An integrin-based nanoparticle that targets activated hepatic stellate cells and alleviates liver fibrosis.

J Control Release. 2019 Apr 17;:

Authors: Li Y, Pu S, Liu Q, Li R, Zhang J, Wu T, Chen L, Li H, Yang X, Zou M, Xiao J, Xie W, He J

Abstract
Activation of hepatic stellate cells (HSCs) contributes to the development of liver fibrosis. Because of a relatively small population of HSCs in the liver and the lack of specific membrane targeting proteins, HSC-targeted therapy remains a major clinical challenge. Here we first showed that a hallmark of activated HSC (aHSC) is their increased expression of integrin αvβ3. Thus we established sterically stable liposomes that contain the cyclic peptides (cRGDyK) with a high affinity to αvβ3 to achieve aHSC-specific delivery. Our results showed that the cRGDyK-guided liposomes were preferentially internalized by activated HSCs in vitro and in vivo, and the internalization was abolished by excess free cRGDyK or knockdown of αvβ3. In contrast, quiescent HSCs, hepatocytes, Kupffer cells, sinusoidal endothelial cells, or biliary cells showed minimal uptake of the cRGDyK-guided liposomes. When loaded with the hedgehog inhibitor vismodegib, the cRGDyK-guided liposomes inhibited hedgehog pathway signaling specifically in activated HSCs. Moreover, treatment of mice with vismodegib-loaded cRGDyK-liposomes markedly inhibited the fibrogenic phenotype in bile duct ligation- or thioacetamide-treated mice. We conclude that the cRGDyK-guided liposomes can specifically target the activated HSCs, but not quiescent HSCs. This nanoparticle system showed great promise to deliver therapeutic agents to aHSC to treat liver fibrosis.

PMID: 31004666 [PubMed - as supplied by publisher]

Come Dance With Me: Transformative Changes in the Science and Practice of Drug-Drug Interactions.

Clin Pharmacol Ther. 2019 Apr 20;:

Authors: Venkatakrishnan K, Rostami-Hodjegan A

Abstract
The past 2 decades have witnessed transformative changes in our approach to drug-drug interactions (DDIs) from scientific research to clinical practice. Collaborative cooperation across the sectors of academia, pharmaceutical industry, providers of translational research tools and services, global regulatory agencies, and healthcare providers has created and galvanized a science-informed and patient-centered approach. Multidisciplinary innovations in mechanistic assessment of absorption, distribution, metabolism, and excretion (ADME), population pharmacology and pharmacogenetics, physiologically based modeling, and regulatory science have enabled a profound shift in mindset from risk aversion to informative prescribing guidance for optimal risk management. Foundational to this transformation is a commitment to maximizing the value of innovative therapeutics for all patients and across clinical contexts of use through rational knowledge management and translation based on the totality of best available evidence, thereby removing the void that can lead to arbitrary decisions in clinical therapeutics.

PMID: 31004453 [PubMed - as supplied by publisher]

Navigating the Labyrinth of Pharmacogenetic Testing: A Guide to Test Selection.

Clin Pharmacol Ther. 2019 Apr 20;:

Authors: Bousman CA, Zierhut H, Müller DJ

PMID: 31004441 [PubMed - as supplied by publisher]

9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer.

J Cell Physiol. 2019 Apr 19;:

Authors: Liu R, Chen Z, Yi X, Huang F, Hu G, Liu D, Li X, Zhou H, Liu Z

Abstract
Non-small-cell lung cancer (NSCLC) is an aggressive subtype of pulmonary carcinomas with high mortality. However, chemotherapy drug resistance and high recurrence rates hinder the curative effect of platinum-based first-line chemotherapy, which makes it urgent to develop new antitumor drugs for NSCLC. 9za, a new candidate drug synthesized by our research group, has been verified with potent antilung cancer activity in preliminary experiments. However, the underlying molecular mechanism of 9za remains largely vague. This work revealed that 9za could play important cytotoxic and proapoptotic roles in NSCLC cells. Moreover, 9za could induce autophagy and promote autophagy flux. Interestingly, the cytotoxic and proapoptotic roles were significantly dependent on 9za-induced cytoprotective autophagy. That is, the coadministration of 9za with an autophagy inhibitor such as chloroquine or 3-methyladenine exhibited increased cytotoxic and proapoptotic effects compared with 9za treatment alone. In addition, 9za exposure suppressed the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (Akt), mammalian targets of rapamycin (mTOR), p70 S6 kinase, and 4E binding protein 1 by a dose-dependent way, manifesting that the Akt/mTOR axis was implicated in 9za-induced autophagy. In addition, the overexpression of PDK1 resulted in increased phosphorylation of PDK1 and Akt and blocking of 9za-mediated autophagy. These data showed that the PDK1/Akt/mTOR pathway was involved in 9za-induced autophagy. Hence, this work provides a theoretical basis for exploiting 9za as a new antilung cancer candidate drug and hints that the combination of 9za with an autophagy inhibitor is a feasible alternative approach for the therapy of NSCLC.

