Triple-negative breast cancer and the potential for targeted therapy.

Pharmacogenomics. 2017 Nov;18(17):1595-1609

Authors: Jhan JR, Andrechek ER

Abstract
Breast cancer is composed of several well-recognized subtypes including estrogen receptor, progesterone receptor and HER2 triple-negative breast cancer (TNBC). Without available targeted therapy options, standard of care for TNBC remains chemotherapy. It is of interest to note that TNBC tumors generally have better responses to chemotherapy compared with other subtypes. However, patients without complete response account for approximately 80% of TNBC. Mounting evidence suggests significant heterogeneity within the TNBC subtype, and studies have focused on genetic targets with high rates of altered expression. Recent studies suggest clear possibilities for benefits from targeted therapy in TNBC. In this review, we summarize studies of targeted therapy, including within mouse models, and discuss their applications in the development of combinatorial treatments to treat TNBC.

PMID: 29095114 [PubMed - indexed for MEDLINE]

SLCO1B1 rs4149056 genetic polymorphism predicting methotrexate toxicity in Chinese patients with non-Hodgkin lymphoma.

Pharmacogenomics. 2017 Nov;18(17):1557-1562

Authors: Yang L, Wu H, Gelder TV, Matic M, Ruan JS, Han Y, Xie RX

Abstract
AIM: To investigate the impact of polymorphisms in the FPGS, GGH and SLCO1B1 genes on high dose methotrexate (HD-MTX) related toxicity in Chinese patients with non-Hodgkin lymphoma (NHL).
MATERIALS & METHODS: We analyzed FPGS (rs10106), GGH (rs719235, rs10464903, rs12681874), SLCO1B1 (rs4149056) genetic polymorphisms in 105 Chinese patients with NHL treated with HD-MTX.
RESULTS: There was a statistically significant impact of the SLCO1B1 rs4149056 polymorphism on hepatotoxicity. Patients with TC and CC genotype had more hepatotoxicity than TT genotype (60 vs 32.94%, p = 0.025). After adjusting for disease stage, dosage, infusion time and therapy method, SLCO1B1 rs4149056 genotype remained significantly associated with hepatotoxicity (p = 0.028).
CONCLUSION: SLCO1B1 rs4149056 genetic variants can affect the HD-MTX-related toxicity in Chinese patients with NHL.

PMID: 29095107 [PubMed - indexed for MEDLINE]

Rethinking ovarian cancer genomics: where genome-wide association studies stand?

Pharmacogenomics. 2017 Nov;18(17):1611-1625

Authors: Pinto R, Assis J, Nogueira A, Pereira C, Pereira D, Medeiros R

Abstract
Genome-wide association studies (GWAS) allow the finding of genetic variants associated with several traits. Regarding ovarian cancer (OC), 15 GWAS have been conducted since 2009, with the discovery of 49 SNPs associated with disease susceptibility and 46 with impact in the clinical outcome of patients (p < 5.00 × 10-2). Among them, 14 variants reached the genome-wide significance (p < 5.00 × 10-8). Despite the results obtained, they should be validated in independent sets. So far, five validation studies have been conducted which could confirm the association of 12 OC susceptibility SNPs. Consequently, post-GWAS studies are crucial unravel the biological plausibility of GWAS' findings and the allelic spectrum of OC.

PMID: 29095100 [PubMed - indexed for MEDLINE]

Introducing personalized health for the family: the experience of a single hospital system.

Pharmacogenomics. 2017 Nov;18(17):1589-1594

Authors: Huddleston KL, Klein E, Fuller A, Jo G, Lawrence G, Haga SB

Abstract
Pharmacogenetic testing is leading the personalized health movement, gradually being implemented in a variety of healthcare settings. To inform the efforts of other hospital and clinical practices implementing personalized health or medicine applications, we describe the implementation of a newborn pharmacogenetic testing program at Inova Health System (VA, USA). In particular, we describe the efforts to gather patient feedback through focus groups, the training and program staff, the pilot program and our experiences to date. In our experience, a multidisciplinary team was essential to address the myriad facets of program development and implementation as well as an in-person approach to introduce testing and patient education.

