Periconceptional Non-medical Maternal Determinants Influence the Tryptophan Metabolism: The Rotterdam Periconceptional Cohort (Predict Study).

Background: The vital role of the maternal tryptophan (TRP) metabolism in maternal health and pregnancy is well established. However, non-medical maternal determinants influencing the TRP metabolism have been poorly investigated. We hypothesise that periconceptional maternal non-medical determinants alter the TRP metabolism, affecting both kynurenine (KP) and serotonin pathway (SP) metabolite concentrations. Therefore, we investigated the influence of non-medical maternal determinants on the TRP metabolism during the periconception period. Methods: About 1916 pregnancies were included from the Rotterdam Periconceptional Cohort between November 2010 and December 2020. Data on periconceptional non-medical maternal determinants were collected through questionnaires. Serum samples were collected at 8.5 (SD = 1.6) weeks of gestation and TRP, kynurenine (KYN), 5-hydroxytryptophan (5-HTP), 5-HT (5-hydroxytryptamine) and 5-hydroxyindole acetic acid (5-HIAA) were determined using validated liquid chromatography (tandem) mass spectrometry. Mixed models were used to determine associations between periconceptional non-medical maternal determinants and these metabolites. Results: In total 11 periconceptional non-medical maternal determinants were identified. Protein intake was positively associated with TRP (ß = .12, 95% CI = 0.07-0.17), while age, energy intake and body mass index (BMI) (ß = -.24, 95% CI = -0.37 to -0.10) were negatively associated with TRP. Age, BMI and total homocysteine were associated with higher KYN, whereas non-western geographical origin was associated with lower KYN (ß = -.09, 95% CI = -0.16 to -0.03). Protein intake and total homocysteine (ß = .07, 95% CI = 0.03-0.11) had a positive association with 5-HTP, while a negative association was found for energy intake. A non-western geographical origin and drug use were associated with higher 5-HT, and BMI with lower 5-HT (ß = -6.32, 95% CI = -10.26 to -2.38). Age was positively associated with 5-HIAA (ß = .92, 95% CI = 0.29-1.56), and BMI negatively. Conclusions: Periconceptional non-medical maternal determinants, including age, geographical origin, drug use, energy and protein intake, BMI and total homocysteine, influence KP and SP metabolite concentrations.

The fully automated Sysmex XN-31 hematology analyzer can detect bloodstream form Trypanosoma brucei.

BACKGROUND: For fully automated detection and quantification of Plasmodium parasites, Sysmex developed the XN-31 hemocytometer. This study investigated whether the XN-31 can also detect and quantify bloodstream form trypanosomes (trypomastigotes). METHODS: Axenic cultures of Trypanosoma brucei brucei were used to prepare two dilution series of trypomastigotes in the whole blood of a healthy donor, which were subsequently examined by the XN-31 as well as by microscopic examination of thin and thick blood films. Trypomastigote intactness during the procedures was evaluated by microscopy. RESULTS: The XN-31 hemocytometer detected trypomastigotes with a detection limit of 26 trypomastigotes/µL. Scattergram patterns of Trypanosoma and Plasmodium parasites were clearly distinct, but current interpretation settings do not allow the identification of trypomastigotes yet, and therefore, need future refinement. CONCLUSION: Proof of concept was provided for an automated fluorescent flow cytometry method that can detect and quantify Plasmodium spp., as well as Trypanosoma brucei trypomastigotes.

The Sixth European Society of Pharmacogenomics and Personalised Therapy Congress.

On 8-9 November 2022, the European Society of Pharmacogenomics and Personalised Therapy organized its sixth biennial congress, in Belgrade, Serbia (congress website: www.sspt.rs). The congress aimed to address the current status and future perspectives of pharmacogenomics, share latest knowledge in the field of precision medicine and showcase the implementation of clinical applications in pharmacogenomics/pharmacogenetics. The 2 day congress consisted of 17 lectures given by key-opinion leaders and included a poster session plus discussions. The meeting was a great success by generating an informal environment and enabling the exchange of information between 162 participants from 16 different countries.

OPRM1 and COMT polymorphisms: implications on postoperative acute, chronic and experimental pain after cardiac surgery.

