Pharmacogenetic Factors Research Articles

Population pharmacokinetic modelling of imatinib in healthy subjects receiving a single dose of 400 mg

PurposeImatinib is indicated for treatment of CML, GIST, etc. The population pharmacokinetics (popPK) of imatinib in patients under long-term treatment are reported in literature. Data obtained from bioequivalence trials for healthy subjects were used to evaluate the influence of demographic and pharmacogenetic factors on imatinib pharmacokinetics (PK) in a collective without concurrent drugs, organ dysfunction, inflammation etc. In addition, the differences in PK between the healthy subjects and a patient cohort was examined to identify possible disease effects.Methods26 volunteers were administered orally with single dose of 400 mg imatinib. 16–19 plasma samples per volunteer were collected from 0.5 up to 72 h post-dose. The popPK was built and post hoc estimates were compared with previously published PK parameters evaluated by non-compartmental analysis in the same cohort. The predictivity of the model for data collected from 40 patients with gastrointestinal stromal tumors at steady state was evaluated.ResultsThe popPK was best described by a two-compartment transit model with first-order elimination. No significant covariates were identified, probably due to the small cohort and the narrow range of demographic covariates; CYP3A5 phenotypes appeared to have some influence on the clearance of imatinib. Good agreement between non-compartment and popPK analyses was observed with the differences of the geometric means/ median of PK estimates below 10%. The model indicated lower clearance for patients compared to healthy volunteers (p value < 0.01).ConclusionThe two-compartment transit model adequately describes the absorption and distribution of imatinib in healthy volunteers. For patients, a lower clearance of imatinib compared to healthy volunteer was estimated by the model. The model can be applied for dose individualization based on trough concentrations assuming no significant differences in absorption between patients and healthy volunteers.

Evidence of pharmacogenetics-based fluvoxamine use as an add-on to clozapine treatment in psychiatry.

Pharmacological treatments used for psychiatric disorders, such as clozapine, demonstrate large interindividual variability in terms of possible adverse effects and therapeutic benefit. This variability can be explained by multiple factors, including pharmacogenetic factors. Clozapine efficacy can be impacted by CYP polymorphisms. A growing body of literature on pharmacogenetics suggests the clinical benefit of concomitant use of clozapine and fluvoxamine to improve global pharmacotherapeutic management. This article reviews and discusses available clinical and pharmacological data and limitations of clozapine augmentation with fluvoxamine based on pharmacogenetic rationale and clinical experience. The aim is to provide an updated approach on how to use the pharmacological and pharmacogenetic profile to improve clozapine efficacy and tolerance in severely ill patients.

A Double-Blind Randomized Trial to Investigate Mechanisms of Antidepressant-Related Dysfunctional Arousal in Depressed or Anxious Youth at Familial Risk for Bipolar Disorder.

Antidepressants are standardly used to treat moderate to severe symptoms of depression and/or anxiety in youth but may also be associated with rare but serious psychiatric adverse events such as irritability, agitation, aggression, or suicidal ideation. Adverse events are especially common in youth with a family history of bipolar disorder (BD) who are at heightened risk for dysfunction in neurobiological systems that regulate emotion and arousal. To further understand this phenomenon, this study will examine (a) baseline risk factors associated with dysfunctional arousal in a sample of youth at high-risk for BD treated with or without an antidepressant, (b) whether antidepressant-related changes in arousal are mediated by changes in prefrontal-limbic circuitry, and (c) whether pharmacogenetic factors influence antidepressant-related changes in arousal. High-risk youth (aged 12–17 years with moderate to severe depressive and/or anxiety symptoms and at least one first-degree relative with bipolar I disorder) will be randomized to receive psychotherapy plus escitalopram or psychotherapy plus placebo. Neuroimaging and behavioral measures of arousal will be collected prior to randomization and at 4 weeks. Samples for pharmacogenetic analysis (serum escitalopram concentration, CYP2C19 metabolizer phenotype, and HTR2A and SLC6A4 genotypes) will be collected at 8 weeks. Youth will be followed for up to 16 weeks to assess change in arousal measures.

