Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent

Michaud, Véronique; Kreutz, Yvonne; Skaar, Todd C.; Ogburn, Evan T.; Thong, Nancy; Flockhart, David A.; Desta, Zeruesenay

doi:10.1038/tpj.2013.17

Cited by 19 publications

(26 citation statements)

References 42 publications

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“…It is not clear whether efavirenz affects the NAT metabolic pathway of PAS. Efavirenz is known to affect both phase I and phase II metabolic enzymes, including induction of CYP3A4, 2B6, 2C19, UGT1A1 2B7, and bile efflux transporters and inhibition of CYP3A5, 2C9, 2C19 and UDP 1A4 and 1A9 (28)(29)(30)(31)(32)(33)(34). The effect of efavirenz on CYP3A4 was previously shown to be due to the activation of the human pregnane X receptor, which regulates the CYP3A4 transcription (35).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics ofpara-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

Kock

Rosenkranz

et al. 2014

Antimicrob Agents Chemother

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dThe emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. In sub-Saharan Africa, MDR/XDR tuberculosis with HIV coinfection is common, and concurrent treatment of HIV infection and MDR/XDR tuberculosis is required. Out of necessity, patients receive multiple drugs, and PAS therapy is frequent; however, neither potential drug interactions nor the effects of HIV infection are known. Potential drug-drug interaction with PAS and the effect of HIV infection was examined in 73 pulmonary tuberculosis patients; 22 (30.1%) were HIV coinfected. Fortyone pulmonary MDR or XDR tuberculosis patients received 4 g PAS twice daily, and in a second crossover study, another 32 patients were randomized, receiving 4 g PAS twice daily or 8 g PAS once daily. A PAS population pharmacokinetic model in two dosing regimens was developed; potential covariates affecting its pharmacokinetics were examined, and Monte Carlo simulations were conducted evaluating the pharmacokinetic-pharmacodynamic index. The probability of target attainment (PTA) to maintain PAS levels above MIC during the dosing interval was estimated by simulation of once-, twice-, and thrice-daily dosing regimens not exceeding 12 g daily. Concurrent efavirenz (EFV) medication resulted in a 52% increase in PAS clearance and a corresponding >30% reduction in mean PAS area under the concentration curve in 19 of 22 HIV-M. tuberculosis-coinfected patients. Current practice recommends maintenance of PAS concentrations at >1 g/ml (the MIC of M. tuberculosis), but the model predicts that at only a minimum dose of 4 g twice daily can this PTA be achieved in at least 90% of the population, whether or not EFV is concomitantly administered. Once-daily dosing of 12 g PAS will not provide PAS concentrations exceeding the MIC over the entire dosing interval if coadministered with EFV, while 4 g twice daily ensures concentrations exceeding MIC over the entire dosing interval, even in HIV-infected patients who received EFV.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics ofpara-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

Kock

Rosenkranz

et al. 2014

Antimicrob Agents Chemother

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“…At this time, venous blood was also drawn for DNA isolation, and demographic characteristics such as body weight, height, sex, race, or ethnic background were collected. Detailed dietary restrictions and inclusion and exclusion criteria have been previously reported and are outlined in the text in the supplemental material (58,59). The trial was registered at Clinical Trials.gov (http://www.clinicaltrials.gov) under identifier no.…”

Section: Methodsmentioning

confidence: 99%

“…Genomic DNA was extracted from whole blood with a DNA minikit (Qiagen, Valencia, CA). Genotyping for variants of the CYP genes were performed using two platforms: TaqMan assay reagent allelic discrimination kits according to the supplier's instructions (Applied Biosystems, Foster City, CA) as previously described (58) and/or the OpenArray platform (Applied Biosystems, Inc., Foster City, CA). The following variants were assayed: CYP2B6*2 (rs8192709), CYP2B6*4 (rs2279343), CYP2B6*5 (rs3211371), CYP2B6*9 (rs3745274), CYP2B6*16 (rs28399499), CYP2B6*18 (rs28399499); CYP2A6*2 (rs1801272), CYP2A6*9 (rs8192726), CYP2A6*12 (rs4803380); CYP2C8*2 (rs11572103), CYP2C8*3 (rs11572080, rs10509681); CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910); CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560); CYP3A4 (rs2246709), CYP3A4 (rs35599367); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), and CYP3A5*7 (rs41303343).…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