PMID: 31004362 [PubMed - as supplied by publisher]

Orthogonal joint sparse NMF for microarray data analysis.

J Math Biol. 2019 Apr 19;:

Authors: Esposito F, Gillis N, Del Buono N

Abstract
The 3D microarrays, generally known as gene-sample-time microarrays, couple the information on different time points collected by 2D microarrays that measure gene expression levels among different samples. Their analysis is useful in several biomedical applications, like monitoring dose or drug treatment responses of patients over time in pharmacogenomics studies. Many statistical and data analysis tools have been used to extract useful information. In particular, nonnegative matrix factorization (NMF), with its natural nonnegativity constraints, has demonstrated its ability to extract from 2D microarrays relevant information on specific genes involved in the particular biological process. In this paper, we propose a new NMF model, namely Orthogonal Joint Sparse NMF, to extract relevant information from 3D microarrays containing the time evolution of a 2D microarray, by adding additional constraints to enforce important biological proprieties useful for further biological analysis. We develop multiplicative updates rules that decrease the objective function monotonically, and compare our approach to state-of-the-art NMF algorithms on both synthetic and real data sets.

PMID: 31004215 [PubMed - as supplied by publisher]

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Varicose veins of lower extremities: Insights from the first large-scale genetic study.

PLoS Genet. 2019 Apr 18;15(4):e1008110

Authors: Shadrina AS, Sharapov SZ, Shashkova TI, Tsepilov YA

Abstract
Varicose veins of lower extremities (VVs) are a common multifactorial vascular disease. Genetic factors underlying VVs development remain largely unknown. Here we report the first large-scale study of VVs performed on a freely available genetic data of 408,455 European-ancestry individuals. We identified the 12 reliably associated loci that explain 13% of the SNP-based heritability, and prioritized the most likely causal genes CASZ1, PIEZO1, PPP3R1, EBF1, STIM2, HFE, GATA2, NFATC2, and SOX9. VVs-associated variants within these loci exhibited pleiotropic effects on several phenotypes including blood pressure/hypertension and blood cell traits. Gene set enrichment analysis revealed gene categories related to abnormal vasculogenesis. Genetic correlation analysis confirmed known epidemiological associations between VVs and deep venous thrombosis, weight, rough labor, and standing job, and found a genetic overlap with multiple traits that have not been previously suspected to share common genetic background with VVs. These traits included educational attainment, fluid intelligence and prospective memory scores, walking pace (negative correlation with VVs), smoking, height, number of operations, pain, and gonarthrosis (positive correlation with VVs). Finally, Mendelian randomization analysis provided evidence for causal effects of plasma levels of MICB and CD209 proteins, and anthropometric traits such as waist and hip circumference, height, weight, and both fat and fat-free mass. Our results provide novel insight into both VVs genetics and etiology. The revealed genes and proteins can be considered as good candidates for follow-up functional studies and might be of interest as potential drug targets.

PMID: 30998689 [PubMed - as supplied by publisher]

Clopidogrel Pharmacogenetics.

Circ Cardiovasc Interv. 2019 Apr;12(4):e007811

Authors: Pereira NL, Rihal CS, So DYF, Rosenberg Y, Lennon RJ, Mathew V, Goodman SG, Weinshilboum RM, Wang L, Baudhuin LM, Lerman A, Hasan A, Iturriaga E, Fu YP, Geller N, Bailey K, Farkouh ME

Abstract
Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in increased risk of major adverse cardiovascular events, especially after percutaneous coronary intervention. The Food and Drug Administration has issued a black box warning advising practitioners to consider alternative treatment in CYP2C19 poor metabolizers who might receive clopidogrel and to identify such patients by genotyping. However, routine clinical use of genotyping for CYP2C19 loss-of-function alleles in patients undergoing percutaneous coronary intervention is not recommended by clinical guidelines because of lack of prospective evidence. To address this critical gap, TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) is a large, pragmatic, randomized trial comparing point-of-care genotype-guided antiplatelet therapy with routine care to determine whether identifying CYP2C19 loss-of-function allele patients prospectively and prescribing alternative antiplatelet therapy is beneficial.