Novel concepts in psoriasis: histopathology and markers related to modern treatment approaches.

Psoriasis is a chronic autoimmune disease affecting over 2% of the worldwide population. From an anatomopathological point of view, psoriasis is characterized by immune cells infiltration, epidermal hyperproliferation, and abnormal keratinocyte differentiation. Understanding the pathogenesis of psoriasis will allow clinicians to manage this complex disease. Under these conditions, the application of effective treatments requires a thorough knowledge of all the pathogenetic mechanisms that lead to psoriasis. Numerous immunopathological pathways play crucial roles in the development of new therapies, such as biological therapies, which have been a breakthrough in psoriasis’s treatment. Pharmacogenetics is an essential factor in the patient’s response to treatment. One important pathway targeted by modern treatments is the interleukin (IL)-23/T-helper (Th)17 axis. Like IL-17 inhibitors, IL-23 blockers are a very effective therapy for this autoimmune disease. It is considered that micro-ribonucleic acids (microRNAs) are the starting point for any autoimmune disease. Studying certain microRNA (miR) involved in the inflammatory pathway in psoriasis can find direct targets to future treatments that can even be more specific than actual biological therapies. As such, miR-210 has proven to be up-regulated in psoriasis, also leading to the up-regulation of the Th1/Th17 axis. On the other hand, miR-187 was found to be down-regulated, influencing the outcome of psoriasis by increasing the proliferation of IL-6 stimulated keratinocytes and consecutively generating epidermal thickening. In this review, we are aiming to do an up-to-date briefing of psoriasis histopathology and pharmacogenetic factors that are considered for the accurate evaluation of treatment response.

Assessing the Roles of Molecular Markers of Antimalarial Drug Resistance and the Host Pharmacogenetics in Drug-Resistant Malaria.

Malaria caused by the Plasmodium parasites is a major public health concern in malaria-endemic regions with P. falciparum causing the most severe form of the disease. The use of antimalarial drugs for the management of the disease proves to be one of the best methods to manage the disease. Unfortunately, P. falciparum has developed resistance to almost all the current in-use antimalarial drugs. Parasite development of resistance is primarily caused by both parasite and host genetic factors. The parasite genetic factors involve undergoing mutation in the drug target sites or increasing the drug target gene copy number to prevent the intended action of the antimalarial drugs. The host pharmacogenetic factors which determine how a particular antimalarial drug is metabolized could result in variations of drug plasma concentration and consequently contribute to variable treatment outcomes and the emergence or propagation of resistant parasites. Since both host and parasite genomes play a role in antimalarial drug action, a key question often asked is, “which of the two strongly drives or controls antimalarial drug resistance?” A major finding in our recent study published in the Malaria Journal indicates that the parasite's genetic factors rather than the host are likely to energize resistance to an antimalarial drug. However, others have reported contrary findings suggesting that the host genetic factors are the force behind resistance to antimalarial drugs. To bring clarity to these observations, there is the need for deciphering the major driving force behind antimalarial drug resistance through optimized strategies aimed at alleviating the phenomenon. In this direction, literature was systematically reviewed to establish the role and importance of each of the two factors aforementioned in the etiology of drug-resistant malaria. Using Internet search engines such as Pubmed and Google, we looked for terms likely to give the desired information which we herein present. We then went ahead to leverage the obtained information to discuss the globally avid aim of combating antimalarial drug resistance.

Abstract #1184055: The RS7903146 Variant of TCF7L2 and the Risk for Sulfonylurea-Induced Hypoglycemia in Patients with Type 2 Diabetes

There is considerable interindividual variation in the hypoglycemic response to sulfonylureas (SU) in type 2 diabetes (T2D) patients. Typical risk factors for hypoglycemia in users of SU include advanced age, long duration of T2D, multimorbidity with particular renal impairment and polypharmacy. Moreover, a number of pharmacogenetic factors could be of critical importance for the risk of SU-induced hypoglycemia. The aim of the present study was to investigate the effects of the rs7903146 variant of TCF7L2 on risk for gliclazide-induced hypoglycemia in patients with T2D.

