Miriam Saiz-Rodríguez

Polymorphisms associated with etanercept response in moderate-to-severe plaque psoriasis

AIMnFew studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with etanercept.nnnMATERIALS & METHODSnWe evaluated the association between 124 polymorphisms with the response to etanercept in patients with moderate-to-severe plaque psoriasis at 3 months (n = 78) and 6 months of treatment (n = 68).nnnRESULTSnThe results of the multivariate analysis showed an association between polymorphisms rs13437088 (HLA-B/MICA), rs96844 (MAP3K1), rs2431697 (PTTG1), rs9304742 (ZNF816A) and the response to etanercept at 3 months. Besides polymorphisms rs928655 (GBP6) and rs2546890 (IL12B) were associated to response at 6 months.nnnCONCLUSIONSnNevertheless, these biomarkers should be validated in large-scale studies before its implementation in clinical practice.

Influence of CYP2D6,CYP3A4,CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers

The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P‐glycoprotein (P‐gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro‐aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC‐MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC0−t, Cmax and t1/2 of aripiprazole were higher and clearance of aripiprazole, AUC0−t of dehydro‐aripiprazole and ratio dehydro‐aripiprazole/aripiprazole were lower. AUC0−t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC0−t of dehydro‐aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC0−t (p = 0.039) and Cmax of dehydro‐aripiprazole (p = 0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro‐aripiprazole/aripiprazole than *1/*3 (p = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC0−t of aripiprazole (p = 0.001), especially nausea/vomiting, which were more common in women (p = 0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p = 0.034; p = 0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro‐aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro‐aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.

Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers

Sertraline is a selective serotonin reuptake inhibitor widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P‐glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of this study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty‐six healthy volunteers (24 men and 22 women) receiving a 100‐mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP‐binding cassette subfamily B member 1 (ABCB1), solute carrier family 6 member 4 (SLC6A4), 5‐hydroxytryptamine receptor 2A (HTR2A) and 5‐hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Individuals carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half‐life (T1/2). Moreover, CYP2C19*17 was related to a decreased AUC and T1/2. No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate‐lowering effect, directly related to maximum concentration (Cmax) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T individuals.

Pharmacogenetics of trazodone in healthy volunteers: association with pharmacokinetics, pharmacodynamics and safety

AIMnThe aim was to evaluate the effect of polymorphisms in metabolizing enzymes and transporters on the pharmacokinetics, pharmacodynamics and adverse effects of trazodone in healthy volunteers.nnnMATERIALS & METHODSn36 healthy volunteers receiving a single 100-mg oral dose of trazodone were genotyped for 11 variants in CYP3A4, CYP3A5, CYP2D6 and ABCB1 by real-time PCR. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry method.nnnRESULTS & CONCLUSIONnSex affected the pharmacokinetics of trazodone with higher clearance in women. Polymorphisms in ABCB1, but not in CYP3A or CYP2D6, influenced trazodone pharmacokinetics. Trazodone decreased blood pressure and prolonged the corrected QT interval interval. CYP2D6 and ABCB1 polymorphisms were associated with the incidence of dizziness and prolonged corrected QT interval, respectively. Subjects with adverse drug reactions had lower concentrations of trazodone suggesting its metabolite (m-chlorophenylpiperazine) could be responsible for these effects.

Pharmacogenetics and Pharmacogenomics in Moderate-to-Severe Psoriasis.

Pharmacogenetics is the study of variations in DNA sequence related to drug response. Moreover, the evolution of biotechnology and the sequencing of human DNA have allowed the creation of pharmacogenomics, a branch of genetics that analyzes human genes, the RNAs and proteins encoded by them, and the inter-and intra-individual variations in expression and function in relation to drug response. Pharmacogenetics and pharmacogenomics are being used to search for biomarkers that can predict response to systemic treatments, including those for moderate-to-severe psoriasis. Psoriasis is a chronic inflammatory disease with an autoimmune contribution. Although its etiology remains unknown, genetic, epigenetic, and environmental factors play a role in its development. Diverse systemic and biologic therapies are used to treat moderate-to-severe psoriasis. However, these treatments are not curative, and patients exhibit a wide range of responses to them. Moderate-to-severe psoriasis is usually treated with systemic immunomodulators such as acitretin, ciclosporin, and methotrexate. Anti-tumor necrosis factor (TNF) drugs (adalimumab, etanercept, or infliximab) are the first-line treatment for patients resistant to conventional systemic therapies. Although these therapies are very efficient, around 30–50% of patients have inadequate response. Ustekinumab is a monoclonal antibody that targets interleukin (IL)-12 and IL-23 and is used for moderate-to-severe psoriasis. New drugs (apremilast, brodalumab, guselkumab, ixekizumab, and secukinumab) have recently been approved for psoriasis. However, response rates to systemic treatments for moderate-to-severe psoriasis range from 35 to 80%, so it is necessary to identify non-invasive biomarkers that could help predict treatment outcomes of these therapies and individualize care for patients with psoriasis. These biomarkers could improve patient quality of life and reduce health costs and potential side effects. Pharmacogenetic studies have identified potential biomarkers for response to biologic treatments for moderate-to-severe psoriasis. These biomarkers need to be validated in clinical trials involving large cohorts of patients before they can be translated to the clinic. We review pharmacogenetics and pharmacogenomics studies for the treatment of moderate-to-severe plaque psoriasis.

