Oxid Med Cell Longev. 2022 Apr 25;2022:8615242. doi: 10.1155/2022/8615242. eCollection 2022.

ABSTRACT

Bergapten (BP) or 5-methoxypsoralen (5-MOP) is a furocoumarin compound mainly found in bergamot essential oil but also in other citrus essential oils and grapefruit juice. This compound presents antibacterial, anti-inflammatory, hypolipemic, and anticancer effects and is successfully used as a photosensitizing agent. The present review focuses on the research evidence related to the therapeutic properties of bergapten collected in recent years. Many preclinical and in vitro studies have been evidenced the therapeutic action of BP; however, few clinical trials have been carried out to evaluate its efficacy. These clinical trials with BP are mainly focused on patients suffering from skin disorders such as psoriasis or vitiligo. In these trials, the administration of BP (oral or topical) combined with UV irradiation induces relevant lesion clearance rates. In addition, beneficial effects of bergamot extract were also observed in patients with altered serum lipid profiles and in people with nonalcoholic fatty liver. On the contrary, there are no clinical trials that investigate the possible effects on cancer. Although the bioavailability of BP is lower than that of its 8-methoxypsoralen (8-MOP) isomer, it has fewer side effects allowing higher concentrations to be administered. In conclusion, although the use of BP has therapeutic applications on skin disorders as a sensitizing agent and as components of bergamot extract as hypolipemic therapy, more trials are necessary to define the doses and treatment guidelines and its usefulness against other pathologies such as cancer or bacterial infections.

PMID:35509838 | PMC:PMC9060977 | DOI:10.1155/2022/8615242

Croat Med J. 2022 Apr 30;63(2):117-125.

ABSTRACT

AIM: To compare the Croatian and European population in terms of allele frequencies of clinically relevant polymorphisms in drug absorption, distribution, metabolism, and excretion (ADME) genes.

METHODS: In 429 Croatian participants, we genotyped 27 loci in 20 ADME genes. The obtained frequencies were merged with the published frequencies for the Croatian population by sample size weighting. The study sample obtained in this way was compared with the average data for the European population from the gnomAD database.

RESULTS: Variant allele frequencies in the Croatian population were higher in three and lower in two polymorphisms (Benjamini-Hochberg-corrected P values: 0.0027 for CYP2B6*4 rs2279343, CYP2C9*2 rs1799853, and VKORC1 rs9923231; 0.0297 for GSTP1 rs1695; 0.0455 for CYP2A6 rs1801272) compared with the European population. The most marked difference was observed for CYP2B6*4 (9.3% in Europe vs 24.3% in Croatia). The most clinically relevant findings were higher variant allele frequencies in two polymorphisms related to lower warfarin requirements: VKORC1*2 (34.9% in Europe vs 40.1% in Croatia) and CYP2C9*2 (12.3% in Europe vs 14.7% in Croatia). This indicates that three-quarters of Croatian people have at least one variant allele at these loci. Variants in genes GSTP1 and CYP2A6 were significantly less frequently observed in Croatia.

CONCLUSIONS: Croatian population has a higher bleeding and over-anticoagulation risk, which is why we recommend the prescription of lower doses of anticoagulation drugs such as warfarin and acenocoumarol. Lower phenytoin, and higher bupropion and efavirenz doses are also recommended in the Croatian population.

PMID:35505645

Methods Mol Biol. 2022;2449:187-196. doi: 10.1007/978-1-0716-2095-3_7.

ABSTRACT

The prediction of the cancer cell lines sensitivity to a specific treatment is one of the current challenges in precision medicine. With omics and pharmacogenomics data being available for over 1000 cancer cell lines, several machine learning and deep learning algorithms have been proposed for drug sensitivity prediction. However, deciding which omics data to use and which computational methods can efficiently incorporate data from different sources is the challenge which several research groups are working on. In this review, we summarize recent advances in the representative computational methods that have been developed in the last 2 years on three public datasets: COSMIC, CCLE, NCI-60. These methods aim to improve the prediction of the cancer cell lines sensitivity to a given treatment by incorporating drug's chemical information in the input or using a priori feature selection. Finally, we discuss the latest published method which aims to improve the prediction of clinical drug response of real patients starting from cancer cell line molecular profiles.

PMID:35507263 | DOI:10.1007/978-1-0716-2095-3_7

Clin Transl Sci. 2022 May 3. doi: 10.1111/cts.13277. Online ahead of print.