Asia-Inclusive Clinical Research and Development Enabled by Translational Science and Quantitative Clinical Pharmacology: Toward a Culture That Challenges the Status Quo.

Access lag to innovative therapies in Asian populations continues to present a challenge to global health. Recent progressive changes in the global regulatory landscape, including newer guidelines, are enabling simultaneous global drug development and near-simultaneous global drug registration. The International Conference on Harmonization (ICH) E17 guideline outlines general principles for the design and analysis of multiregional clinical trials (MRCTs). We posit that translational research and quantitative clinical pharmacology tools are core enablers for Asia-inclusive global drug development aligned with ICH E17 principles. Assessment of ethnic sensitivity should be initiated early in the development lifecycle to inform the need for, and extent of, Asian phase I ethno-bridging data. Relevant ethno-bridging data may be generated as standalone Asian phase I trials, as part of Western First-In-Human trials, or under accelerated development settings as a lead-in phase in an MRCT. Quantitative understanding of human clearance mechanisms and pharmacogenetic factors is vital to forecasting ethnic sensitivity in drug exposure using physiologically-based pharmacokinetic models. Stratification factors to control heterogeneity in MRCTs can be identified by reverse translational research incorporating pharmacometric disease models and model-based meta-analyses. Because epidemiological variations can extend to the molecular level, quantitative systems pharmacology models may be useful in forecasting how molecular variation in therapeutic targets or pathway proteins across populations might impact treatment outcomes. Through prospective evaluation of conservation in drug- and disease-related intrinsic and extrinsic factors, a pooled East Asian region can be implemented in Asia-inclusive MRCTs to maximize efficiency in substantiating evidence of benefit-risk for the region at-large with a Totality of Evidence approach.

Exploring the usefulness of plasma level determination and pharmacogenetics for patients treated with clozapine.

Aims: The aims of the present study were to assess the variance of plasma clozapine (CLZ) levels and to identify the influence of sociodemographic and pharmacogenetic factors on it and to introduce these tools in a clinical setting. Patients & methods: CLZ concentration was measured and genetic variants of CLZ pharmacokinetic and pharmacodynamic factors were assessed in 23 patients with psychotic disorders. Results: A significant association between mean concentration/dose ratio (C/D) and smoking status, age and weight were found. There was a significant difference in mean plasma CLZ levels and gender. The rs762551 AA genotype in smokers had a significantly lower C/D. Conclusion: In addition to classical factors, monitoring of plasma concentrations together with pharmacogenetics led to greater individualization of treatment.

The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance

Introduction/Objective. Coumarin therapy represents one of the best models for applying pharmacogenetics. The contribution of factors influencing coumarin therapy can vary significantly between ethnic groups, which justifies conducting population-specific studies. The aim of this study was to analyze the influence of the most important genetic factors (VKORC1 and CYP2C9 genes) that affect coumarin therapy in patients from Serbia. Methods. A retrospective study involving 207 patients on acenocoumarol therapy was conducted. Genetic analyses were performed by direct sequencing. Influence on acenocoumarol dose of variants (VKORC1, CYP2C9*2, CYP2C9*3) causing hypersensitivity and VKORC1 variants causing resistance to acenocoumarol were analyzed. Multiple regression analysis was used to design a mathematical model for predicting individual drug dosage based on clinical-demographic and genetic data. Results. The study confirmed significant influence of the analyzed genetic factors on acenocoumarol maintenance dose. We designed mathematical model for predicting individual acenocoumarol dose and its unadjusted R2 was 61.8. In the testing cohort, our model gave R2 value of 42.6 and showed better prediction in comparison with model given by other authors. In the analyzed patients, nine different variants in the VKORC1 coding region were found. Among carriers of these variants 78% were completely resistant, and it was not possible to achieve therapeutic effect even with high doses of acenocoumarol. Conclusions. Population-specific model for prediction individual dose of acenocoumarol, may show advantages over protocols that are used in a generalized manner. Also, VKORC1 variants which cause coumarin resistance should be considered when planning therapy.

