Complex Drug Interactions of HIV Protease Inhibitors 2: In Vivo Induction and In Vitro to In Vivo Correlation of Induction of Cytochrome P450 1A2, 2B6, and 2C9 by Ritonavir or Nelfinavir

Abstract

ABSTRACT:Drug-drug interactions (DDIs) with the HIV protease inhibitors (PIs) are complex, paradoxical (e.g., ritonavir/alprazolam), and involve multiple mechanisms. As part of a larger study to better understand these DDIs and to devise a framework for in vitro to in vivo prediction of these DDIs, we determined the inductive effect of ϳ2 weeks of administration of two prototypic PIs, nelfinavir (NFV), ritonavir (RTV), and rifampin (RIF; induction positive control) on the cytochrome P450 enzymes CYP1A2, CYP2B6, CYP2C9, and CYP2D6 and the inductive or inductive plus inhibitory effect of NFV, RTV, or RIF on CYP3A and P-glycoprotein in healthy human volunteers. Statistically significant induction of CYP1A2 (2.1-, 2.9-, and 2.2-fold), CYP2B6 (1.8-, 2.4-, and 4-fold), and CYP2C9 (1.3-, 1.8-, and 2.6-fold) was observed after NFV, RTV, or RIF treatment, respectively (as expected, CYP2D6 was not induced). Moreover, we accurately predicted the in vivo induction of these enzymes by quantifying their induction by the PIs in human hepatocytes and by using RIF as an in vitro to in vivo scalar. On the basis of the modest in vivo induction of CYP1A2, CYP2B6, or CYP2C9, the in vivo paradoxical DDIs with the PIs are likely explained by mechanisms other than induction of these enzymes such as induction of other metabolic enzymes, transporters, or both.

Quantitative Prediction of CYP2B6 Induction by Estradiol During Pregnancy: Potential Explanation for Increased Methadone Clearance During Pregnancy

“…Carbamazepine decreases bupropion area under the curve (AUC) by 87% and increases OH-bupropion to bupropion AUC ratio by 11.5-fold (Ketter et al, 1995), suggesting an 11-fold increase in hydroxybupropion formation clearance, assuming that the clearance of hydroxybupropion is unaffected by carbamazepine. Rifampicin decreases bupropion AUC by 46-67% (Loboz et al, 2006) and increases hydroxybupropion formation clearance by 4-fold (2.3-6.8-fold) (Kirby et al, 2011), an effect slightly less than that predicted from the hepatocyte data.…”

Reliability and Extension of Quantitative Prediction of CYP3A4-Mediated Drug Interactions Based on Clinical Data

“…1 (see text). AUC area under the plasma concentration-time curve is frequently prescribed, and interactions due to ritonavir (21)(22)(23) and telaprevir, which are strong inhibitors. These predictions showed that the interactions with colchicine result in AUC ratios that are never >3.5, whereas ritonavir and telaprevir were confirmed as strong inhibitors with an IR of 0.99 and 0.97, respectively.…”

“…Ritonavir, which is not only a CYP3A4 inhibitor, was nevertheless included because its properties have been well characterized. Ritonavir is also an inhibitor of CYP2D6 and P-glycoprotein and an inducer of CYP2C9 and CYP2C19 (21)(22)(23). To estimate and validate the IR of ritonavir, we selected interaction studies for which CYP3A4 inhibition was thought to be the major mechanism.…”

Evaluation of Normalization Methods To Predict CYP3A4 Induction in Six Fully Characterized Cryopreserved Human Hepatocyte Preparations and HepaRG Cells

“…Predictive mathematical models incorporating either induction alone or induction in combination with inhibition mechanisms have been applied by a number of authors (Fahmi et al, 2008b;Shou et al, 2008;Fahmi and Ripp, 2010;Kirby et al, 2011;Templeton et al 2011). Dynamic models based on an inducer concentration-time profile to account for the change in enzyme expression have also been proposed (Almond et al, 2009;Fahmi et al, 2009).…”