ABSTRACT

Effects of UGT1A1*6 and UGT1A1*28 genetic polymorphisms on irinotecan-induced severe toxicities in Asian cancer patients are inconclusive. Also, ABCC2 c.3972C>T may affect toxicity of irinotecan. It was aimed to assess the aggregated risk of neutropenia or diarrhea in Asian cancer patients taking irinotecan and inherited UGT1A1*6, UGT1A1*28 or ABCC2 c.3972C>T genetic variants. Literature was searched in PubMed for eligible studies. Odds ratios (ORs) were measured using RevMan software where P-values<0.05 were statistically significant. Patients inherited both UGT1A1*6 and UGT1A1*28 genetic variants (heterozygous:UGT1A1*1/*6+*1/*28 and homozygous:UGT1A1*6/*6+*28/*28) were significantly associated with increased risk of neutropenia and diarrhea compared to patients with UGT1A1*1/*1 (Neutropenia: OR 2.89; 95% CI 1.97-4.23; P<0.00001; Diarrhea: OR 2.26; 95% CI 1.71-2.99; P<0.00001). Patients carried homozygous variants had much stronger effects in developing toxicities (Neutropenia: OR 6.23; 95% CI 3.11-12.47; P<0.00001; Diarrhea: OR 3.21; 95% CI 2.13-4.85; P<0.00001) than with heterozygous variants. However, patients carried ABCC2 c.3972C>T genetic variant were not significantly associated with neutropenia (OR 1.67; 95% CI 0.98-2.84; P=0.06) but reduced diarrhea significantly (OR 0.31; 95% CI 0.11-0.81; P=0.02). Both UGT1A1*6 and UGT1A1*28 genetic variants should be screened in Asian cancer patients to reduce substantially irinotecan induced severe toxicities.

PMID:35506159 | DOI:10.1111/cts.13277

Mol Ther Nucleic Acids. 2022 Apr 6;28:464-476. doi: 10.1016/j.omtn.2022.04.001. eCollection 2022 Jun 14.

ABSTRACT

RNA chemical modifications are a new but rapidly developing field. They can directly affect RNA splicing, transport, stability, and translation. Consequently, they are involved in the occurrence and development of diseases that have been studied extensively in recent years. However, few studies have focused on the correlation between chemical modifications and drug effects. Here, we provide a landscape of six RNA modifications in pharmacogene RNA (pharmacoepitranscriptomics) to fully clarify the correlation between chemical modifications and drugs. We performed systematic and comprehensive analyses on pharmacoepitranscriptomics, including basic characteristics of RNA modification and modification-associated mutations and drugs affected by them. Our results show that chemical modifications are common in pharmacogenes, especially N6-methyladenosine (m6A) modification. In addition, we found a very close relationship between chemical modifications and anti-tumor drugs. More interestingly, the results demonstrate the importance of m6A modification for anti-tumor drugs, especially for drugs in triple-negative breast cancer (TNBC), ovarian cancer, and acute myelocytic leukemia (AML). These results indicate that pharmacoepitranscriptomics could be a new source of drug-effect biomarkers, especially for m6A and anti-tumor drugs.

PMID:35505958 | PMC:PMC9044172 | DOI:10.1016/j.omtn.2022.04.001

J Clin Invest. 2022 May 3:e145666. doi: 10.1172/JCI145666. Online ahead of print.

ABSTRACT

Patients with high-risk non muscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical BCG therapy and may have a dismal outcome. Resistance mechanisms to such immunotherapy remain misunderstood. Here, using cancer cell lines, freshly resected human bladder tumors and cohorts of bladder cancer patients pre- and post-BCG therapy, we demonstrate two distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a post-transcriptional downregulation of HLA-I membrane expression via an inhibition of the autophagy flux. Patients with HLA-I deficient cancer cells post-BCG therapy displayed a myeloid immunosuppressive tumor microenvironment with epithelial-to-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I proficient cancer cells post-BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines and inhibitory immune checkpoint molecules. Those patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse post-BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts dismal prognosis. Cancer cells HLA-I scoring by immunohistochemistry (IHC) staining can be easily implemented by pathologists in routine practice in order to stratify future urothelial cancer patient treatment strategies.