Role of pharmacogenetic factors in the development of side effects of methotrexate in the treatment of malignant tumors: A review

Methotrexate (MTX) is one of the main chemotherapeutic agents that has determined the high effectiveness of protocols for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphomas. The reverse side of the high anti-tumor activity of MTX is the adverse reactions, which require accompanying preventive therapy. But even modern accompanying therapy in some cases does not avoid severe toxicity from the skin and mucous membranes, nervous system, kidneys, liver. MTX pharmacokinetics exhibits significant individual variability, which may be a reflection of genetic variability. Numerous pharmacogenetic studies have evaluated the effect of polymorphism of various genes involved in MTX metabolism on MTX pharmacokinetics and the development of toxic manifestations in order to improve patient outcomes and decrease drug toxicity. This review presents impact of key metabolic MTX genes (ATIC, DHFR, GGH, FPGS, MTHFR, MTR, MTRR, TYMS) and transporter proteins genes (ABCB1, ABCG2, ABCC2, ABCC4, SLC19A1, SLCO1B1) in the development of MTX side effects. Polymorphic markers in SLCO1B1 gene have the most influence with MTX pharmacokinetic.

The impact of cytochrome P450 3A5 genotype on early tacrolimus metabolism and clinical outcomes in lung transplant recipients.

Background Tacrolimus (Tac) is the cornerstone of immunosuppressant therapy after lung transplantation (LTx). It shows great inter-individual variability in pharmacokinetics, which could partly be explained by pharmacogenetic factors. Aim We aim to investigate the influence of cytochrome P450 3A5 (CYP3A5) genotypes on early post-LTx Tac metabolism and whether it is affected by concomitant use of azole antifungals. Also, we explored the association between CYP3A5 genotype and clinical outcomes. Method 90 recipients who underwent LTx from 2017 to 2019 were enrolled in the study. The effect of CYP3A5 genotype on Tac metabolism and interaction with azole antifungals were assessed during week 1-4 after transplantation. Associations between CYP3A5 genotype and the incidence of acute kidney injury (AKI), length of hospital stay and mortality were analyzed. ResultsCYP3A5*1 carriers had lower dose adjusted concentration (C/D) than CYP3A5*3/*3 group at all time points (p < 0.05). The dose ratio of CYP3A5*1 carriers to CYP3A5*3/*3 was between 1.3 and 2.4 when comparable concentrations were reached. Use of azole antifungals did not blunt the effect of CYP3A5 genotypes on Tac metabolism. Logistic regression showed Tac concentration ≥ 7.5 ng/mL at week 1 was associated with higher incidence of AKI. No statistically significant difference was found between CYP3A5 genotypes and the length of hospital stay. Kaplan-Meier analysis showed no statistically significant difference between 30-day or 1-year mortality and CYP3A5 genotype. Conclusion CYP3A5 genotype could affect Tac metabolism early after LTx. However, it had no influence on the incidence of AKI, length of hospital stay and mortality.

Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients.