PMID: 29061078 [PubMed - indexed for MEDLINE]

The Value of Evidence in the Decision-Making Process for Reimbursement of Pharmacogenetic Dosing of Warfarin.

Am J Cardiovasc Drugs. 2017 Oct;17(5):399-408

Authors: Janzic A, Locatelli I, Kos M

Abstract
BACKGROUND: After early clinical trials that evaluated pharmacogenetic (PG) algorithms, many healthcare payers were reluctant to cover this technology and, consequently, PG dosing of warfarin could not be translated into clinical practice.
OBJECTIVE: The aim of this study was to estimate the value of upgrading evidence relating to PG dosing of warfarin from the healthcare payer perspective.
METHODS: Randomized controlled trials (RCTs) that evaluated PG dosing of warfarin were identified through a systematic literature search, and their findings were combined by a cumulative meta-analysis. A health economic model was used to estimate economic outcomes and to calculate the expected value of perfect information (EVPI) as a measure of the value of clinical trials for decision makers.
RESULTS: Nine RCTs were identified and included in our analysis. The estimated difference in the percentage of time in the therapeutic range was 5.6 percentage points in 2007, decreasing to 4.3 percentage points when all studies were included. At a reimbursement price of €160 per PG testing, the EVPI for the clinical benefit was estimated at €80 and €90 per patient in 2007 and 2014, respectively. A reduction in the price of PG testing to €40, which was observed in this period, resulted in an EVPI of €3 per patient.
CONCLUSIONS: The estimated cumulative effect of PG dosing has remained similar since 2007, but additional evidence has contributed to a more precise estimation. While these variations should not affect the reimbursement decision, a large decline in the cost of PG testing in recent years calls for reconsideration.

PMID: 28528365 [PubMed - indexed for MEDLINE]

Are patients willing to incur out-of-pocket costs for pharmacogenomic testing?

Pharmacogenomics J. 2017 01;17(1):1-3

Authors: Bielinski SJ, St Sauver JL, Olson JE, Wieland ML, Vitek CR, Bell EJ, Mc Gree ME, Jacobson DJ, McCormick JB, Takahashi PY, Black JL, Caraballo PJ, Sharp RR, Beebe TJ, Weinshilboum RM, Wang L, Roger VL

PMID: 27779246 [PubMed - indexed for MEDLINE]

The CYP2D6 VCF Translator.

Pharmacogenomics J. 2017 07;17(4):301-303

Authors: Qiao W, Wang J, Pullman BS, Chen R, Yang Y, Scott SA

PMID: 26975230 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/07/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/07/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder.

Pharmgenomics Pers Med. 2018;11:113-119

Authors: Zastrozhin MS, Grishina EA, Denisenko NP, Skryabin VY, Markov DD, Savchenko LM, Bryun EA, Sychev DA

Abstract
Background: Fluvoxamine therapy is used for treatment of patients with depressive disorder, but it is often ineffective, and some patients suffer from dose-dependent undesirable side effects such as vertigo, headache, indigestion, xerostomia, increased anxiety, etc. CYP2D6 is involved in the biotransformation of fluvoxamine. Meanwhile, the genes encoding these isoenzymes have a high level of polymorphism, which may affect the protein synthesis.
Objective: The primary objective of our study was to investigate the effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder, in order to develop the algorithms of optimization of fluvoxamine therapy for reducing the risk of dose-dependent undesirable side effects and pharmacoresistance.
Methods: The study involved 45 male patients (average age: 36.44±9.96 years) with depressive disorder and comorbid alcohol use disorder. A series of psychometric scales was used in the research. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction.
Results: According to results of Mann-Whitney U-test, statistically significant differences between the efficacy and safety of fluvoxamine were obtained on 9th and 16th days of therapy in patients with GG and GA genotypes (The Hamilton Rating Scale for Depression: 10.0 [10.0; 23.0] vs 25.0 [24.0; 16.0] (P<0.001) on the 9th day and 4.0 [2.0; 5.0] vs 6.0 [6.0; 7.0] on the 16th day; The UKU Side Effect Rating Scale: 6.0 [4.0; 6.0] vs 9.0 [9.0; 10.0] (P<0.001) on the 9th day and 5.0 [1.0; 9.0] vs 19.0 [18.0; 22.0] on the 16th day).
Conclusion: This study demonstrated the lower efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorders with GA genotype in CYP2D6 1846G>A polymorphic marker.