Aim: Investigate the potential role of OPRM1 (mu-opioid receptor) and COMT (catechol-O-methyltransferase enzyme) polymorphisms in postoperative acute, chronic and experimental thermal pain. Methods: A secondary analysis of 125 adult cardiac surgery patients that were randomized between fentanyl and remifentanil during surgery and genotyped. Results: Patients in the fentanyl group with the COMT high-pain sensitivity haplotype required less postoperative morphine compared with the average-pain sensitivity haplotype (19.4 [16.5; 23.0] vs 34.6 [26.2; 41.4]; p = 0.00768), but not to the low-pain sensitivity group (30.1 [19.1; 37.7]; p = 0.13). No association was found between COMT haplotype and other pain outcomes or OPRM1 polymorphisms and the different pain modalities. Conclusion:COMT haplotype appears to explain part of the variability in acute postoperative pain in adult cardiac surgery patients.

Effects of pharmacogenetic variants on vemurafenib-related toxicities in patients with melanoma.

Aim: The pharmacokinetics and pharmacodynamics of vemurafenib are characterized by a wide interpatient variability. Since multiple polymorphic enzymes and drug transporters are involved in vemurafenib pharmacokinetics, we studied associations of polymorphisms on vemurafenib-associated toxicities. Patients & methods: Prospectively collected samples of 97 melanoma patients treated with vemurafenib alone (n = 62) or in combination with cobimetinib (n = 35) were genotyped for ABCB1 (3435C>T), ABCG2 (421C>A, 34G>A) and CYP3A4 (*22, 15389C>T) polymorphisms. Associations between these variants and the incidence of toxicities were studied. Results:CYP3A4*22 was significantly associated with increased risk for grade ≥3 nausea, grade 1-4 hyperbilirubinemia, and cutaneous squamous cell carcinoma. ABCB1 3435C>T was a predictor for grade ≥3 toxicity. Conclusion: Genetic variants in CYP3A4 and ABCB1 are associated with vemurafenib-associated toxicities.

4th ESPT Conference: pharmacogenomics and personalized medicine - research progress and clinical implementation.

The Fourth European Society of Pharmacogenomics and Personalized Therapy biennial conference was organized in collaboration with the Italian Society of Personalized Medicine (SIMeP) and was held at Benedictine Monastery of San Nicolò l'Arena in Catania, Sicily (Italy) on 4-7 October 2017. The congress addressed the research progress and clinical implementation in pharmacogenomics and personalized medicine. The Fourth European Society of Pharmacogenomics and Personalized Therapy congress brought together leading international scientists and healthcare professionals actively working in the fields of pharmacogenomics and personalized therapy. Altogether, 25 speakers in 15 session comprehensively covered broad spectrum of pharmacogenetics and pharmacogenomics research, clinical applications in different clinical disciplines attended by 270 delegates.

Pharmacogenomics education in medical and pharmacy schools: conclusions of a global survey.

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005.

CYP2D6 genotype can help to predict effectiveness and safety during opioid treatment for chronic low back pain: results from a retrospective study in an Italian cohort.

BACKGROUND: Opioids are widely used for chronic low back pain (CLBP); however, it is still unclear how to predict their effectiveness and safety. Codeine, tramadol and oxycodone are metabolized by CYP/CYP450 2D6 (CYP2D6), a highly polymorphic enzyme linked to allele-specific related differences in metabolic activity. PURPOSE: CYP2D6 genetic polymorphisms could potentially help to predict the effectiveness and safety of opioid-based drugs in clinical practice, especially in the treatment of CLBP. PATIENTS AND METHODS: A cohort of 224 Italian patients with CLBP treated with codeine or oxycodone was retrospectively evaluated to determine whether adverse reactions and effectiveness were related to CYP2D6 single-nucleotide polymorphisms. CYP2D6 genotyping was performed using the xTAG® CYP2D6 Kit v3 (Luminex) to determine CYP2D6 metabolizer phenotype (poor, intermediate, rapid and ultrarapid). Subjects from the cohort were categorized into two groups according to the occurrence of side effects (Case) or benefit (Control) after chronic analgesic treatment. The impact of CYP2D6 polymorphism on treatment outcome was tested at the metabolizer phenotype, diplotype and haplotype levels. RESULTS: CYP2D6 polymorphism was significantly associated with opioid treatment outcome (Omnibus P=0.018, for both global haplotype and diplotype distribution test). CYP2D6*6 and *9 carriers, alleles characterized by a reduced (*9) or absent (*6) enzymatic activity, were significantly (P<0.05) associated with therapeutic failure. CYP2D6 ultrarapid metabolizers (CYP2D6*2N patients) showed an increased risk of side effects, as would be predicted. Despite their low frequency, CYP2D6 *1/*11, *4/*6 and *41/* 2N diplotypes showed significant (P<0.05) associations of efficacy and side effects with chronic opioid treatment. CONCLUSION: Our results showed that reduced CYP2D6 activity is correlated with lack of therapeutic effect. We found that the pharmacogenetic analysis of CYP2D6 could be helpful in foreseeing the safety and effectiveness of codeine or oxycodone treatment in CLBP.