PMID: 30998396 [PubMed - in process]

Genetics Guideline Is Excellent, but the Pharmacogenetics Section Is Weak.

J Clin Psychiatry. 2019 Apr 09;(3):

Authors: de Leon J

PMID: 30997962 [PubMed - in process]

Lipid Disturbances in Adolescents Treated With Second-Generation Antipsychotics: Clinical Determinants of Plasma Lipid Worsening and New-Onset Hypercholesterolemia.

J Clin Psychiatry. 2019 Apr 09;80(3):

Authors: Delacrétaz A, Vandenberghe F, Glatard A, Dubath C, Levier A, Gholam-Rezaee M, Holzer L, Ambresin AE, Conus P, Eap CB

Abstract
OBJECTIVE: Lipid disturbances following treatment with second-generation antipsychotics (SGAs) represent a major health concern. A previous study determined that early changes of plasma lipid levels ≥ 5% during the first month of treatment with SGAs predicts further lipid worsening and development of dyslipidemia. This current study aimed to determine the proportion of adolescents with early lipid changes ≥ 5% and who develop dyslipidemia during SGA treatment.
METHODS: Data were obtained from a 1-year longitudinal study ongoing since 2007 including 53 adolescent psychiatric (ICD-10) patients (median age 16.5 years; interquartile range [IQR], 14.8-17.5 years) whose metabolic parameters were monitored prospectively during treatment. Plasma lipid levels (total, low-density lipoprotein, high-density lipoprotein [HDL-C], and non-high-density lipoprotein cholesterol and fasting triglycerides ) were measured at baseline and after 1, 3, and/or 12 months of SGA treatment.
RESULTS: Half (n = 26; 49%) the adolescents had an early increase of total cholesterol levels by 5% or more during the first month of treatment, and one-third (n = 8/24; 33%) developed new-onset hypercholesterolemia during the first year of treatment. Hypercholesterolemia developed more frequently in female patients (P = .01) and in patients with an early increase of total cholesterol ≥ 5% (P = .02). Finally, patients whose HDL-C levels decreased by ≥ 5% during the first month of treatment had a larger HDL-C worsening after 3 months of treatment as compared with patients with early decrease of HDL-C by < 5% (P = .02).
CONCLUSIONS: This study underlines the importance of prospectively monitoring metabolic parameters in adolescents after the introduction of SGAs.

PMID: 30997960 [PubMed - in process]

Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid.

Pharmacogenomics J. 2019 Apr 17;:

Authors: Tague LK, Byers DE, Hachem R, Kreisel D, Krupnick AS, Kulkarni HS, Chen C, Huang HJ, Gelman A

Abstract
Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan-Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37-44.04), p = 0.021; rs4149117 HR 7.28 (1.27-41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06-3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13-4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.

PMID: 30992538 [PubMed - as supplied by publisher]

Influences of cytochrome b5 expression and its genetic variant on the activity of CYP2C9, CYP2C19 and CYP3A4.

Drug Metab Pharmacokinet. 2019 Apr 01;:

Authors: Yoo SE, Yi M, Kim WY, Cho SA, Lee SS, Lee SJ, Shin JG

Abstract
The objective of the present study was to investigate the effects of cytochrome b5 (cytb5) on the drug metabolism catalyzed by CYP2C9, CYP2C19 and CYP3A4. Activities of CYP2C9, CYP2C19, and CYP3A4 were determined by using the prototypical substrates tolbutamide, omeprazole and midazolam, respectively. Cytb5 protein and mRNA contents showed large inter-individual variations with 11- and 6-fold range, respectively. All of three P450s showed an increased activity in proportion to the amount of cytb5 expression. Particularly, CYP3A4 showed the strongest correlation between cytb5 protein amount and the activity, followed by CYP2C9 and CYP2C19. The putative splicing variant, c.288G>A (rs7238987) was identified and was screened in 36 liver tissues by direct DNA sequencing. Liver tissues having a splicing variant exhibited unexpected sizes of cytb5 mRNA and a decreased expression tendency of cytb5 protein compared to the wild-type. A decreased activity in the metabolism of the CYP2C19 substrate omeprazole was observed in liver tissues carrying the splicing variant when compared to the wild-type Cytb5 (P < 0.05). The present results propose that different expression of cytb5 can cause variations in CYP mediated drug metabolism, which may explain, at least in part, the inter-individual difference in drug responses in addition to the CYP genetic polymorphisms.