PMID:35503263 | DOI:10.1172/JCI145666

Pharmacogenet Genomics. 2022 May 2. doi: 10.1097/FPC.0000000000000473. Online ahead of print.

ABSTRACT

OBJECTIVES: In the era of quality management in clinical laboratories, method validation can be a challenge without appropriate guidelines, such as in the field of pharmacogenetics. The present work describes a method validation for DNA extraction and CYP3A5*3 genotyping, which would meet ISO15189:2012 requirements.

METHODS: DNA extraction was performed using a QIAamp DSP DNA Blood kit, DNA purity and concentration were determined using a Nanodrop, and the genotyping assay was a real-rime PCR using TaqMan reagents. Validation criteria were similar to those usually verified when validating methods in the analytical field: specificity, sensitivity, cross-over contamination, stability of reagents, robustness, lower and upper limits of detection, and between-run and within-run precisions. A comparison to alternate or reference methods was also performed (i.e. QiAamp kit versus DNA extractor and TaqMan genotyping versus Sanger sequencing). Each validation step is described from the pharmacogenetic point of view, as well as acceptance criteria for both DNA extraction [i.e. concentration relative SD (RSD) below 25%, verified purity, and no DNA in blank samples] and genotyping assay (i.e. specificity and diagnostic sensitivity, RSD of mean threshold cycle below 15%, no amplification in blank samples).

RESULTS: Concerning CYP3A5 genotyping following a DNA extraction described as an example, validation criteria were met, allowing routine use of this analytical process. Cost estimation of the overall validation procedure was approximately 290 euros, concerning reagents and consumables.

CONCLUSION: This work aims to provide a reference for method validation for pharmacogenetic analysis using real-time PCR to detect single nucleotide polymorphisms, in accordance with ISO15189:2012.

PMID:35503003 | DOI:10.1097/FPC.0000000000000473

BMC Pediatr. 2022 May 2;22(1):243. doi: 10.1186/s12887-022-03311-4.

ABSTRACT

Hyperbilirubinemia is the main mechanism that causes neonatal jaundice, and genetics is one of the risk factors of hyperbilirubinemia. Therefore, this study aims to explore the correlation between two genes, UGT1A1 and SLCO1B1, and hyperbilirubinemia in Thai neonates. One hundred thirty seven neonates were recruited from Division of Clinical Chemistry, Ramathibodi Hospital. UGT1A1*28 and *6 were determined by pyrosequencing whereas, SLCO1B1 388A > G and 521 T > C genetic variants were determined by TaqMan® real-time polymerase chain reaction. Neonates carrying with homozygous (AA) and heterozygous (GA) variants in UGT1A1*6 were significantly related to hyperbilirubinemia development compared with wild type (GG; P < 0.001). To the combined of UGT1A1, total bilirubin levels in homozygous variant were higher significantly than heterozygous variant and wild type (P = 0.002, P = 0.003, respectively). Moreover, SLCO1B1 combination was significant differences between the hyperbilirubinemia and the control group (P = 0.041). SLCO1B1 521 T > C variant provide protection for Thai neonatal hyperbilirubinemia (P = 0.041). There are no significant differences in UGT1A1*28 and SLCO1B1 388A > G for the different severity of hyperbilirubinemia. The combined UGT1A1*28 and *6 polymorphism is a strong risk factor for the development of severe hyperbilirubinemia in Thai neonates. Therefore, we suggest neonates with this gene should be closely observed to avoid higher severities of bilirubin.

PMID:35501760 | DOI:10.1186/s12887-022-03311-4

Thorax. 2022 May 2:thoraxjnl-2021-217674. doi: 10.1136/thoraxjnl-2021-217674. Online ahead of print.

ABSTRACT

INTRODUCTION: Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults.

METHODS: A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases.

RESULTS: In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10-5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1, CRADD and DST for the OCS burst outcome and GM2A, SNW1, CACNA1C, DPH1, and RPS10 for the asthma-related exacerbation outcome.

CONCLUSIONS: Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4.

PMID:35501119 | DOI:10.1136/thoraxjnl-2021-217674

Evol Bioinform Online. 2022 Apr 24;18:11769343221095834. doi: 10.1177/11769343221095834. eCollection 2022.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx), forming the basis of precision medicine, has revolutionized traditional medical practice. Currently, drug responses such as drug efficacy, drug dosage, and drug adverse reactions can be anticipated based on the genetic makeup of the patients. The pharmacogenomic data of Pakistani populations are limited. This study investigates the frequencies of pharmacogenetic variants and their clinical relevance among ethnic groups in Pakistan.