Polymorphisms associated with adalimumab and infliximab response in moderate-to-severe plaque psoriasis

AIMnThis study evaluated the influence of pharmacogenetics in psoriatic patients treated with adalimumab and/or infliximab.nnnMATERIALS & METHODSnProspective observational study evaluating the association of 124 polymorphisms with the response to adalimumab or infliximab (PASI75) in patients with moderate-to-severe plaque psoriasis at 3xa0months (nxa0=xa095) and 6xa0months of treatment (nxa0=xa090). Significant SNPs for univariate analysis were subjected to multivariate analysis.nnnRESULTSnFive SNPs were associated with PASI75 at 3xa0months: rs6661932 (IVL), rs2546890 (IL-12B), rs2145623 (NFKBIA), rs9304742 (ZNF816A) and rs645544 (SLC9A8). Furthermore, rs1061624 (TNFR1B) was associated with PASI75 at 6xa0months.nnnCONCLUSIONnNevertheless, these biomarkers should be validated in large-scale studies before implementation in clinical practice.

Influence of CYP2C19 Phenotype on the Effect of Clopidogrel in Patients Undergoing a Percutaneous Neurointervention Procedure

This observational retrospective study assessed the antiplatelet response and clinical events after clopidogrel treatment in patients who underwent percutaneous neurointervention, related to CYP2C19 metabolizer status (normal (NM), intermediate/poor (IM‐PM), and ultrarapid (UM); inferred from *2, *3, and *17 allele determination). From 123 patients, IM‐PM had a higher aggregation value (201.1 vs. 137.6u2009NM, 149.4 UM, Pu2009<u20090.05) and lower response rate (37.5% vs. 69.8% NM, 61.1% UM), along with higher treatment change rate (25% vs. 5.7% NM, 10.5% UM). The highest ischemic events incidence occurred in NM (11.3% vs. 6.3% IM, 10.5% UM) and hemorrhagic events in UM (13.2% vs. 0% IM and 3.8% NM). No differences were found regarding ischemic event onset time, while hemorrhagic event frequency in UM was higher with shorter onset time (Pu2009=u20090.047). CYP2C19 no‐function and increased function alleles defined the clopidogrel response. UM patients had increased bleeding risk. Therapeutic recommendations should include dose reduction or treatment change in UM.

Epigenetic biomarkers associated with anti-TNF drugs response in moderate-to- severe psoriasis

It has recently been discovered that epigenetic modifications, specially DNA methylation, participates in the pathology of psoriasis. DNA methylation is a covalent modification dynamic and heritable that takes place in Cytosine-Phosphate-Guanine (CpG) sites and may exert transcriptional effects. Although anti-tumour necrosis factor α (TNF) therapies (adalimumab, etanercept and infliximab) are efficient drugs for moderate-to-severe psoriasis, around 30–50% of psoriasis patients present an inadequate response. n nThis article is protected by copyright. All rights reserved.

How to make P-glycoprotein (ABCB1, MDR1) harbor mutations and measure its expression and activity in cell cultures?

Several polymorphisms have been identified in ABCB1, the gene encoding for the P-glycoprotein. This transporter alters the pharmacokinetics or effectiveness of drugs by excreting them from cells where it is expressed (e.g., blood-brain barrier, intestine or tumors). No consensus has been reached regarding the functional consequences of these polymorphisms in the transporters function. The aim of this review was to describe a methodology that allows the assessment of P-gp function when harboring polymorphisms. We describe how to obtain cell lines with high expression levels of the transporter with polymorphisms and several tactics to measure its expression and activity. This methodology may help elucidate the contribution of polymorphisms in ABCB1 to drug pharmacokinetics, effectiveness and safety or to cancer chemotherapy failure.

Effects of aripiprazole on pupillometric parameters related to pharmacokinetics and pharmacogenetics after single oral administration to healthy subjects

Background: Pupillometry is used for the detection of autonomic dysfunction related to numerous diseases and drug administration. Genetic variants in cytochrome P450 (CYP2D6, CYP3A4), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP-binding cassette subfamily B (ABCB1) genes were previously associated with aripiprazole response. Aims: Our aim was to evaluate if aripiprazole affects pupil contraction and its relationship with pharmacokinetics and pharmacogenetics. Methods: Thirty-two healthy volunteers receiving a 10 mg single oral dose of aripiprazole were genotyped for 15 polymorphisms in ABCB1, CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by reverse transcription polymerase chain reaction. Aripiprazole and dehydro-aripiprazole plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Pupil examination was performed by automated pupillometry. Results: Aripiprazole caused pupil constriction and reached the peak value at Cmax. HTR2A rs6313 T allele carriers and HTR2C rs3813929 C/T subjects showed higher maximum constriction velocity and maximum pupil diameter. Besides, Gly/Gly homozygotes for DRD3 rs6280 showed significantly lower maximum constriction velocity values. A/G heterozygotes for DRD2 rs6277 showed higher total time taken by the pupil to recover 75% of the initial resting size values. CYP2D6 intermediate metabolisers showed higher area under the curve, Cmax and T1/2 than extensive metabolisers. ABCB1 G2677T/A A/A homozygotes had greater T1/2 in comparison with C/C homozygotes. ABCB1 C3435T T allele carriers and C1236T C/T subjects showed greater area under the curve than C/C homozygotes. Conclusions: Aripiprazole affects pupil contraction, which could be a secondary effect through dopamine and serotonin receptors. Pupillometry could be a useful tool to assess autonomic nervous system activity during antipsychotic treatment.