PMID: 30992242 [PubMed - as supplied by publisher]

Genome sequencing analysis of blood cells identifies germline haplotypes strongly associated with drug resistance in osteosarcoma patients.

BMC Cancer. 2019 Apr 16;19(1):357

Authors: Bhuvaneshwar K, Harris M, Gusev Y, Madhavan S, Iyer R, Vilboux T, Deeken J, Yang E, Shankar S

Abstract
BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children. Survival remains poor among histologically poor responders, and there is a need to identify them at diagnosis to avoid delivering ineffective therapy. Genetic variation contributes to a wide range of response and toxicity related to chemotherapy. The aim of this study is to use sequencing of blood cells to identify germline haplotypes strongly associated with drug resistance in osteosarcoma patients.
METHODS: We used sequencing data from two patient datasets, from Inova Hospital and the NCI TARGET. We explored the effect of mutation hotspots, in the form of haplotypes, associated with relapse outcome. We then mapped the single nucleotide polymorphisms (SNPs) in these haplotypes to genes and pathways. We also performed a targeted analysis of mutations in Drug Metabolizing Enzymes and Transporter (DMET) genes associated with tumor necrosis and survival.
RESULTS: We found intronic and intergenic hotspot regions from 26 genes common to both the TARGET and INOVA datasets significantly associated with relapse outcome. Among significant results were mutations in genes belonging to AKR enzyme family, cell-cell adhesion biological process and the PI3K pathways; as well as variants in SLC22 family associated with both tumor necrosis and overall survival. The SNPs from our results were confirmed using Sanger sequencing. Our results included known as well as novel SNPs and haplotypes in genes associated with drug resistance.
CONCLUSION: We show that combining next generation sequencing data from multiple datasets and defined clinical data can better identify relevant pathway associations and clinically actionable variants, as well as provide insights into drug response mechanisms.

PMID: 30991985 [PubMed - in process]

The prominent impairment of liver/intestinal cytochrome P450 and intestinal drug transporters in sepsis-induced acute kidney injury over acute and chronic renal ischemia, a mouse model comparison.

Ren Fail. 2019 Nov;41(1):314-325

Authors: Sukkummee W, Jittisak P, Wonganan P, Wittayalertpanya S, Chariyavilaskul P, Leelahavanichkul A

Abstract
Drug dosing adjustment in sepsis-induced acute kidney injury (sepsis-AKI) is currently adjusted based on renal function. Sepsis is a multiorgan injury, and thus, drug metabolism in sepsis-AKI might be interfered by non-renal factors such as changes in functions of drug-metabolizing enzymes in the liver and functions of intestinal drug transporters. We compared the defect on mouse CYP3A11 (human CYP3A4 representative) in liver and intestine along with several intestinal drug transporters (MDR1a, MRP2, and OATP3) in three mouse models; chronic ischemic reperfusion injury (Chr I/R; 4-week), acute ischemic reperfusion injury (Acute I/R; 24-h), and cecal ligation and puncture (CLP; 24-h) as representative of sepsis-AKI. Decreased expression of CYP3A11 and drug transporters was demonstrated in all models. Among these models, sepsis-AKI had the least severe renal injury (increased BUN and Scr) with the most severe liver injury (increased ALT and changes in liver histopathology), the most severe intestinal leakage (increased serum (1→3)-β-D-glucan) and the highest increase in serum IL-6. A reduced expression and activity of liver and intestinal CYP3A11 along with intestinal efflux-drug transporter expressions (MDR1a and MRP2), but not drug uptake transporter (OATP3), was predominant in sepsis-AKI compared with acute I/R. Additionally, a reduction of CYP3A4 expression with IL-6 was demonstrated on HepG2 cells implying a direct injury of IL-6 on human liver cells. Differences in drug metabolism were reported between sepsis-AKI and ischemic-AKI confirming that drug dosing adjustment in sepsis-AKI depends not just only on renal function but also on several non-renal factors. Further studies are warranted.

PMID: 30991873 [PubMed - in process]

The genetics of antipsychotic response in schizophrenia.

Lancet Psychiatry. 2018 04;5(4):291-292

Authors: Ikeda M, Mushiroda T

PMID: 29503162 [PubMed - indexed for MEDLINE]

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants.

Genes (Basel). 2019 Apr 04;10(4):

Authors: Lucafò M, Stocco G, Martelossi S, Favretto D, Franca R, Malusà N, Lora A, Bramuzzo M, Naviglio S, Cecchin E, Toffoli G, Ventura A, Decorti G

Abstract
The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn's disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio and 30% decrease in clinical efficacy. GSTA1 variant (12.8% of patients) showed a trend (p = 0.049, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics.