METHODS: The Pharmacogenomics Knowledge Base (PharmGKB) database was used to extract pharmacogenetic variants that are involved in medical conditions with high (1A + 1B) to moderate (2A + 2B) clinical evidence. Subsequently, the allele frequencies of these variants were searched among multiethnic groups of Pakistan (Balochi, Brahui, Burusho, Hazara, Kalash, Pashtun, Punjabi, and Sindhi) using the 1000 Genomes Project (1KGP) and ALlele FREquency Database (ALFRED). Furthermore, the published Pharmacogenomics literature on the Pakistani population was reviewed in PubMed and Google Scholar.

RESULTS: Our search retrieved (n = 29) pharmacogenetic genes and their (n = 44) variants with high to moderate evidence of clinical association. These pharmacogenetic variants correspond to drug-metabolizing enzymes (n = 22), drug-metabolizing transporters (n = 8), and PGx gene regulators, etc. (n = 14). We found 5 pharmacogenetic variants present at >50% among 8 ethnic groups of Pakistan. These pharmacogenetic variants include CYP2B6 (rs2279345, C; 70%-86%), CYP3A5 (rs776746, C; 64%-88%), FLT3 (rs1933437, T; 54%-74%), CETP (rs1532624, A; 50%-70%), and DPP6 (rs6977820, C; 61%-86%) genes that are involved in drug response for acquired immune deficiency syndrome, transplantation, cancer, heart disease, and mental health therapy, respectively.

CONCLUSIONS: This study highlights the frequency of important clinical pharmacogenetic variants (1A, 1B, 2A, and 2B) among multi-ethnic Pakistani populations. The high prevalence (>50%) of single nucleotide pharmacogenetic variants may contribute to the drug response/diseases outcome. These PGx data could be used as pharmacogenetic markers in the selection of appropriate therapeutic regimens for specific ethnic groups of Pakistan.

PMID:35497687 | PMC:PMC9047794 | DOI:10.1177/11769343221095834

Pharmgenomics Pers Med. 2022 Apr 23;15:409-427. doi: 10.2147/PGPM.S348851. eCollection 2022.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) is the study of how genetic variations for functional proteins, such as metabolizing enzymes and drug receptors, impact drug pharmacokinetics and pharmacodynamics. In theory, pharmacists are well suited to utilize PGx in tailoring medications to patient genetics when providing medication therapy management services. However, PGx education needs to reach pharmacists prior to implementation. The aim of this study is to develop and evaluate a PGx course for pharmacists.

METHODS: A PGx education program was created and offered synchronously (virtual) and asynchronously (self-study) to pharmacists in Alberta, Canada. Lectures were delivered by experts live (virtual) with a question-and-answer period for synchronous sessions. These sessions were recorded for asynchronous delivery. Six case studies were discussed in large and small groups ("breakout rooms") in synchronous sessions, and provided for self-study in the asynchronous subgroup. Topics included genetic and PGx concepts; therapeutic applications; ethical, legal, and social considerations; and practical implementation. Pre- and post-course surveys measured self-rated knowledge using a 5-point Likert Scale and tested objective knowledge with a graded quiz.

RESULTS: Thirty-six pharmacists completed the course and both surveys. Participants reported backgrounds in community (88.9%) and hospital (38.9%) practice. Prior education in PGx was reported by 44.4% from degree programs and 27.8% from continuing education. Overall responses to statements about confidence in PGx moved from a median of "Disagree" at baseline to "Agree" after receiving PGx education (2-point difference [1,2] on 5-point Likert Scale; p < 0.001), indicating an increase in self-assessed competency in PGx. Likewise, mean participant grades on the knowledge quiz improved (20.8±21.9% pre-course vs 70.2±19.1% post-course, p < 0.001). There was no difference in these results between synchronous and asynchronous groups.

CONCLUSION: A didactic and case-based PGx education program was effective at increasing pharmacist knowledge and confidence in PGx in both synchronous and asynchronous environments. Knowledge gained can be utilized in delivery of patient-centered, personalized medication therapy management in the pharmacy setting.

