Population Pharmacokinetic Modeling of the Association between 63396C→T Pregnane X Receptor Polymorphism and Unboosted Atazanavir Clearance
| العنوان: | Population Pharmacokinetic Modeling of the Association between 63396C→T Pregnane X Receptor Polymorphism and Unboosted Atazanavir Clearance |
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| المؤلفون: | Saye Khoo, Alessandro Schipani, Giovanni Di Perri, Marco Simiele, Antonio D'Avolio, Howard L. McLeod, Gerry Davies, Charoen Chuchuttaworn, Sonia Rodríguez Novoa, Marco Siccardi, Janelle M. Hoskins, Vincent Soriano, Natpratou Saguenwong, Andrew Owen, David Back, Lorena Baietto, Anne M. Dvorak, Nitipatana Chierakul, Stefano Bonora, Lorena Cuenca |
| المصدر: | Antimicrobial Agents and Chemotherapy. 54:5242-5250 |
| بيانات النشر: | American Society for Microbiology, 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Adult, Male, Receptors, Steroid, medicine.medical_specialty, ATP Binding Cassette Transporter, Subfamily B, Genotype, Pyridines, Atazanavir Sulfate, Population, Organic Anion Transporters, HIV Infections, Pharmacology, Polymorphism, Single Nucleotide, Young Adult, Gene Frequency, Pharmacokinetics, Internal medicine, medicine, Cytochrome P-450 CYP3A, Humans, Pharmacology (medical), ATP Binding Cassette Transporter, Subfamily B, Member 1, education, Aged, education.field_of_study, biology, CYP3A4, Liver-Specific Organic Anion Transporter 1, Pregnane X Receptor, Middle Aged, Circadian Rhythm, Bioavailability, Atazanavir, Infectious Diseases, Endocrinology, biology.protein, Female, Ritonavir, SLCO1B1, Oligopeptides, human activities, medicine.drug |
| الوصف: | 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 |
| تدمد: | 1098-6596 0066-4804 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ea0c40bb12e28f42007d3168cf036e6eTest https://doi.org/10.1128/aac.00781-10Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ea0c40bb12e28f42007d3168cf036e6e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10986596 00664804 |
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