PMID: 30987408 [PubMed]

FARMAPRICE: A Pharmacogenetic Clinical Decision Support System for Precise and Cost-Effective Therapy.

Genes (Basel). 2019 Apr 04;10(4):

Authors: Roncato R, Dal Cin L, Mezzalira S, Comello F, De Mattia E, Bignucolo A, Giollo L, D'Errico S, Gulotta A, Emili L, Carbone V, Guardascione M, Foltran L, Toffoli G, Cecchin E

Abstract
Pharmacogenetic (PGx) guidelines for the precise dosing and selection of drugs remain poorly implemented in current clinical practice. Among the barriers to the implementation process is the lack of clinical decision support system (CDSS) tools to aid health providers in managing PGx information in the clinical context. The present study aimed to describe the first Italian endeavor to develop a PGx CDSS, called FARMAPRICE. FARMAPRICE prototype was conceived for integration of patient molecular data into the clinical prescription process in the Italian Centro di Riferimento Oncologico (CRO)-Aviano Hospital. It was developed through a coordinated partnership between two high-tech companies active in the computerization of the Italian healthcare system. Introducing FARMAPRICE into the clinical setting can aid physicians in prescribing the most efficacious and cost-effective pharmacological therapy available.

PMID: 30987397 [PubMed]

Rifampin induces expression of P-glycoprotein on the THP1 cell- derived macrophages, causing decrease intra-macrophage concentration of prothionamide.

J Pharm Sci. 2019 Apr 13;:

Authors: Hasanuzzaman M, Yi M, Cho M, Parvez MM, Lee SJ, Shin JG

Abstract
Rifampin (RIF) has been widely used for the treatment of bacterial infections, including tuberculosis. Treatment of drug-resistant tuberculosis (TB) is a global problem due to reduced drug efficacy. The present study determined the effect of rifampin (RIF) on MDR1 gene (P-glycoprotein, P-gp) expression in THP1 macrophages and analyzed the intracellular concentration of the anti-TB drug prothionamide in the presence of RIF. RIF treatment significantly induced MDR1 protein and mRNA levels in phorbol 12-myristate 13-acetate (PMA)-stimulated THP1 macrophages (P< 0.001 and 0.01, respectively). The PXR inhibitors resveratrol and ketoconazole significantly suppressed RIF-induced P-gp expression in THP1 macrophages (P < 0.05). RIF-treated THP1 macrophages also exhibited strong efflux of P-gp substrate, resulting in a reduced intracellular concentration of rhodamine-123 and prothionamide (P< 0.01 and 0.05, respectively). In contrast, the P-gp inhibitor cyclosporine A significantly increased intracellular concentration of rhodamine-123 and prothionamide (P< 0.001 and 0.05, respectively).The present results suggest that the usage of RIF together with P-gp-substrate drugs to treat TBmay lead to deteriorated treatment efficacy due to the lower intracellular drug concentration. Further studies would be necessary to know the influence of RIF-induced P-gp induction on the treatment outcome of TB patients.

PMID: 30991038 [PubMed - as supplied by publisher]

Enantiospecific pharmacogenomics of fluvastatin.

Clin Pharmacol Ther. 2019 Apr 16;:

Authors: Hirvensalo P, Tornio A, Neuvonen M, Kiander W, Kidron H, Paile-Hyvärinen M, Tapaninen T, Backman JT, Niemi M

Abstract
The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S- and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 × 10-9 and P = 3.19 × 10-12 ). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 × 10-8 ). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single nucleotide variations (SNVs) may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity. This article is protected by copyright. All rights reserved.

PMID: 30989645 [PubMed - as supplied by publisher]

BSA-Based Dosing Regimen of Caspofungin in Children: A Population Pharmacokinetics Confirmatory Study.

Antimicrob Agents Chemother. 2019 Apr 15;:

Authors: Yang XM, Leroux S, Storme T, Zhang DL, de Beaumais TA, Shi HY, Yang YL, Wang XL, Zhao W, Jacqz-Aigrain E

Abstract
We evaluated the population pharmacokinetics of caspofungin in children (2-12 years old). The real-world data from 48 children were best fit by a two-compartment model with first-order elimination. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics compared to body weight. The population pharmacokinetics of caspofungin confirmed that adjustment of caspofungin based on body surface area is most appropriate for paediatric use.

PMID: 30988148 [PubMed - as supplied by publisher]