PMID:35496350 | PMC:PMC9045709 | DOI:10.2147/PGPM.S348851

Front Pharmacol. 2022 Apr 12;13:884213. doi: 10.3389/fphar.2022.884213. eCollection 2022.

ABSTRACT

Introduction: Minority groups are underrepresented in pharmacogenomics (PGx) research. Recent sub-analysis of CYP-GUIDES showed reduced length of stay (LOS) in depressed patients with CYP2D6 sub-functional status. Our primary objective was to determine whether PGx guided (G) versus standard treatment (S) influenced LOS among different race/ethnic groups. Secondary objectives included prevalence of drug-gene interactions (DGIs) and readmission rates (RAR). Methods: Retrospective sub-analysis of CYP-GUIDES data comprising CYP2D6 phenotypes was reclassified using standardized CYP2D6 genotype to phenotype recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG). The Mann-Whitney test was used to determine differences in LOS between groups G and S and Kruskal Wallis test to compare LOS among different race/ethnic groups. Logistic regression was used to determine covariates associated with RAR. Results: This study included 1,459 patients with 67.3% in G group (n = 982). The majority of patients were White (57.5%), followed by Latinos (25.6%) and Blacks (12.3%). Although there were no differences in LOS between G and S groups, Latinos had significant shorter LOS than Whites (p = 0.002). LOS was significantly reduced by 5.6 days in poor metabolizers in group G compared to S (p = 0.002). The proportion of supra functional and ultra-rapid metabolizers (UMs) were 6 and 20.3% using CYP-GUIDES and CPIC/DPWG definitions, respectively. Prevalence of DGIs was 40% with significantly fewer DGIs in Blacks (p < 0.001). Race/ethnicity was significantly associated with RAR (aOR 1.30; p = 0.003). Conclusion: A greater number of patients were classified as CYP2D6 UMs using CPIC/DPWG definitions as compared to CYP-GUIDES definitions. This finding may have clinical implications for using psychotropics metabolized by CYP2D6.

PMID:35496293 | PMC:PMC9039251 | DOI:10.3389/fphar.2022.884213

Front Pharmacol. 2022 Apr 14;13:907131. doi: 10.3389/fphar.2022.907131. eCollection 2022.

NO ABSTRACT

PMID:35496282 | PMC:PMC9046651 | DOI:10.3389/fphar.2022.907131

Front Pharmacol. 2022 Apr 14;13:849136. doi: 10.3389/fphar.2022.849136. eCollection 2022.

ABSTRACT

Carbamazepine triggers dermatologic hypersensitivity reactions, associated with specific human leukocyte antigens (HLAs), especially HLA-B*15:02 and HLA-A*31:01. Previous efforts to identify single nucleotide variants (SNVs) with high predictive value as HLA proxies, revealed that rs1061235 and rs17179220 fulfill these requirements for HLA-A*31:01 in some but not all populations. Herein we explored the predictive performance of rs1061235 and rs17179220 as HLA-A*31:01 tags in populations of Native American ancestry, which are largely underrepresented in pharmacogenomic studies. The study cohorts comprised the overall Admixed American superpopulation of the 1000 Genomes Project (1 KG_AMR), a subcohort of individuals with predominant Native American ancestry (1 KG_NAT), the Native American population of the Human Genome Diversity Project (HGDP), plus Kaingang (KRC) and Guarani (GRC and GKW) adults from indigenous reservation areas in Brazil. The diversity of cohorts is reflected in the range of frequencies of HLA-A*31:01 (0.02-0.65), rs1061235 (0.03-0.13) and rs17179220 (0.12-0.66), as well as in the predictive performance of these SNVs as HLA-A*31:01 proxies. NPV (negative predictive value), the metric of primary interest for pharmacogenetic-informed carbamazepine prescription was maximal (NPV = 1.0) for both SNVs in 1 KG_AMR and 1 KG_NAT, for rs17179220, but not rs1061235 (NPV = 0.91) in HGDP, and for rs17179220 in GWK, but not GRC (NPV = 0.88) or KRC (NPV = 0.80). Collectively, the data support the notion that rs1061235 and rs17179220 are not optimal proxies for HLA-A*31:01 across populations of Native American ancestry.

PMID:35496269 | PMC:PMC9046591 | DOI:10.3389/fphar.2022.849136

Front Genet. 2022 Apr 14;13:864725. doi: 10.3389/fgene.2022.864725. eCollection 2022.