CYP3A5 and ABCB1 polymorphisms in living donors do not impact clinical outcome after kidney transplantation.

AIM: To investigate the association between donor CYP3A5 and ABCB1 polymorphisms and tacrolimus (Tac)-induced nephrotoxicity and renal function in kidney transplant recipients. METHODS: The CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms were determined in 237 recipients and donors. RESULTS: There was no significant association between Tac-related nephrotoxicity and donor CYP3A5 and ABCB1 genotype. The donor ABCB1 3435C>T polymorphism was associated with estimated glomerular filtration rate on day 7 and month 1. The combined donor-recipient ABCB1 genotype (3435C>T polymorphism) was significantly related with estimated glomerular filtration rate on day 3 and 7 in univariate analysis. However, these differences were no longer statistically significant in multivariate analysis. CONCLUSION: A genetic analysis of ABCB1 and CYP3A5 of kidney transplant donors is not helpful to improve renal transplant outcomes.

Detection of a rare CYP3A4 variant in a transplant patient characterized by a tacrolimus poor metabolizer phenotype.

A validated CYP3A genotype classification system allows clustering patients into poor, intermediate and extensive metabolizer phenotypes. However, substantial overlap exists between the clusters. A rare CYP3A4 allele, named CYP3A4*20 (rs67666821), has been specifically described in the Spanish population. The authors investigated the relevance of CYP3A4*20 testing to see if the above-mentioned metabolic CYP3A classification system can be improved. In a cohort of 204 kidney transplant recipients, one male patient carrying a CYP3A4*20 allele was detected. This patient was receiving very low doses of tacrolimus to maintain therapeutic levels from day 7 onward when compared with the majority of the patients. These data suggest that this patient should be regarded as a CYP3A-poor metabolizer.

Advanced cancer pain: the search for genetic factors correlated with interindividual variability in opioid requirement.

AIM: To assess association between genetic variants and opioid requirement in cancer patients. MATERIALS & METHODS: A prospective observational trial of 243 advanced cancer patients with inadequate analgesia treated by the palliative care team was analyzed for ABCB1, ARRB2, COMT, GCH1, IL1RN, KCNJ6, OPRM1, RHBDF2, SCN9A and Stat6 polymorphisms. RESULTS: For patients carrying OPRM1 118AG/GG and COMT 472GG (Val158Val) or these genotypes alone, a significant higher median percentage dose increase was observed (95.2% [32.8-345]) compared with OPRM1 118AA and COMT 472GA/AA (158Met allele carriers; 48.5% [0-98.8]; p = 0.0016). No associations were found with morphine equivalent dose after consultation palliative care team or ketamine use. CONCLUSION: Patients with the combined OPRM1 118AG/GG and COMT 472GG genotype required 50% higher dose increase for sufficient analgesia.

Minimum information required for a DMET experiment reporting.

