Association of a Single‐Nucleotide Polymorphism in the Pregnane X Receptor (<i>PXR</i>63396C→T) with Reduced Concentrations of Unboosted Atazanavir

Siccardi, Marco; D’Avolio, Antonio; Baietto, Lorena; Gibbons, Sara; Sciandra, Mauro; Colucci, Daniela; Bonora, Stefano; Khoo, Saye; Back, David; Perri, Giovanni Di; Owen, Andrew

doi:10.1086/592304

Cited by 73 publications

(47 citation statements)

References 17 publications

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“…Indeed, the amount of PXR induction that occurs due to the administration of rifampin was shown to be inversely proportional to the baseline PXR activity (12). The trend that we observed of increased CL/F values for PXR C63396T carriers is, however, consistent with the decrease in atazanavir plasma concentrations found for individuals with this polymorphism (22). High levels of P-glycoprotein activity may limit the distribution of rifampin in the body, leading to lower V/F values and higher plasma concentrations, as was previously suggested for digoxin (19).…”

Section: Discussionsupporting

confidence: 82%

The SLCO1B1 rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications

Cosson

Visser

Swart

et al. 2011

Antimicrob Agents Chemother

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136

159

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Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ABCB1 gene) and organic anion-transporting polypeptide 1B1 (coded for by SLCO1B1). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1, SLCO1B1, PXR, and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (C max ) below 8 mg/liter from 63% to 31%. ABCB1, PXR, and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.

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Section: Discussionsupporting

confidence: 82%

The SLCO1B1 rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications

Cosson

Visser

Swart

et al. 2011

Antimicrob Agents Chemother

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136

159

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“…We recently found that homozygosity of 63396C3T is associated with suboptimal ATV C trough (36) in patients receiving an unboosted regimen. Identifying sources of pharmacokinetic variability is important for clinical management and may aid optimal dose selection.…”

mentioning

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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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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“…The most studied polymorphism at NR1I2 is the 63396C>T, which has been associated with an increased activity of CYP3A4, leading to variations in ATV exposure. In this regard, homozygosity for the NR1I2-63396-T genotype is a predictor for sub-therapeutic ATV levels [53,54].…”

Section: Pharmacogenetics Of Atazanavirmentioning

confidence: 99%

“…In a study conducted by Siccardi et al [53], a score based in 3 SNPs, ABCB1 (3435C>T), SLCO1B1 (521T>C) and PXR (63396C>T), was proposed as the best predictor of unboosted ATV plasma exposure in the clinical setting [55]. The pharmacogenetic score was calculated as the sum of favourable genotypes.…”

Section: Pharmacogenetics Of Atazanavirmentioning

confidence: 99%

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

Barc¹

2013

J Pharmacogenom Pharmacoproteomics

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Association of a Single‐Nucleotide Polymorphism in the Pregnane X Receptor (PXR63396C→T) with Reduced Concentrations of Unboosted Atazanavir

Cited by 73 publications

References 17 publications

The SLCO1B1 rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications

The SLCO1B1 rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications

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

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

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