Current Drug Metabolism - Volume 19, Issue 14, 2018

Background: Single Nucleotide Polymorphisms (SNPs) are very common variants of many genes and are also promising markers associated with drug reactions in pharmacogenomics research. In pediatric organ transplantation, tacrolimus is a major immunosuppressive agent used to prevent organ rejection. The SNP of these genes have been studied extensively in adult population, but there is no systematic review in children. This article focuses on the effects of ABCB1 and CYP3A SNPs on tacrolimus in children who are undergoing organ transplantations. Methods: We searched the literature that provided the effect of SNP on metabolism and pharmacokinetics of tacrolimus in pediatric patients in Google, Science Direct and PubMed. Then we accessed the methods used in these studies, the sample size, the model and the conclusions they have obtained. Results: We found that there is no evidence shown that CYP3A4 SNP has an influence on the pharmacokinetic/ pharmacodynamics of tacrolimus in the population of children. Moreover, most studies have failed to find a link between the ABCB1 SNP and the pharmacokinetics of tacrolimus in children. However, although the amount of literature is limited, it does show a link between ABCB1 SNPs and tacrolimus pharmacodynamics. In addition, the literature shows a strong link between CYP3A5 SNP and pharmacokinetics of tacrolimus, but there is no direct evidence that CYP3A5 SNP has the same effect on the pharmacodynamics of tacrolimus. Conclusion: More standardized clinical trials are needed to assess the relationship between CYP3A5 SNP and tacrolimus pharmacodynamics in children, particularly in terms of acute rejection and nephrotoxicity.

Background: Invasive mycoses are serious infections with high mortality and increasing incidence. Voriconazole, an important drug to treat invasive mycosis, is metabolized mainly by the cytochrome P450 family 2 subfamily C member 19 enzyme (CYP2C19) and is affected by the genotypes of CYP2C19. Objective: We reviewed studies on how genotypes affect the pharmacokinetics and pharmacodynamics of voriconazole, and attempted to determine a method to decide on dosage adjustments based on genotypes, after which, the main characteristic of voriconazole was clarified in details. The pharmacokinetics of voriconazole are influenced by various inter and intrapersonal factors, and for certain populations, such as geriatric patients and pediatric patients, these influences must be considered. CYP2C19 genotype represents the main part of the interpersonal variability related to voriconazole blood concentrations. Thus monitoring the concentration of voriconazole is needed in clinical scenarios to minimize the negative influences of inter and intrapersonal factors. Several studies provided evidence on the stable trough concentration range from 1-2 to 4-6 mg/L, which was combined to consider the efficacy and toxicity. However, the therapeutic drug concentration needs to be narrowed down and evaluated by large-scale clinical trials. Conclusion: Though there is insufficient evidence on the relationship between CYP2C19 genotypes and clinical outcomes, there is a great potential for the initial voriconazole dose selection to be guided by the CYP2C19 genotype. Finally, voriconazole therapeutic drug monitoring is essential to provide patient-specific dosing recommendations, leading to more effective anti-fungal regimens to increase clinical efficacy and reduce adverse drug reactions.

Background: Recombinant human growth hormone (rhGH) has been widely used in clinical treatment and technology has achieved a great development in different long-acting formulations. Genetic polymorphisms may play a role in the varies of individual responses in treatment process. This article gives an overview of the genetic polymorphisms research of growth hormone in recent years. Methods: We conducted a scoping literature search of PubMed for all English-language publications to identify studies on recombinant human growth hormone and genetic polymorphism from 2000 to 2016. Included studies were all peer-reviewed primary journal articles. Two authors independently screened titles/abstracts, downloading full-text publications meeting inclusion criteria. Results: In all, 96 studies were included and analyzed. We found that besides some well known factors ,such as races, age, gender, weight, several kinds of gene polymorphism reported ever can also affect the growth hormone response in GHD or non-GHD patients, including GHR-Exon 3, IGF(CA)19, IGFBP-3, APOB, CETP, SOCS2, VDR, LEPR and STAT5B. Conclusion: Serum IGF-1 is a good parameter of GH treatment response. But it is influenced by various factors, including races, age, gender, weight, initial IGF-1 level, injection concentration and frequency. Gene polymorphism research has been a research hopspot in recent years, may helping understand the pathogeny and pharmacogenomics of these response varieties during GH treatment.

