Pharmacogenetics and pharmacogenomics in psoriasis treatment: current challenges and future prospects

Introduction: Topical, systemic, oral disease modifying, and biologic agents are part of the armamentarium to manage psoriatic disease. The choice of therapy depends upon disease severity, relevant co-morbidities and patient preference. There is great variability in patient response with these agents, and there is still no clear method of selecting the preferred therapeutic agent for efficacy or lack of adverse events.

Areas covered: This article will review the pharmacogenetic and pharmacogenomic targets that are currently known with respect to psoriasis vulgaris, and the most frequent co-morbidity of psoriasis, psoriatic arthritis.

Expert opinion: Presently, no clinically actionable biomarker exists for any therapeutic agent used to treat psoriasis or psoriatic arthritis. The lack of validated outcome measures and conflicting results of open-label studies conducted may be attributed to a multitude of issues that confound discovery. Consequently, studies have been underpowered to identify genes or genetic variants worth translating to clinical practice. In order to achieve a pharmacogenetic/pharmacogenomic signature, improvements in study design of future investigations are required, including carefully designed prospective studies. It is imperative to combine known clinical, serological, and molecular markers with consistent outcomes and an adequate health economic evaluation before they can be adopted widely in clinical practice.     

ABCA 1 基因R219K 多态性对 格列美脲疗效的影响

目的 观察三磷酸腺苷结合盒转运体A1（ABCA 1）基因R219K 多态性对格列美脲降糖疗效 的影响,初步探讨格列美脲药效个体化差异的遗传学机制。方法 选取76 例初诊的2 型糖尿病患者,给 予格列美脲治疗12 周,检测患者治疗前后临床生化指标。对所有患者行ABCA 1 基因R219K 分型检测。 结果 ABCA 1 基因R219K 多态性存在3 种基因型。格列美脲治疗前各基因型患者的空腹血糖（FBG）、餐后 2 h 血糖（2h-BG）、糖化血红蛋白（HbA1c）水平比较,差异无统计学意义（P >0.05）。格列美脲治疗12 周后, 各基因型患者FBG、2h-BG、HbA1c 水平下降（P <0.05）;RK、KK 基因型患者的Δ2h-BG（治疗前后差值） 高于RR 基因型患者（P <0.05）;RK、KK 基因型患者2h-BG 水平低于RR 基因型患者（P <0.05）;RK、 KK 基因型患者HbA1c 水平低于RR 基因型患者（P <0.05）。结论 汉族2 型糖尿病患者中存在ABCA 1 基 因R219K 多态性,其可能与格列美脲降糖疗效有关,RK、KK 基因型患者的格列美脲降糖疗效优于RR 基因 型患者。     

Association of farnesyl diphosphate synthase polymorphisms and response to alendronate treatment in Chinese postmenopausal women with osteoporosis

Background Genetic factors are important in the pathogenesis of osteoporosis,but less is known about the genetic determinants of osteoporosis treatment.We aimed to explore the association between the gene polymorphisms of key enzyme farnesyl diphosphate synthase （FDPS） in mevalonate signaling pathway of osteoclast and response to alendronate therapy in osteoporotic postmenopausal women in China.Methods The study group comprised 639 postmenopausal women aged （62.2＆#177;7.0） years with osteoporosis or osteopenia who had been randomly assigned to low dose group （70 mg/2w） or standard dose group （70 mg/w） of alendronate in this 1-year study.We identified allelic variant of the FDPS gene using the polymerase chain reaction and restriction enzyme Faul.Before and after treatment,serum levels of calcium,phosphate,alkaline phosphatase （ALP）,cross linked C-telopeptide of type Ⅰ collagen （β-CTX） were detected.Bone mineral density （BMD） at lumbar spine and proximal femur was measured.The association was analyzed between the polymorphisms of FDPS gene and the changes of BMD,bone turnover biomarkers after the treatment.Results The FDPS rs2297480 polymorphisms were associated with baseline BMD at femoral neck,and patients with CC genotype had significantly higher baseline femoral neck BMD （（733.6＆#177;84.1） mg/cm2） than those with AC genotypes （（703.0＆#177;86.9） mg/cm2） and AA genotypes （（649.8＆#177;62.4） mg/cm2） （P 〈0.01）.No significant difference in BMD at lumbar spine was observed among different genotypes of FDPS.The percentage change of serum ALP level was significantly lower in patients with CC genotype （-22.9%） than that in those with AC genotype （-24.1%） and AA genotype （-29.8%） of FDPS after 12 months of alendronate treatment （P 〈0.05）.Neither percentage change of BMD nor β-CTX level after alendronate treatment had association with FDPS genotype.Conclusions FDPS gene was probably a candidate gene to predict femoral neck BMD at baseline.FDPS gene alleles could predict change percentage of ALP after treatment of alendronate,but possibly had no significant relationship with the responsiveness of BMD to alendronate therapy.     

SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours

Background:

Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.

Methods:

Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development.

Results:

The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m⁻² min⁻¹ and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP.

Conclusion:

Prolonged dFdCTP systemic exposures (⩾72 h) were commonly observed. Infusion rate <25 mg m⁻² min⁻¹ and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.     

阴虚体质原发性高血压的基因多态性研究

[目的]探究阴虚质与平和质原发性高血压(essential hypertension,EH)患者血管紧张素转化酶(angiotensin-converting enzyme,ACE)、血管紧张素Ⅱ-1型受体(angiotensinⅡ-type 1 receptor,AT1R)、血管紧张素Ⅱ-2型受体(angiotens...     

Targeting of tamoxifen to enhance antitumour action for the treatment and prevention of breast cancer: The ‘personalised’ approach?

Tamoxifen is a standard endocrine therapy for the treatment of steroid receptor positive breast cancer. Tamoxifen efficacy depends on the formation of clinically active metabolites 4-hydroxytamoxifen and endoxifen which have a greater affinity to the oestrogen receptor and ability to control cell proliferation as compared to the parent drug. The cytochrome P450 2D6 enzyme plays a key role in this biotransformation and lack of tamoxifen efficacy has been linked to low activity. There is now considerable mechanistic, pharmacologic and clinical pharmacogenetic evidence in support of the notion that CYP2D6 genetic variants and phenocopying effects through drug interaction by CYP2D6 inhibitors influence plasma concentrations of active tamoxifen metabolites and negatively impact tamoxifen outcome. These interrelations are particularly critical for patients with non-functional (poor metaboliser) and severely impaired (intermediate metaboliser) CYP2D6 variants, and, moreover, for patients in need of co-medication such as serotonin re-uptake inhibitors to control adverse effects such as hot flashes and other menopausal symptoms. Therefore, in the future, a personalised approach for an optimal tamoxifen benefit should consider a CYP2D6 genotype guided adjuvant endocrine treatment strategy and avoid non-adherence as well as strong CYP2D6 inhibitors such as co-medications.     

Pharmacogenetic Considerations in Opioid Therapy Prescribing

Drug reactions and interactions are common with opioids. Opioids are often dosed based on clinical indication, patient presentation, and subjective pain scores, resulting in a trial-and-error approach to dosage. Based on the patient’s phenotype, the response to the opioid therapy could range from toxicity and overdose to inadequate control of pain. In patients with genetic opioid metabolism defects, prescribing medications that bypass the cytochrome P450 system can be helpful. Considering pharmacogenetic principles is recommended when prescribing opioids to practice more safely and effectively leading to improved pain, reduced health care costs, and higher patient satisfaction.