Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for <i>CYP2B6</i> and Efavirenz‐Containing Antiretroviral Therapy

Desta, Zeruesenay; Gammal, Roseann S.; Gong, Li; Whirl‐Carrillo, Michelle; Gaur, Aditya H.; Sukasem, Chonlaphat; Hockings, Jennifer; Myers, Alan L.; Swart, Marelize; Tyndale, Rachel F.; Masimirembwa, Collen; Iwuchukwu, Otito F.; Chirwa, Sanika; Lennox, Jeffrey L.; Gaedigk, Andrea; Klein, Teri E.; Haas, David W.

doi:10.1002/cpt.1477

Cited by 140 publications

(164 citation statements)

References 36 publications

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“…The CYP2B6 gene is highly polymorphic, with over 38 alleles reported to date (https://www.pharmvar.org/gene/CYP2B6). The CY2B6*6 allele, which consists of the CYP2B6*4 and CYP2B6*9 variants on the same haplotype, has functional relevance and occurs at high frequency across ethnically and geographically diverse populations . In addition, the CYP2B6*18 allele, which does not express functional protein, is frequent in the black population (4–12%) .…”

Section: Methodsmentioning

confidence: 99%

“…The CY2B6*6 allele, which consists of the CYP2B6*4 and CYP2B6*9 variants on the same haplotype, has functional relevance and occurs at high frequency across ethnically and geographically diverse populations . In addition, the CYP2B6*18 allele, which does not express functional protein, is frequent in the black population (4–12%) . Briefly, genomic DNA was extracted from whole blood (QIAamp DNA Mini Kit; Qiagen, Valencia, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Efavirenz is mainly metabolized by hepatic CYP2B6 . Two gene variants ( CYP2B6*6 and CYP2B6*18 ) produce higher efavirenz exposure after standard dosing in patients with HIV . The extent of efavirenz autoinduction of metabolism is influenced by CYP2B6 genetic variants .…”

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confidence: 99%

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CYP2B6 Genotype‐Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers

Metzger

Dave

Kreutz

et al. 2019

Clinical Translational Sci

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We investigated the effect of efavirenz on the activities of cytochrome P450 (CYP)1A2, CYP2A6, xanthine oxidase (XO), and N‐acetyltransferase 2 (NAT2), using caffeine as a probe. A single 150 mg oral dose of caffeine was administered to healthy volunteers (n = 58) on two separate occasions; with a single 600 mg oral dose of efavirenz and after treatment with 600 mg/day efavirenz for 17 days. Caffeine and its metabolites in plasma and urine were quantified using liquid chromatography/tandem‐mass spectrometry. DNA was genotyped for CYP2B6*4 (785A>G), CYP2B6*9 (516G>T), and CYP2B6*18 (983T>C) alleles using TaqMan assays. Relative to single‐dose efavirenz treatment, multiple doses of efavirenz decreased CYP1A2 (by 38%) and increased CYP2A6 (by 85%) activities (P < 0.05); XO and NAT2 activities were unaffected. CYP2B6*6*6 genotype was associated with lower CYP1A2 activity following both single and multiple doses of efavirenz. No similar association was noted for CYP2A6 activity. This is the first report showing that efavirenz reduces hepatic CYP1A2 and suggesting chronic efavirenz exposure likely enhances the elimination of CYP2A6 substrates. This is also the first to report the extent of efavirenz–CYP1A2 interaction may be efavirenz exposure‐dependent and CYP2B6 genotype‐dependent.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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CYP2B6 Genotype‐Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers

Metzger

Dave

Kreutz

et al. 2019

Clinical Translational Sci

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“…This enzyme accounts for the oxidation of ≈3% of drugs metabolized by CYPs, such as efavirenz, bupropion, and cyclophosphamide [64]. This gene is highly polymorphic, with variants affecting efavirenz metabolism and pharmacokinetics, which have become relevant for the treatment of HIV [65]. Patients carrying variants c.516G>T (p.Gln172Gln, rs3745274, MAF 25.9%) and g.21563C>T (rs8192719, MAF 26.3%) suffering from HIV infection may have decreased plasma concentrations and increased clearance of efavirenz as compared to patients with the GT or TT and CT or TT genotype, respectively.…”

Section: Cyp2b6mentioning

confidence: 99%

Role of Genetic Variations in the Hepatic Handling of Drugs

Marin

Serrano

Monte

et al. 2020

IJMS

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The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.

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“…Since subject 1 and 9 did not permit genetic analysis, only 10 of the 12 participants could be genotyped. The interpretation of the genotype results was performed according to Zhou et al for CYP1A2,21 Desta et al for CYPB6,22 Caudle et al for CYP2C9,23 Moriyama et al for CYP2C1924 and Goetz et al for CYP2D6. Data analysis Inspection of concentration-time profiles, statistical analysis and linear regression models were done in GraphPad Prism 8.1.1 (La Jolla, CA, USA).…”

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confidence: 99%

Pharmacokinetics and phenotyping properties of the Basel phenotyping cocktail combination capsule in healthy male adults

Suenderhauf

Berger

Puchkov

et al. 2019

Brit J Clinical Pharma

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Aims We compared the phenotyping metrics of a combination capsule formulation to its individual components of the newly composed Basel phenotyping cocktail. Moreover, we investigated a reduced sampling regimen for clinical applications. Methods We performed in vitro experiments and a crossover pharmacokinetic study in twelve healthy male subjects to compare the Basel phenotyping cocktail capsule containing 6 cytochrome P450 (CYP) probe drugs with individual administration of the same drugs. Parent compounds and selected metabolites were determined by liquid chromatography–tandem mass spectrometry. Metabolic ratios (MR) for are under the curve (AUC) and single time point measurements and their correlation were determined. Results Experiments with human liver microsomes and primary human hepatocytes in 3D co‐culture confirmed that flurbiprofen is a suitable CYP2C9 substrate. Both cocktail formulations (capsule and individual probe drug administration) were well‐tolerated and yielded reproducible MRs, which were almost identical. Correlations between single time point ratios and the corresponding AUC ratios depended on the sampling time point and the concentration time curve of the probe drugs. The MR of the capsule (Spearman rank correlation coefficient, Rs: 0.77–0.97) as well as the individual components (Rs: 0.69–0.99) correlated best at 6 h post‐treatment considering all 6 CYPs. Moreover, the 2‐h time points of the capsule agreed suitably with the AUC; however, the MR of omeprazole could not be determined for 10 out of 12 subjects. Conclusion The capsule is easy to swallow, well tolerated and provides reliable estimates for CYP activity. The optimal sampling point for the capsule formulation is 6 h after intake.

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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz‐Containing Antiretroviral Therapy

Cited by 140 publications

References 36 publications

CYP2B6 Genotype‐Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers

CYP2B6 Genotype‐Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers

Role of Genetic Variations in the Hepatic Handling of Drugs

Pharmacokinetics and phenotyping properties of the Basel phenotyping cocktail combination capsule in healthy male adults

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