ABSTRACT

Pharmaceuticals are indispensable to healthcare as the burgeoning global population is challenged by diseases. The African continent harbors unparalleled genetic diversity, yet remains largely underrepresented in pharmaceutical research and development, which has serious implications for pharmaceuticals approved for use within the African population. Adverse drug reactions (ADRs) are often underpinned by unique variations in genes encoding the enzymes responsible for their uptake, metabolism, and clearance. As an example, individuals of African descent (14-34%) harbor an exclusive genetic variant in the gene encoding a liver metabolizing enzyme (CYP2D6) which reduces the efficacy of the breast cancer chemotherapeutic Tamoxifen. However, CYP2D6 genotyping is not required prior to dispensing Tamoxifen in sub-Saharan Africa. Pharmacogenomics is fundamental to precision medicine and the absence of its implementation suggests that Africa has, to date, been largely excluded from the global narrative around stratified healthcare. Models which could address this need, include primary human hepatocytes, immortalized hepatic cell lines, and induced pluripotent stem cell (iPSC) derived hepatocyte-like cells. Of these, iPSCs, are promising as a functional in vitro model for the empirical evaluation of drug metabolism. The scale with which pharmaceutically relevant African genetic variants can be stratified, the expediency with which these platforms can be established, and their subsequent sustainability suggest that they will have an important role to play in the democratization of stratified healthcare in Africa. Here we discuss the requirement for African hepatic models, and their implications for the future of pharmacovigilance on the African continent.

PMID:35495161 | PMC:PMC9046844 | DOI:10.3389/fgene.2022.864725

Front Genet. 2022 Apr 14;13:853969. doi: 10.3389/fgene.2022.853969. eCollection 2022.

ABSTRACT

The declared aim of "personalized", "stratified" or "precision" approaches is to place individual variation, as ascertained through genomic and various other biomarkers, at the heart of Scientific Medicine using it to predict risk of disease or response to therapy and to tailor interventions and target therapies so as to maximize benefit and minimize risk for individual patients and efficiency for the health care system overall. It is often contrasted to current practices for which the scientific base is rooted in concepts of a "universal biology" and a "typical" or "average patient" and in which variation is ignored. Yet both approaches equally overlook the hierarchical nature of human variation and the critical importance of differences between populations. Impact of genetic heterogeneity has to be seen within that context to be meaningful and subsequently useful. In Africa such complexity is compounded by the high effective size of its populations, their diverse histories and the diversity of the environmental terrains they occupy, rendering analysis of gene environment interactions including the establishment of phenotype genotype correlations even more cumbersome. Henceforth "Individualized" methods and approaches can only magnify the shortcomings of universal approaches if adopted without due regard to these complexities. In the current perspective we review examples of potential hurdles that may confront biomedical scientists and analysts in genomic medicine in clinical and public health genomics in Africa citing specific examples from the current SARS-COV2 pandemic and the challenges of establishing reference biobanks and pharmacogenomics reference values.

PMID:35495155 | PMC:PMC9047898 | DOI:10.3389/fgene.2022.853969

CPT Pharmacometrics Syst Pharmacol. 2022 May 2. doi: 10.1002/psp4.12793. Online ahead of print.

ABSTRACT

Obesity is an increasingly alarming public health threat, with nearly 20% of children classified as obese in the United States today. Children with obesity are commonly prescribed the opioids fentanyl and methadone, and accurate dosing is critical to reducing the risk of serious adverse events associated with overexposure. However, pharmacokinetic studies in children with obesity are challenging to conduct, so there is limited information to guide fentanyl and methadone dosing in these children. To address this clinical knowledge gap, physiologically-based pharmacokinetic models of fentanyl and methadone were developed in adults and scaled to children with and without obesity to explore the interplay of obesity, age, and pharmacogenomics. These models included key obesity-induced changes in physiology and pharmacogenomic effects. Model predictions captured observed concentrations in children with obesity well, with an overall average fold error of 0.72 and 1.08 for fentanyl and methadone, respectively. Model simulations support a reduced fentanyl dose (1 vs. 2 μg/kg/h) starting at an earlier age (6 years) in virtual children with obesity, highlighting the importance of considering both age and obesity status when selecting an infusion rate most likely to achieve steady-state concentrations within the target range. Methadone dosing simulations highlight the importance of considering genotype in addition to obesity status when possible, as cytochrome P450 (CYP)2B6*6/*6 virtual children with obesity required half the dose to match the exposure of wildtype children without obesity. This physiologically-based pharmacokinetic modeling approach can be applied to explore dosing of other critical drugs in children with obesity.

