Pharmacokinetics and drug–drug interactions of antiretrovirals: An update

Abstract

Current antiretroviral treatment has allowed HIV infection to become a chronic manageable condition with many HIV patients living longer. However, available antiretrovirals are not without limitations, for example the development of resistance and adverse effects. Consequently, new drugs in existing and novel classes are urgently required to provide viable treatment options to patients with few remaining choices. Darunavir, etravirine, maraviroc and raltegravir have been recently approved for treatment-experienced patients and other agents such as rilpivirine, vicriviroc and elvitegravir are currently under phase III study. Clinical studies are necessary to optimise potential treatment combinations and to manage drug–drug interactions to help avoid toxicity or therapy failure. This review aims to summarise the pharmacokinetics and key drug–drug interaction studies for newly available antiretrovirals and those in development. Further information regarding drug–drug interactions of well established antiretrovirals and those recently approved are readily available online at sites such as http://www.hiv-druginteractions.org, http://www.clinicaloptions.com/hiv, http://hivinsite.ucsf.edu.

This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010.

Introduction

The advent of highly active antiretroviral therapy (HAART) targeting two distinct areas of the HIV lifecycle (reverse transcriptase and protease) has had a dramatic effect on the morbidity and mortality of HIV-infected individuals. However the global burden of HIV remains high with an estimated 33 million adults and children living with the disease at the end of 2007. Current treatment, when available, is not without limitations such as high pill burden, occurrence of adverse events and particularly development of resistance and cross-resistance between drug classes. The need for newer antiretrovirals in existing classes and development of therapies aimed at novel targets are paramount in order to provide broader treatment options to those with few choices remaining, as a result of multiple regimen failures or contraction of resistant virus.

Encouragingly, a number of agents have recently gained approval in existing and new drug classes whilst others are still at the developmental stage. Additions to established classes include the protease inhibitor darunavir and non-nucleoside reverse transcriptase inhibitors (NNRTI) etravirine and rilpivirine (formally TMC-278), although the latter is not yet licensed for clinical use. Maraviroc is the first antiretroviral approved to selectively target the CCR5 receptor and raltegravir is the first in the class of integrase inhibitors, providing two additional targets to combat the virus. Also of interest is the development of another integrase inhibitor (elvitegravir) and two new pharmacoenhancers, GS-9350 (Gilead Sciences, Inc.) and SPI-452 (Sequoia Pharmaceuticals, Inc.), which although in early stages of development are well tolerated and demonstrate potent inhibition of CYP3A metabolism without any antiviral activity (Gulnik et al., 2009, Mathias et al., 2009a).

Despite intensive research efforts a cure for HIV infection remains elusive. However as a result of improved antiretroviral treatment, the disease has become a chronic manageable illness in Western countries with infected patients generally living longer. Patients therefore not only require medications for HIV infection but also for related or unrelated co-morbidities, providing further challenges for healthcare providers and patients alike. Drug–drug interactions are common as a result of interacting metabolic pathways and it is of great importance that drug–drug interactions of newly available therapies are investigated to determine optimal treatment combinations and provide maximum therapeutic effect.

In basic terms, pharmacokinetics can be defined as ‘what the body does to the drug’, implying the absorption, distribution in tissues and cells, and elimination (or clearance) via hepatic and/or renal pathways. The concentrations of drug obtained over time can be related to the response or effect of the drug (pharmacodynamics) which can be beneficial (i.e. therapeutic) or potentially toxic (increased side-effects). Plasma concentrations can be used as a surrogate marker to link antiretroviral pharmacokinetics to antiviral response in the form of reduction in viral load, which has been demonstrated for protease inhibitors. However, with some antiretrovirals the relationship is not clear. For example, plasma pharmacokinetic parameters have yet to be definitively related to virological response for raltegravir, and CCR5-receptor occupancy demonstrates a better relationship with virological suppression than plasma concentrations for maraviroc (Jacqmin et al., 2008, Rosario et al., 2008). With newer antiretrovirals acting at novel target sites, the classical example of a plasma pharmacokinetic–pharmacodynamic relationship may not apply. Drug–drug interactions can clearly impact on the efficacy or toxicity of antiretrovirals and/or co-medications by altering drug concentrations either below a recommended threshold for therapeutic effect or above a cut-off for toxicity.

The present review will focus on the pharmacokinetics and known drug–drug interactions of newly available antiretrovirals. A number of agents currently under development will also be briefly discussed. Well established antiretrovirals have been extensively studied and reviewed elsewhere. Furthermore, information on drug–drug interactions of older antiretrovirals is summarised and readily accessible through online resources such as http://www.hiv-druginteractions.org, http://www.clinicaloptions.com/hiv, http://hivinsite.ucsf.edu.