Background: Platelet-derived Growth Factor Receptor (PDGFR) is a kind of Receptor Tyrosine Kinases (RTKs). PDGFR Tyrosine Kinase Inhibitors (TKIs) which are small molecule inhibitors targeting PDGFR prevent and block cell proliferation signal transduction pathways. Recently, there have been 11 TKIs (including imatinib, sunitinib, regorafenib, sorafenib, pazopanib, axitinib, dasatinib, nilotinib, lenvatinib, cabozantinib and ponatinib) targeting PDGFR approved by FDA for the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, renal cell carcinoma et al. Pharmacokinetics (PK) reflects the processes of drugs in body, while pharmacodynamics (PD) reflects the efficacy. Genetic polymorphisms of metabolizers and transporters contribute to highly inter-individual variability in PK and PD. This review aims to introduce the clinical applications, instruction and usage, PK, PD and pharmacogenetics of these PDGFR TKIs. Methods: In vivo and in vitro studies about PDGFR TKIs were searched from PubMed. Data and information were analyzed and summarized. Results: The overview of (1) general information on PDGFR kinase inhibitors; (2) PK parameters of PDGFR kinase inhibitors; (3) metabolic enzymes and transporters of PDGFR kinase inhibitors; (4) main drug interactions of PDGFR kinase inhibitors; (5) adverse events of PDGFR kinase inhibitors; and (6) genetic polymorphism on PK and PD of PDGFR kinase inhibitors, was exhibited and discussed in this review. Conclusion: This review summarized the general information, PK, metabolic enzymes and transporters, main drug interactions, adverse events and pharmacogenetics of FDA approved PDGFR TKIs. Studies showed that Single nucleotide polymorphisms of metabolic enzymes and transporters had influence on the PK and PD of PDGFR TKIs.

Background: Methotrexate (MTX) is a folate analogue with high therapeutic efficiency in the treatment of cancers and autoimmune diseases. The efficacy and toxicity of MTX may be altered by genetic polymorphisms in genes involved in MTX metabolic pathway. Personalized pharmacotherapy based on gene polymorphisms enables a more efficient, compatible and cost-effective treatment of patients. Objective: The present article aims to review genetic polymorphisms associated with MTX pharmacokinetics, toxicity, and outcome, and points out future development directions of individualized MTX therapy. Methods: Details regarding the pharmacogenetics and pharmacogenomics of MTX are obtained from PubMed literatures. Conclusion: The influences of single nucleotide polymorphisms (SNPs) in genes involved in MTX pathway are controversial. Many pharmacogenetic associations are disease specific and race specific. Present studies have almost limited to some certain ethnic groups and diseases. The data from these studies are not convincing enough to draw far-reaching conclusions about the applicability of MTX pharmacogenetics in clinical practice. Studies with large scale and multiple centers are needed in the future. MTX-PG inhibits folic metabolism through three mechanisms. TS, MTHFR and ATIC are the rate-limiting enzymes separately. The function of SNPs in these genes is often onesided. Works focusing on the analysis of polymorphism in MTX transporters should be more efficient and meaningful.

Background: Asthma is one of the most significant diseases worldwide and causes overwhelming costs physically and economically. The study of asthma has revealed various groups of asthma patients who share phenotypic characteristics that naturally elicit the need for personalized asthma therapy. An increasing amount of pharmacogenetics research, genotype-based trials and precision medicine trials have been conducted to investigate this problem. Methods: A systematic bibliography retrieval was performed in MEDLINE (Ovid) and PubMed for our topic and all relative records were exported and screened. Results: We identified 377 publications and added 4 articles related to this topic artificially to reach a bigger scope, of which 36 met the inclusion criteria. Our review focuses on the three most widely used treatments for asthma management, which are β-adrenergic receptor agonists, inhaled corticosteroids (ICS) and anti-leukotriene modifiers. We summarize the existing loci reported in the literature that are potentially associated with drug responses to typically used medications. Conclusion: Our results suggest that a genetic test with high predictive accuracy could predict therapeutic responses, and proper management can be achieved in asthma patients. This personalized approach to curative medicine should make way for the realization of personalized preventive and predictive medicine in the coming years.