BackgroundTacrolimus is a key drug in kidney transplantation with a narrow therapeutic index. However, whether tacrolimus exposure variability affects clinical outcomes and adverse reactions remains unknown.ObjectiveOur study investigated the factors that influence tacrolimus exposure in kidney transplantation recipients and the relationship between tacrolimus concentration and clinical outcomes and adverse reactions.Settings and MethodsWe examined the effect of tacrolimus concentration on clinical outcomes and adverse reactions in 201 kidney transplantation recipients, and identified clinical and pharmacogenetic factors that explain tacrolimus exposure.ResultsThe CYP3A5 genotype was clearly associated with dose-adjusted trough blood tacrolimus concentrations (C0/D), whereas no significant difference was observed in patients with the CYP3A4*1B, CYP3A4*22, ABCB1, ABCC2, POR*28 or PXR alleles. Clinical factors such as red blood cell count, hemoglobin, and albumin were the most useful influence factors affecting tacrolimus C0/D. Besides, Wuzhi capsule increased tacrolimus C0/D in kidney transplantation recipients. Furthermore, higher tacrolimus concentrations were associated with higher diarrhea and post-transplant diabetes mellitus (PTDM) risk but not with acute rejection and chronic allograft kidney dysfunction.ConclusionClinical factors, medication, and CYP-enzyme polymorphisms accounted for tacrolimus concentration variability in kidney transplantation recipients. Furthermore, higher tacrolimus concentrations were associated with higher diarrhea and PTDM risk.

Racial and Ethnic Differences in Drug Disposition and Response: Review of New Molecular Entities Approved Between 2014 and 2019.

Race and ethnicity can contribute to differences in drug exposure and/or response. Here, we report that about 10% of the new molecular entities (NMEs) approved between 2014 and 2019 by the US Food and Drug Administration's Center for Drug Evaluation and Research showed differences in exposure and/or response based on race/ethnicity or pharmacogenetic factors known to vary in frequency across global populations. Fewer NMEs (10%) reported differences in the labeling in 2014 to 2019 when compared to about 21% of NMEs approved between 2008 and 2013 that had differences in pharmacokinetics, safety, response, and/or pharmacogenetics. Understanding the underlying mechanisms that lead to such differences and adequate enrollment of racial and ethnic subgroups is essential to obtain sufficient information on exposure and response. Though drug development is global, when heterogeneous populations are not adequately enrolled, the risk-benefit assessments can remain incomplete for certain subgroups. Consequently, this can result in regional differences in drug approval, population-specific prescribing recommendations, or need for additional postmarketing studies to address concerns related to exposure, response, or lack of representation that lead to gaps in information.

CYP2D6 phenotype and ABCB1 haplotypes are associated with antipsychotic safety in adolescents experiencing acute psychotic episodes.

To identify possible associations of CYP2D6, CYP3A4/5, and ABCB1 gene polymorphisms with the efficacy and safety of antipsychotics in adolescents with acute psychotic episodes. We examined the associations of pharmacogenetic factors with the efficacy and safety of antipsychotics in 101 adolescents with acute psychotic episodes. The diagnosis on admission was "Brief psychotic disorder" (F23.0-23.9 by ICD-10). All patients were administered antipsychotics for 14days. Treatment efficacy and safety were assessed using the PANSS, CGAS, CGI-S(I), UKU SERS, BARS, and SAS scales. Pharmacokinetic genotyping was performed for the CYP2D6*4, *10, ABCB1 1236C>T, 2677G>T, and 3435C>T genes. CYP2D6 intermediate metabolisers had "Micturition disturbances" more often than extensive metabolisers (24.2 vs. 7.4%; p=0.026). "Wild" homozygote ABCB1 3435C>T CC was associated with more prominent akathisia. Haplotype analysis of three ABCB1 polymorphisms revealed that the "wild" alleles "C-G-C" (ABCB1 1236-2677-3435) were associated with higher risk of "Reduced salivation" (OR=2.95; 95% CI=1.35-6.45; p=0.0078). CYP2D6 intermediate metabolism was associated with the risk of urinary difficulties under treatment with antipsychotics. We found that "wild" homozygotes ABCB1 1236C>T, 2677G>T, and 3435C>T were predictors of adverse drug effects caused by treatment with antipsychotics.

CYP2D6 phenotype and ABCB1 haplotypes are associated with antipsychotic safety in adolescents experiencing acute psychotic episodes.

