Ritonavir-boosted protease inhibitors in HIV therapy

Abstract

The advent of combination antiretroviral therapy has led to significant improvement in the care of HIV-infected patients. Originally designed as a protease inhibitor (PI), ritonavir is currently exclusively used as a pharmacokinetic enhancer of other protease inhibitors, predominantly due to ritonavir's potent inhibition of the cytochrome P450 3A4 isoenzyme. Ritonavir-boosting of PIs decrease pill burden and frequency of dosing. Boosted PIs are recommended for first-line therapy in treatment and play a key role in the management of treatment-experienced patients. Potential problems associated with PIs include metabolic abnormalities (e.g. dyslipidemia), increased cardiovascular risk, and drug interactions.

Metabolic Switching of BILR 355 in the Presence of Ritonavir. I. Identifying an Unexpected Disproportionate Human Metabolite

“…Extensive first-pass metabolism by intestinal and hepatic CYP3A was proposed as an explanation for the low systemic exposure and short half-life after oral administration to humans (Huang et al, 2008). A favorable PK profile, with increased systemic exposure, was achieved after concomitant administration of the CYP3A inhibitor RTV (Huang et al, 2008) as seen with other HIV drugs (Hull and Montaner, 2011). An unexpected consequence of the inhibition of this primary clearance pathway was a metabolic switching, leading to the formation of a disproportionate human metabolite.…”

“…Our in vitro data demonstrated signif-icant metabolism of BILR 355 by cytochrome P450 (P450) 3A. Thus, in an attempt to overcome the resulting low exposure in humans, BILR 355 was administered with ritonavir (RTV), a potent CYP3A inhibitor previously used to boost plasma concentrations and to increase the t 1/2 of HIV protease inhibitors (Hull and Montaner, 2011). With concomitant administration of RTV, the t 1/2 of BILR 355 increased to approximately 10 to 16 h and the maximum plasma concentration (C max ) increased 2-to 5-fold with the area under the plasma concentration-time curve from time 0 to infinity (AUC 0 -ϱ ) increasing 15-to 30-fold (Huang et al, 2008), a profile more consistent with once daily dosing.…”

Metabolic Switching of BILR 355 in the Presence of Ritonavir. II. Uncovering Novel Contributions by Gut Bacteria and Aldehyde Oxidase

“…In vitro metabolism studies suggested that cytochrome P450 (P450) 3A4 was playing a significant role in limiting systemic exposure to BILR 355 (Li et al, 2012). Ritonavir (RTV) is a potent inhibitor of CYP3A that has been used as a boosting agent to increase the exposure of a number of drugs, such as atazanavir and darunavir (Hull and Montaner, 2011). After concomitant administration of BILR 355 with RTV, BILR 355 exposure improved dramatically with AUC increasing 16-to 30-fold (Huang et al, 2008).…”

Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

“…Among the HIV PI that have been approved, lopinavir, atazanavir, darunavir and fosamprenavir are most frequently prescribed. 5,6 HIV PI are extensively metabolized by CYP3A enzymes 7,8 and their biliary excretion is mediated by the efflux transporters P-gp (ABCB1) and MRP2 (ABCC2). 8,9 In addition, it has been shown that some HIV PI (or their metabolites) are excreted via the feces for more than 75 %.…”