PMID: 29988737 [PubMed]

DNA methylation landscapes in the pathogenesis of type 2 diabetes mellitus.

Nutr Metab (Lond). 2018;15:47

Authors: Zhou Z, Sun B, Li X, Zhu C

Abstract
Although genetic variations and environmental factors are vital to the development and progression of type 2 diabetes mellitus (T2DM), emerging literature suggest that epigenetics, especially DNA methylation, play a key role in the pathogenesis of T2DM by affecting insulin secretion of pancreatic β cells and the body's resistance to insulin. Previous studies have elucidated how DNA methylation interacted with various factors in T2DM pathogenesis. This review summarized the role of related methylation genes in insulin-sensitive organs, such as pancreatic islets, skeletal muscle, liver, brain and adipose tissue, as well as peripheral blood cells, comparing the tissue similarity and specificity of methylated genes, aiming at a better understanding of the pathogenesis of T2DM and providing new ideas for the personalized treatment of this metabolism-associated disease.

PMID: 29988495 [PubMed]

Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial.

BMC Med. 2018 Jul 10;16(1):104

Authors: Syn NL, Wong AL, Lee SC, Teoh HL, Yip JWL, Seet RC, Yeo WT, Kristanto W, Bee PC, Poon LM, Marban P, Wu TS, Winther MD, Brunham LR, Soong R, Tai BC, Goh BC

Abstract
BACKGROUND: Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved.
METHODS: An open-label, non-inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy.
RESULTS: Among 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2.93, difference -1.16, 90% CI -1.48 to -0.84, P < 0.001 for both non-inferiority and superiority). The percentage of time within the therapeutic range over 3 months and median time to stable international normalized ratio (INR) did not differ between the genotype-guided and traditional dosing groups. The frequency of dose titrations (incidence rate ratio 0.76, 95% CI 0.67 to 0.86, P = 0.001), but not frequency of INR measurements, was lower at 1, 2, and 3 months in the genotype-guided group. The proportions of patients who experienced minor or major bleeding, recurrent venous thromboembolism, or out-of-range INR did not differ between both arms. For predicting maintenance doses, the pharmacogenetic algorithm achieved an R2 = 42.4% (P < 0.001) and mean percentage error of -7.4%.
CONCLUSIONS: Among Asian adults commencing warfarin therapy, a pharmacogenetic algorithm meets criteria for both non-inferiority and superiority in reducing dose titrations compared with a traditional dosing approach, and performs well in prediction of actual maintenance doses. These findings imply that clinicians may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages in Asian patients.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00700895 . Registered on June 19, 2008.

PMID: 29986700 [PubMed - in process]

Understanding cancer lineage plasticity: reversing therapeutic resistance in metastatic prostate cancer.

Pharmacogenomics. 2017 05;18(7):597-600

Authors: Ellis L

PMID: 28468521 [PubMed - indexed for MEDLINE]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/07/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Population pharmacokinetics of valproic acid in epileptic children: Effects of clinical and genetic factors.