PMID:35491971 | DOI:10.1002/psp4.12793

Hum Genet. 2022 Apr 30:1-8. doi: 10.1007/s00439-022-02452-x. Online ahead of print.

ABSTRACT

Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.

PMID:35488921 | PMC:PMC9055005 | DOI:10.1007/s00439-022-02452-x

Int J Infect Dis. 2022 Apr 27:S1201-9712(22)00253-3. doi: 10.1016/j.ijid.2022.04.052. Online ahead of print.

ABSTRACT

OBJECTIVES: To compare the unbound plasma meropenem concentrations at mid-dosing intervals (Cmid, 50%fT), end-dosing intervals (Ctrough, 100%fT), and proportions of patients achieving 50%fT and 100%fT above MIC (50%fT>MIC and 100%fT>MIC) between extended infusion (EI) and intermittent bolus (IB) administration in a therapeutic drug monitoring (TDM) program in children.

METHODS: A prospective observational study was conducted in children aged 1 month to 18 years receiving meropenem every 8 h by either EI or IB. Meropenem Cmid, Ctrough, and proportions of patients achieving 50%fT>MIC and 100%fT>MIC were compared.

RESULTS: TDM data from 72 patients with a median age (IQR) of 12 months (3-37) were used. Meropenem dose was 120 and 60 mg/kg/day in EI and IB groups, respectively. Geometric mean (95% CI) Cmid of EI versus IB was 17.3 mg/L (13.7-21.8) versus 3.4 mg/L (1.7-6.7) (P<0.001). Geometric mean (95% CI) Ctrough of EI versus IB was 2.3 mg/L (1.6-3.4) versus 0.8 mg/L (0.4-1.5) (P=0.005). Greater proportions of patients achieving 50%fT>MIC and 100%fT>MIC were observed in the EI group.

CONCLUSIONS: A meropenem dose of 20 mg/kg/dose given by IB should not be used in critically ill children, even if they are not suspected of having a CNS infection. A dose of 40 mg/kg/dose given by EI resulted in higher Cmid, Ctrough, and proportions of patients achieving 50%fT>MIC and 100%fT>MIC.

PMID:35489632 | DOI:10.1016/j.ijid.2022.04.052

Clin Transl Sci. 2022 Apr 30. doi: 10.1111/cts.13294. Online ahead of print.

ABSTRACT

There are limited comparison data throughout the dosing interval for generic versus brand metoprolol extended-release (ER) tablets. We compared the pharmacokinetics (PK) and pharmacodynamics (PD) of brand name versus two generic formulations (Drugs 1 and 2) of metoprolol ER tablets with different time to maximum concentration (Tmax ) in adults with hypertension. Participants were randomized to equal drug doses (50-150 mg/day) administered in one of two sequences (Brand-Drug1-Brand-Drug2 or Brand-Drug2-Brand-Drug1) and completed 24-hour PK, digital heart rate (HR), ambulatory blood pressure (BP) and HR studies after taking each formulation for ≥7 days. Metoprolol concentrations were determined by LC-MS/MS, with non-compartmental analysis performed to obtain PK parameters in Phoenix WinNonlin. Heart rate variability (HRV) low-to-high frequency ratio was determined per quartile over the 24-hour period. Thirty-six participants completed studies with the brand name and at least one generic product. Among 30 participants on the 50 mg dose, the primary PK endpoints of area under the concentration-time curve and maximum concentration were similar between products; Tmax was 6.1±3.6 for the brand versus 3.5±4.9 for Drug 1 (p=0.019) and 9.6±3.2 for Drug 2 ( p<0.001). Among all 36 participants, 24-hour BP and HR were similar between products. Mean 24-hr HRV low-to-high ratio was also similar for Drug 1 (2.04±1.35), Drug 2 (1.86±1.35), and Brand (2.04±1.77), but was more sustained over time for the brand versus Drug 1 (drug×quartile interaction p=0.017). Differences in Tmax between metoprolol ER products following repeated doses may have implications for drug effects on autonomic balance over the dosing interval.

PMID:35488487 | DOI:10.1111/cts.13294