Long-term efficacy of boosted and unboosted atazanavir-containing regimens: results from the SCOLTA Project

Quirino, Tiziana; Ricci, Elena; Giuntini, R; Martinelli, Canio; Vichi, Francesca; Gianelli, Erika; Madeddu, Giordano; Menzaghi, Barbara; Socio, G De; Orofino, Giancarlo; Palvarini, Loredana; Penco, Giovanni; Rosella, Elena; Marconi, P; Carradori, Silvia; Grosso, Carmela; Pellicanò, Giovanni Francesco; Bonfanti, Paolo

doi:10.1186/1758-2652-11-s1-p74

JIAS

2008

DOI: 10.1186/1758-2652-11-s1-p74

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Long-term efficacy of boosted and unboosted atazanavir-containing regimens: results from the SCOLTA Project

Tiziana Quirino

Elena Ricci

R Giuntini

et al.

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2010

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“…Although the 400-mg once-daily dosage is not licensed in Europe, in the United States it is licensed for the treatment of naive patients who cannot tolerate RTV. In a recent study in Europe, approximately 20% of ATV recipients were reported to be administered the drug off-label with an unboosted regimen (35). Therefore, unboosted ATV is an important alternative for patients with RTV intolerance (19) when there are not more effective regimens available using other drug classes.…”

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Population Pharmacokinetic Modeling of the Association between 63396C→T Pregnane X Receptor Polymorphism and Unboosted Atazanavir Clearance

Schipani

Siccardi

D’Avolio

et al. 2010

Antimicrob Agents Chemother

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Atazanavir (ATV) plasma concentrations are influenced by CYP3A4 and ABCB1, which are regulated by the pregnane X receptor (PXR; NR1I2). PXR expression is correlated with CYP3A4 in liver in the absence of enzyme inducers. The PXR single nucleotide polymorphism (SNP) 63396C3T (rs2472677) alters PXR expression and CYP3A4 activity in vitro, and we previously showed an association of this polymorphism with unboosted ATV plasma concentrations. The aim of this study was to develop a population pharmacokinetic analysis to quantify the impact of 63396C3T and diurnal variation on ATV clearance. A population analysis was performed with 323 plasma samples from 182 randomly selected patients receiving unboosted ATV. Two hundred fifty-nine of the blood samples were collected at random time points, and 11 patients had a full concentration-time profile at steady state. Nonlinear mixed effects modeling was applied to explore the effects of PXR 63396C3T, patient demographics, and diurnal variation. A one-compartment model with first-order absorption and lag time best described the data. Population clearance was 19.7 liters/h with interpatient variability or coefficient of variation (CV) of 21.5%. Homozygosity for the T allele for PXR 63396 was associated with a 17.0% higher clearance that was statistically significant. Evening dosing was associated with 34% higher bioavailability than morning dosing. Patient demographic factors had no effect on ATV clearance. These data show an association of PXR 63396C3T and diurnal variation on unboosted ATV clearance. The association is likely to be mediated through an effect on hepatic PXR expression and therefore expression of its target genes (e.g., CYP3A4, SLCO1B1, and ABCB1), which are known to be involved in ATV clearance. Atazanavir (ATV) is an HIV protease inhibitor (PI) administered once daily (OD) at a dose of 300 mg with 100 mg of ritonavir (RTV) to "boost" its plasma concentrations. ATV can be used without boosting at 400 mg once daily, a dose recently validated in a simplification trial (13). Although the 400-mg once-daily dosage is not licensed in Europe, in the United States it is licensed for the treatment of naive patients who cannot tolerate RTV. In a recent study in Europe, approximately 20% of ATV recipients were reported to be administered the drug off-label with an unboosted regimen (35). Therefore, unboosted ATV is an important alternative for patients with RTV intolerance (19) when there are not more effective regimens available using other drug classes.ATV is metabolized mainly by cytochrome P450 3A4 (CYP3A4), which is present in intestine and liver. There is marked interindividual variability in CYP3A4 expression and function which is not explained by current knowledge of single nucleotide polymorphisms (SNPs) in the CYP3A4 gene. ATV is also a substrate for P glycoprotein (P-gp; ABCB1), and this transporter may influence both intestinal absorption and excretion into the bile (9, 25). Recently, we showed that many PIs are also substrates for OATP1B1 (encoded by the SLC...

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confidence: 99%

Population Pharmacokinetic Modeling of the Association between 63396C→T Pregnane X Receptor Polymorphism and Unboosted Atazanavir Clearance

Schipani

Siccardi

D’Avolio

et al. 2010

Antimicrob Agents Chemother

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Long-term efficacy of boosted and unboosted atazanavir-containing regimens: results from the SCOLTA Project

Cited by 1 publication

References 0 publications

Population Pharmacokinetic Modeling of the Association between 63396C→T Pregnane X Receptor Polymorphism and Unboosted Atazanavir Clearance

Population Pharmacokinetic Modeling of the Association between 63396C→T Pregnane X Receptor Polymorphism and Unboosted Atazanavir Clearance

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