Eur J Pharm Sci. 2018 Jul 04;:

Authors: Xu S, Chen Y, Zhao M, Guo Y, Wang Z, Zhao L

Abstract
Valproic acid (VPA) is a first-line anti-epileptic drug that is used in the treatment of generalized and partial seizures. Gene variants had been proved to influence the pharmacokinetics (PK) of VPA and contribute to its inter-individual variability (IIV). The aim of this study was to systematically investigate the effects of candidate gene variants (CYPs, UGTs, ABC transporters, and nuclear receptors) on VPA PK in Chinese children with epilepsy. A total of 1065 VPA serum trough concentrations at steady state were collected from 264 epileptic pediatric patients aged 3 months to 16 years. The population pharmacokinetic (PPK) model was developed using a nonlinear mixed effects modelling (NONMEM) approach. For the final PPK model, the oral clearance (CL/F) of VPA was estimated to be 0.259 L/h with IIV of 13.3%. The estimates generated by NONMEM indicated that the VPA CL/F was significantly influenced by patient body weight (increased by an exponent of 0.662), co-administration with carbamazepine (increased CL/F by 22%), and daily dose of VPA (increased by an exponent of 0.22). CL/F in patients with the LEPR rs1137101 variant (668 AG and GG genotypes) was much lower than in patients with the AA genotype (17.8% and 22.6% lower, respectively). However, none of the CYPs or UGTs gene variants was found to influence the PK of VPA in this study. Evaluation by bootstrap and normalized prediction distribution error (NPDE) showed that the final model was stable. The predictive performance was evaluated by goodness-of-fit (GOF) plots and visual predictive checks (VPC), and the results indicated satisfactory precision. Our model suggests a correlation between VPA CL/F and LEPR rs1137101 variants, which might be beneficial in the context of individual dose optimization.

PMID: 29981400 [PubMed - as supplied by publisher]

CYP2D6 genotype and endoxifen plasma concentration do not predict hot flash severity during tamoxifen therapy.

Breast Cancer Res Treat. 2018 Jul 06;:

Authors: Jansen LE, Teft WA, Rose RV, Lizotte DJ, Kim RB

Abstract
PURPOSE: Tamoxifen is frequently prescribed to prevent breast cancer recurrence. Tamoxifen is a prodrug and requires bioactivation by CYP2D6. Tamoxifen use is often limited by adverse effects including severe hot flashes. There is paucity of prospectively collected data in terms of CYP2D6 genotype and measured tamoxifen, 4-hydroxytamoxifen and endoxifen concentrations in relation to hot flash severity during tamoxifen therapy.
METHODS: We conducted a longitudinal prospective study of breast cancer patients on tamoxifen (n = 410). At each visit, blood samples were collected, and patients completed a standardized hot flash survey (n = 1144) that reflected hot flash severity during the 7 days prior to the visit. Plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using liquid chromatography-tandem mass spectrometry and genotyping was carried out for CYP2D6. A linear mixed-effects regression analysis assessed the association of covariates in relation to the hot flash severity score (HFSS).
RESULTS: Median age at first assessment was 50 years with 61.9% of patients considered peri-menopausal. Most patients (92.2%) experienced hot flash symptoms with 51.0% having low HFSS (0-4) and 7.32% experiencing HFSS > 25. Age was significantly associated with hot flash severity, with patients aged 45-59 more likely to have higher HFSS. Neither duration of tamoxifen therapy nor observed tamoxifen, endoxifen and 4-hydroxy tamoxifen plasma concentration predicted hot flash severity. Genetic variation in CYP2D6 or CYP3A4 was not predictive of hot flash severity.
CONCLUSIONS: Hot flash severity during tamoxifen therapy can not be accounted for by CYP2D6 genotype or observed plasma concentration of tamoxifen, 4-hydroxytamoxifen, or endoxifen.

PMID: 29980881 [PubMed - as supplied by publisher]

Single Nucleotide Polymorphisms (SNPs) Distant from Xenobiotic Response Elements Can Modulate Aryl Hydrocarbon Receptor Function: SNP-Dependent CYP1A1 Induction.