Background: Mycophenolic Acid (MPA) is an immunosuppressive drug widely used in the treatment of organ transplantation and autoimmune diseases. Pharmacokinetics and pharmacodynamics of MPA varies between individuals, the potential reasons being the genetic polymorphisms in key enzymes, drug transporters and target proteins of MPA. Objective: We try to provide pharmacogenomics information for drug selection and dose adjustment, aiming to improve drug efficacy and reduce side effects in clinical application of MPA. Methods: In this review, we summarize the literatures in Pubmed that reported MPA-related Single Nucleotide Polymorphisms (SNPs) of renal transplant patients in recent 15 years. Results: Genetic polymorphisms involving uridine diphosphate glucuronosyltransferase enzymes, organic anion transport polypeptides, multidrug resistance-associated protein 2, inosine monophosphate dehydrogenase and immune- response mediators may be associated with the metabolism, efficacy and toxicity of MPA, thus resulting in different MPA exposure and patient outcomes in renal transplantation. Conclusion: Several SNPs show significant association with MPA pharmacokinetics and pharmacodynamics, but conflicting results are reported, and no studies on MPA genetic polymorphisms have been translated into clinical practice. More prospective studies are needed to clear the role of genetic polymorphisms on MPA in renal transplantation patients.

Backgroud: While endotype-driven therapeutic strategies are increasingly successful for asthma, the issues of dissociated effect and drug efficacy at the target sites remain unresolved. This review is to provide a comprehensive overview of the pharmacogenomics of asthma along with its endotype subsets. Methods: We undertook a search in NCBI All Databases by key words “pharmacogenomics AND allergen”, “pharmacogenomics AND asthma AND rhinitis”, etc. The remaining papers were reviewed without bias after the exclusion of redundant papers and non-English papers (except for Chinese papers). Papers regarding similar issues or items were then pooled together to support the corresponding viewpoints and subtitles, conclusions were thus drawn. Result: Eighty of the retrieved 139 papers were included in the review. Immunopathogenesis of asthma found that the induction of asthma involves genetic variation, TLR gene-activated immune responses, cell-mediated inflammation, and other immunological changes. Human lung mast cell has a crucial effect on the symptoms of asthma. JAK-3 mediates cytokine signaling, while DNA methylation in the ADRB2 gene decreases asthma symptom severity. Pharmacotherapeutics of asthma has focused on fewer candidate genes, relating to glucocorticoid, leukotriene, and β2-adrenergic receptor pathways, and other pathways involving IgE, IL-5, IL-4, IL-13 and IL-17. Conclusion: The genetic profiles of gene variants can predict individual disease susceptibility and risk for disease progression. Fewer genes, relating to glucocorticoid, leukotriene, histamine, and β2-adrenergic receptor pathways, have been concentrated. A personalized, tailored approach is necessary for health care delivery according to the individual variability in genes, environment and lifestyle of each individual.

Background: Natalizumab (NAT), a humanized monoclonal antibody, binding in both α4β1 and α4β7 integrins, is approved for the treatment of Multiple Sclerosis (MS) and Crohn's Disease (CD). This review highlights the detailed Pharmacokinetics (PK) and Pharmacodynamics (PD) information of NAT, with the Pharmacogenomics (PG) properties of NAT. Methods: We undertake a systemic English-language search of Medline, EMBASE, Cochrane Library electronic databases to identify all potential studies with PK, PD or PG properties of NAT (up to October 2017). Results: Five papers contain detailed pharmacokinetic parameters are included in this review. Body weight is the most important factor associated with NAT concentration. Greater PK similarity and PD comparability is observed following Subcutaneous (SC) administration than Intramuscular (IM) administration. Initial difference in PK measures was observed between SC and Intravenous (IV) administration. However, trough NAT serum concentrations are similar between SC and IV administration after repeated dosing. Antibodies against NAT result in a low serum NAT concentration and cause a loss of efficacy of NAT. Gln-152, Lys-201, and Lys-256 are the three important point mutation on the α4 residues that NAT binds to. Syndecan-1 gene is a potential candidate gene for personalized approach for NAT use in MS. Conclusion: As MS is a disease that affects young women most and NAT can pass placental barrier before delivery and into breast milk, a proper risk-benefit analysis of NAT therapy in lactating women are still needed. The relationship between Single Nucleotide Polymorphisms (SNPs) and NAT treatment are still not clear.