To identify possible associations of CYP2D6, CYP3A4/5, and ABCB1 gene polymorphisms with the efficacy and safety of antipsychotics in adolescents with acute psychotic episodes. We examined the associations of pharmacogenetic factors with the efficacy and safety of antipsychotics in 101 adolescents with acute psychotic episodes. The diagnosis on admission was "Brief psychotic disorder" (F23.0-23.9 by ICD-10). All patients were administered antipsychotics for 14days. Treatment efficacy and safety were assessed using the PANSS, CGAS, CGI-S(I), UKU SERS, BARS, and SAS scales. Pharmacokinetic genotyping was performed for the CYP2D6*4, *10, ABCB1 1236C>T, 2677G>T, and 3435C>T genes. CYP2D6 intermediate metabolisers had "Micturition disturbances" more often than extensive metabolisers (24.2 vs. 7.4%; p=0.026). "Wild" homozygote ABCB1 3435C>T CC was associated with more prominent akathisia. Haplotype analysis of three ABCB1 polymorphisms revealed that the "wild" alleles "C-G-C" (ABCB1 1236-2677-3435) were associated with higher risk of "Reduced salivation" (OR=2.95; 95% CI=1.35-6.45; p=0.0078). CYP2D6 intermediate metabolism was associated with the risk of urinary difficulties under treatment with antipsychotics. We found that "wild" homozygotes ABCB1 1236C>T, 2677G>T, and 3435C>T were predictors of adverse drug effects caused by treatment with antipsychotics.

Pharmacoeconomic and pharmacogenetic aspects of the implementation of a personalized approach in the treatment of cardiac patients

To investigate the possibilities of pharmacoeconomic and pharmacogenetic factors monitoring to assess the effectiveness of treatment of a cardiological profile patients as a part of the implementation of a personalized approach. 200 patients with arterial hypertension and CHD were examined. Pharmacotherapy was analyzed. ABC/VEN and DDD analysis, pharmacoeconomic analysis were applied. Genetic analysis of the polymorphism of the genes CYP2D6*4 and CYP2D6*10 encoding the subfamily of the cytochrome isoenzyme Р-450 was carried out. An original monitoring method was used to assess the effect of pharmacoeconomic and pharmacogenetic factors on the performance of cardiac care. When conducting a pharmacoeconomic analysis of cases of cardiac care, it was found that the costs of drug therapy are significant and take over 10% of the total costs. However, its effectiveness is insufficient in 58% of cases in inpatient and 37% in outpatient care. The analysis showed that there is an inverse mean correlation between gene polymorphism and clinical performance of cardiac care (r = -0.62) and a direct strong correlation between polypharmacy in pharmacotherapy, not accounting for interdrug interaction and clinical performance (r = 0.89).

Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics.

Atremorine is a novel bioproduct obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba. Atremorine is a potent dopamine (DA) enhancer with powerful effects on the neuronal dopaminergic system, acting as a neuroprotective agent in Parkinson's disease (PD). Over 97% of PD patients respond to a single dose of Atremorine (5 g, p.o.) 1 h after administration. This response is gender-, time-, dose-, and genotype-dependent, with optimal doses ranging from 5 to 20 g/day, depending upon disease severity and concomitant medication. Drug-free patients show an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ml; and patients chronically treated with anti-PD drugs show an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effects of conventional anti-PD drugs. Atremorine also influences the levels of other neurotransmitters (adrenaline, noradrenaline) and hormones which are regulated by DA (e.g., prolactin, PRL), with no effect on serotonin or histamine. The variability in Atremorine-induced DA response is highly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic (SNCA, NUCKS1, ITGA8, GPNMB, GCH1, BCKDK, APOE, LRRK2, ACMSD), mechanistic (DRD2), metabolic (CYP2D6, CYP2C9, CYP2C19, CYP3A4/5, NAT2), transporter (ABCB1, SLC6A2, SLC6A3, SLC6A4) and pleiotropic genes (APOE) influence the DA response to Atremorine and its psychomotor and brain effects. Atremorine enhances DNA methylation and displays epigenetic activity via modulation of the pharmacoepigenetic network. Atremorine is a novel neuroprotective agent for dopaminergic neurons with potential prophylactic and therapeutic activity in PD.

Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies.

Simple SummaryHigh-dose methotrexate is commonly used to treat several types of cancer. While effective, elimination of high-dose methotrexate from the body is highly variable and delayed elimination can lead to serious and sometime life-threatening adverse events. There have been many clinical studies to better understand how genetics influence the variability in methotrexate elimination, mostly through candidate gene studies and three genome-wide association studies. Unfortunately, there are conflicting results and some studies lack the appropriate replication and validation needed to confirm their effects on methotrexate elimination. Therefore, the purpose of this systematic review was to summarize all of the germline pharmacogenetic association studies of genetic associations influencing high-dose methotrexate elimination in children with cancer.Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1.

Role of pharmacogenomics in T-cell hypersensitivity drug reactions.

An update of the pharmacogenetic risk factors associated with T-cell-mediated delayed hypersensitivity reactions. Recent HLA associations relevant to our understanding of immunopathogenesis and clinical practice include HLA-B∗13:01 with co-trimoxazole-induced SCAR, and HLA-A∗32:01 with vancomycin-DRESS, for which an extended HLA class II haplotype is implicated in glycopeptide antibiotic cross-reactivity. Hypoactive variants of ERAP1, an enzyme-trimming peptide prior to HLA loading, are now associated with protection from abacavir-hypersensitivity in HLA-B∗57:01+ patients, and single-cell sequencing has defined the skin-restricted expansion of a single, public and drug-reactive dominant TCR across patients with HLA-B∗15:02-restricted carbamazepine-induced SJS/TEN. More recent strategies for the use of HLA and other risk factors may include risk-stratification, early diagnosis, and diagnosis in addition to screening. HLA is necessary but insufficient as a risk factor for the development of most T-cell-mediated reactions. Newly emerged genetic and ecological risk factors, combined with HLA-restricted response, align with underlying immunopathogenesis and drive towards enhanced strategies to improve positive-predictive and negative-predictive values. With large population-matched cohorts, genetic studies typically focus on populations that have been readily accessible to research studies, but it is now imperative to address similar risk in globally relevant and understudied populations.

Appropriate Systemic Therapy Dosing for Obese Adult Patients With Cancer: ASCO Guideline Update.

To provide recommendations for appropriate dosing of systemic antineoplastic agents in obese adults with cancer. A systematic review of the literature collected evidence regarding dosing of chemotherapy, immunotherapy, and targeted therapies in obese adults with cancer. PubMed and the Cochrane Library were searched for randomized controlled trials, meta-analyses, or cohort studies published from November 1, 2010, through March 27, 2020. ASCO convened an Expert Panel to review the evidence and formulate recommendations. Sixty studies, primarily retrospective, were included in the review. Overall, the evidence supported previous findings that obese adult patients tolerate full, body-size-based dosing of chemotherapy as well as nonobese patients. Fewer studies have addressed the dosing of targeted therapies and immunotherapies in relation to safety and efficacy in obese patients. The Panel continues to recommend that full, weight-based cytotoxic chemotherapy doses be used to treat obese adults with cancer. New to this version of the guideline, the Panel also recommends that full, approved doses of immunotherapy and targeted therapies be offered to obese adults with cancer. In the event of toxicity, the consensus of the Panel is that dose modifications of systemic antineoplastic therapies should be handled similarly for obese and nonobese patients. Important areas for future research include the impact of sarcopenia and other measures of body composition on optimal antineoplastic dosing, and more customized dosing based on pharmacokinetic or pharmacogenetic factors.Additional information is available at www.asco.org/supportive-care-guidelines.