Drug Metab Dispos. 2018 Jul 06;:

Authors: Liu D, Qin S, Ray B, Kalari KR, Wang L, Weinshilboum RM

Abstract
CYP1A1 expression can be up-regulated by the ligand-activated aryl hydrocarbon receptor (AHR). Based on prior observations with estrogen receptors and estrogen response elements, we tested the hypothesis that single-nucleotide polymorphisms (SNPs) mapping hundreds of base pairs (bp) from xenobiotic response elements (XREs) might influence AHR binding and subsequent gene expression. Specifically, we analyzed DNA sequences 5 Kb up- and down-stream of the CYP1A1 gene for putative XREs. SNPs located ±500 bp of these putative XREs were studied using a genomic data-rich human lymphoblastoid cell line (LCL) model system. CYP1A1 mRNA levels were determined after treatment with varying concentrations of 3-methylcholanthrene (3MC). The rs2470893 (-1694G>A) SNP, located 196 bp from an XRE in the CYP1A1 promoter was associated with two-fold variation in AHR-XRE binding in a SNP-dependent fashion. LCLs with the AA genotype displayed significantly higher AHR-XRE binding and CYP1A1 mRNA expression after 3MC treatment than did those with the GG genotype. Electrophoretic mobility shift assay (EMSA) showed that oligonucleotides with the AA genotype displayed higher LCL nuclear extract binding after 3MC treatment than did those with the GG genotype, and mass spectrometric analysis of EMSA protein-DNA complex bands identified three candidate proteins, two of which were co-immunoprecipitated with AHR. In conclusion, we have demonstrated that the rs2470893 SNP which maps 196 bp from a CYP1A1 promoter XRE is associated with variation in 3MC-dependent AHR binding and CYP1A1 expression. Similar "distant SNP effects" on AHR binding to an XRE motif and subsequent gene expression might occur for additional AHR-regulated genes.

PMID: 29980579 [PubMed - as supplied by publisher]

The effect of ERCC1 and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients.

BMC Med Genet. 2018 Jul 06;19(1):112

Authors: Obiedat H, Alrabadi N, Sultan E, Al Shatti M, Zihlif M

Abstract
BACKGROUND: Cisplatin is one of the major drugs that used in the treatment of osteosarcoma. Cisplatin exerts its function by making cisplatin-DNA adducts culminating in cellular death. These adducts found to be repaired by nucleotide excision repair (NER) pathway. This study aimed to evaluate if polymorphisms in two main genes in the NER pathway, excision repair cross-complementing group 1 and 2 (ERCC1 and ERCC2) could affect the histological response to cisplatin based chemotherapy or clinical outcomes, particularly, event free survival (EFS) and overall survival (OS) rates.
METHOD: ERCC1 (C118T (rs11615) and C8092A (rs3212986)) and ERCC2 (A751C (rs171140) and G312A (rs1799793)) polymorphisms were analysed in 44 patients with osteosarcoma, who were treated with cisplatin based neoadjuvant chemotherapy. DNA was extracted from patient's formalin-fixed paraffin-embedded (FFPE) samples, patient's genotypes were determined by using polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP assay. The distribution of the patients' genotype and the allele frequencies were reported. The association between each of these genotypes and many clinical and patho-histological parameters (e.g. EFS, OS and patho-histological response to treatment) was examined. The associations between gender, tumor location, presence of metastasis at diagnosis, histological subtypes, and type of neoadjuvant chemotherapy and between the histological response, EFS and OS rates were also examined.
RESULTS: This study revealed that there was a positive and significant association between ERCC1 C8092 A genotypes and median EFS rate in years; patients who were carriers of C allele (CC & CA) were found to have longer EFS rates than patients with AA genotype (P value = 0.006) and the median EFS rates were respectively as following: 2.04, 0.24 years. As well, both the presence of metastasis and the histological subtype at the time of diagnosis, were able to affect the EFS rate but not the OS. However, there was a positive correlation between OS rate and the patients' primary response to treatment.
CONCLUSIONS: Our results suggested that ERCC1 8092 C allele may play a role as a candidate prognostic marker in patients with osteosarcoma.

PMID: 29980176 [PubMed - in process]

Genetic polymorphisms of organic cation transporter 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes: A systematic review.