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Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6. While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported. The aim of this analysis was to develop a pharmacometric model to quantify the contribution of genetic and nongenetic factors to efavirenz pharmacokinetics. A population-based pharmacokinetic model was developed using 1,132 plasma efavirenz concentrations obtained from 73 HIV-seronegative volunteers administered a single oral dose of 600 mg efavirenz. A two-compartment structural model with absorption occurring by zero-and firstorder processes described the data. Allometric scaling adequately described the relationship between fat-free mass and apparent oral clearance, as well as fat mass and apparent peripheral volume of distribution. Inclusion of fat-free mass and fat mass in the model mechanistically accounted for correlation between these disposition parameters and sex, weight, and body mass index. Apparent oral clearance of efavirenz was reduced by 25% and 51% in subjects predicted to have intermediate and slow CYP2B6 metabolizer status, respectively. The final pharmacokinetic model accounting for fat-free mass, fat mass, and CYP2B6 metabolizer status was consistent with known mechanisms of efavirenz disposition, efavirenz physiochemical properties, and pharmacokinetic theory. (This study has been registered at ClinicalTrials.gov under identifier NCT00668395.) KEYWORDS body composition, cytochrome P450 2B6 (CYP2B6), efavirenz, population pharmacokinetics E favirenz is a nonnucleoside reverse transcriptase inhibitor that is used in combination with nucleoside/nucleotide reverse transcriptase inhibitors to treat HIVinfected individuals older than 3 years who are naive to antiretroviral drugs. Due to its proven efficacy and low cost relative to newer antiretrovirals, efavirenz-based therapy remains the preferred first-line regimen in many low-income nations and is consequently one of the most commonly prescribed antiretroviral drugs (1). Efavirenz pharmacokinetics (PK) is characterized by large interindividual variability in plasma concentrations following a single dose (2, 3) and during chronic administration (4), which has important clinical implications. During the induction phase, efavirenz exposure is associated with central nervous system and psychiatric adverse events, liver enzyme elevation, and rash, among others (5, 6). This may result in increasing rates of

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“…However, clinical application of CYP2C19 pharmacogenetics is limited to certain genotypes [49]. The number of study population that would benefit from pharmacogenomics research would be greatly reduced if such studies focused on common variants for strong statistically evidence.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenomics Study of Clopidogrel by RFLP based Genotyping of CYP2C19 in Cardiovascular Disease Patients in North-East Population of India

Jamd¹

2013

J Pharmacogenomics Pharmacoproteomics

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analysis [30,33,34], and perhaps an increased risk of bleeding complications [28]. However, other studies have not documented an effect of CYP2C19*17, and satisfactory evidence for an independent effect of this allele on clinical outcomes is missing [31,35,36]. In this study, AbstractIntroduction and Objective: Pharmacogenetics is a genetically determined variability in drug responses. The genes and their allelic variants which affect our response to drugs are the main routes in development of pharmacogenetics. Clopidogrel is an antiplatelet drug, used against athero-thrombotic events in cardiovascular patients. The objective of our study was to identify the CYP2C19 Single Nucleotide Polymorphisms, responsible for altering the metabolism of clopidogrel, at gene level. And to document the prevalence of CYP2C19 gene mutations in clopidogrel treated cardiovascular disease patients in Assam population, Patients and Methods:We have studied 60 patients who received clopidogrel from Gauhati medical college and hospital Assam. Genomic DNA was extracted by using Hipura blood genomic DNA extracting mini preparation kit by following the manufacturer's instructions.RFLP analysis was done by DNA amplification which was carried out by using set of primers and resulting ampicons of CYP2C19*2;CYP2C19*3 and CYP2C19*17 were subjected for Restriction digestion with SmaI, BamHI and Lwe0I respectively. Results:We found that CYP2C19*2 had allelic frequency of ~40% in Gauhati Medical College and Hospital, Assam, North East India. None of the samples were mutated with CYP2C19*3 andCYP2C19*17 allele. Other CYP2C19 variant alleles with reduced or absent enzymatic activity have been identified. Conclusion:We found that loss of functional allele CYP2C19*2 had higher carriage frequency; whereas, CYP2C19*3 and *17 alleles were not found in cardiovascular patients who were taking clopidogrel. Personalized therapy targeting patients who carry these genetic variants might help to improve the clinical outcome.

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Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent

Cited by 19 publications

References 42 publications

Pharmacokinetics ofpara-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

Pharmacokinetics ofpara-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Pharmacogenomics Study of Clopidogrel by RFLP based Genotyping of CYP2C19 in Cardiovascular Disease Patients in North-East Population of India

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