as ritonavir or cobicistatas inhibitors of CYP3Amediated metabolism or efflux transport by P-glycoprotein is given along with antiviral medications to enhance their systemic plasma concentrations and bring exposures to a clinically effective range. [60,61,63] In the case of resveratrol, pharmacokinetic boosting is most effectively directed towards the principal mechanism of clearance, which is glucuronide conjugation.…”

Core Entrustable Professional Activities in Clinical Pharmacology: Pearls for Clinical Practice

“…The mechanistic background of this concept is based on the observation that many of the key HIV treatment entities are CYP3A and/or P‐gp substrates and consequently have low oral systemic availability. Even with high doses, achievement of therapeutic plasma concentrations may be difficult or impossible without coadministration of a boosting agent . The US Food and Drug Administration approved boosting HIV therapy in the year 2000 with the approval of a fixed combination product containing lopinavir as the principal therapeutic agent together with low‐dose ritonavir as the boosting agent .…”

“…Even with high doses, achievement of therapeutic plasma concentrations may be difficult or impossible without coadministration of a boosting agent. 22 The US Food and Drug Administration approved boosting HIV therapy in the year 2000 with the approval of a fixed combination product 23 containing lopinavir as the principal therapeutic agent together with low-dose ritonavir as the boosting agent. 24 Systemic AUC for lopinavir is increased by a factor of 70-to 80-fold with ritonavir coadministration.…”