Medicine (Baltimore). 2018 Jul;97(27):e11349

Authors: Mofo Mato EP, Guewo-Fokeng M, Essop MF, Owira PMO

Abstract
BACKGROUND: Metformin is one of the most commonly used drugs for the treatment of type 2 diabetes mellitus (T2DM). Despite its widespread use, there are considerable interindividual variations in metformin response, with about 35% of patients failing to achieve initial glycemic control. These variabilities that reflect phenotypic differences in drug disposition and action may indeed be due to polymorphisms in genes that regulate pharmacokinetics and pharmacodynamics of metformin. Moreover, interethnic differences in drug responses in some cases correspond to substantial differences in the frequencies of the associated pharmacogenomics risk allele.
AIM: This study aims to highlight and summarize the overall effects of organic cation transporter 1(OCT1) polymorphisms on therapeutic responses to metformin and to evaluate the potential role of such polymorphisms in interethnic differences in metformin therapy.
METHODS: We conducted a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We searched for PubMed/MEDLINE, Embase, and CINAHL, relevant studies reporting the effects of OCT1 polymorphisms on metformin therapy in T2DM individuals. Data were extracted on study design, population characteristics, relevant polymorphisms, measure of genetic association, and outcomes. The presence of gastrointestinal side effects, glycated hemoglobin A1 (HbA1c) levels, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) concentrations after treatment with metformin were chosen as measures of the metformin responses. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO).
RESULTS: According to the data extracted, a total of 34 OCT1 polymorphisms were identified in 10 ethnic groups. Significant differences in the frequencies of common alleles were observed among these groups. Met408Val (rs628031) variant was the most extensively explored with metformin responses. Although some genotypes and alleles have been associated with deleterious effects on metformin response, others indeed, exhibited positive effects.
CONCLUSION: Genetic effects of OCT1 polymorphisms on metformin responses were population specific. Further investigations in other populations are required to set ethnicity-specific reference for metformin responses and to obtain a solid basis to design personalized therapeutic approaches for T2DM treatment.

PMID: 29979413 [PubMed - in process]

A Common mdr1 Gene Polymorphism is Associated with Changes in Linezolid Clearance.

Ther Drug Monit. 2018 Jul 03;:

Authors: Allegra S, Di Paolo A, Cusato J, Fatiguso G, Arrigoni E, Danesi R, Corcione S, D'Avolio A

Abstract
BACKGROUND: Several factors contribute to the high variability of linezolid plasma exposure in patients. Very recently, it has been suggested that linezolid could be an ABCB1 substrate. Therefore, the present clinical study was aimed at investigating whether ABCB1 polymorphisms could predict linezolid pharmacokinetics in 27 critically ill patients.
METHODS: Genotypes were assessed through a real-time polymerase chain reaction allelic discrimination system, and linezolid plasma concentrations, considering trough concentration (Ctrough) and area under the time concentration curve (AUC), were analyzed through a nonlinear mixed-effects modeling approach.
RESULTS: A significant effect of abcb1 c.3435C>T polymorphism on linezolid clearance was found, whose values accounted for 13.19L/h in wild-type homozygotes and 7.82 L/h in the remaining individuals. That difference was statistically significant despite the large interindividual variability (60.8%). Terminal half-life and volume of distribution values significantly differed between c.3435CC and c.3435CT/TT patients (2.78 vs. 5.45 h and 37.43 vs. 46.71L, respectively). On the contrary, a modest trend was observed for the difference in AUC and Ctrough based on c.3435C>T genotypes. Simulation according to the final model revealed that the cumulative response fraction for the AUC/MIC parameter was better for .3435CC individuals compared to individuals carrying at least one c.3435T allele with respect to MSSA, MRSA, and S. pneumoniae species.
CONCLUSIONS: The obtained results suggest the possible influence of ABCB1 in linezolid pharmacokinetics, bringing new interest for pharmacogenetic analyses in antimicrobial chemotherapy. These analyses could be incorporated in therapeutic protocols for precision medicine, including a combined use of genetic evaluation (for starting dose) and follow-up TDM.

PMID: 29979333 [PubMed - as supplied by publisher]