AIM: To provide pharmacogenomics reporting guidelines, the information and tools required for reporting to public omic databases. MATERIAL & METHODS: For effective DMET data interpretation, sharing, interoperability, reproducibility and reporting, we propose the Minimum Information required for a DMET Experiment (MIDE) reporting. RESULTS: MIDE provides reporting guidelines and describes the information required for reporting, data storage and data sharing in the form of XML. CONCLUSION: The MIDE guidelines will benefit the scientific community with pharmacogenomics experiments, including reporting pharmacogenomics data from other technology platforms, with the tools that will ease and automate the generation of such reports using the standardized MIDE XML schema, facilitating the sharing, dissemination, reanalysis of datasets through accessible and transparent pharmacogenomics data reporting.

Polymorphisms in SLCO1B1 and UGT1A1 are associated with sorafenib-induced toxicity.

AIM: Sorafenib-treated patients display a substantial variation in the incidence of toxicity. We aimed to investigate the association of genetic polymorphisms with observed toxicity on sorafenib. PATIENTS & METHODS: We genotyped 114 patients that were treated with sorafenib at the Erasmus MC Cancer Institute, the Netherlands, for SLCO1B1, SLCO1B3, ABCC2, ABCG2, UGT1A1 and UGT1A9. RESULTS: The UGT1A1 (rs8175347) polymorphism was associated with hyperbilirubinemia and treatment interruption. Polymorphisms in SLCO1B1 (rs2306283, rs4149056) were associated with diarrhea and thrombocytopenia, respectively. None of the investigated polymorphisms was associated with overall or progression-free survival in hepatocellular cancer patients. CONCLUSION: Polymorphisms in SLCO1B1 and UGT1A1 are associated with several different sorafenib side effects.

Pharmacokinetic drug-drug interaction study between raltegravir and citalopram.

BACKGROUND: Depression is the most common mental health disorder among HIV-infected patients. When treating HIV-infected patients with a selective serotonin reuptake inhibitor (SSRI), potential drug-drug interactions with antiretroviral agents have to be taken into account. We investigated the two-way pharmacokinetic drug-drug interaction and tolerability of concomitant administration of the SSRI citalopram and the HIV-1 integrase inhibitor raltegravir in healthy volunteers. METHODS: An open-label, crossover, two-period trial was conducted in 24 healthy volunteers. Subjects received the following treatments: citalopram 20 mg once daily for 2 weeks followed by the combination with raltegravir 400 mg twice daily for 5 days and after a washout period raltegravir 400 mg twice daily for 5 days. Intensive steady-state pharmacokinetic blood sampling was performed. Geometric mean ratios (GMRs) of the combination versus the reference treatment and 90% CIs were calculated for the area under the plasma concentration-time curve (AUC). CYP2C19 genotyping was performed because it influences N-demethylation of citalopram to desmethylcitalopram. RESULTS: A total of 22 healthy volunteers completed the trial. GMRs (90% CI) were 1.00 (0.98, 1.03) for citalopram AUC0-24 h, 0.99 (0.88, 1.12) for desmethylcitalopram AUC0-24 h and 0.77 (0.50, 1.19) for raltegravir AUC0-12 h. Raltegravir plasma concentration 12 h after intake (C12 h) did not change with concomitant use of citalopram. Within each CYP2C19 phenotype subgroup the citalopram metabolite-to-parent ratio, which is a measure for metabolic enzyme activity, was not influenced by concomitant raltegravir use. CONCLUSIONS: Raltegravir does not influence the pharmacokinetics of citalopram and desmethylcitalopram. Citalopram did not change the pharmacokinetics of raltegravir in a clinically meaningful way. The combination was well tolerated and can be administered without dose adjustments. ClinicalTrials.gov NCT01978782.

Conference scene: pharmacogenomics: from cell to clinic (part 2).

Second International ESPT Meeting Lisbon, Portugal, 26-28 September 2013 The second European Society of Pharmacogenomics and Theranostics (ESPT) conference was organized in Lisbon, Portugal, and attracted 250 participants from 37 different countries. The participants could listen to 50 oral presentations, participate in five lunch symposia and were able to view 83 posters and an exhibition. Part 1 of this Conference Scene was presented in the previous issue of Pharmacogenomics. This second part will focus on: clinical implementation of pharmacogenomics tests; transporters and pharmacogenomics; stem cells and other new tools for pharmacogenomics and drug discovery; from system pharmacogenomics to personalized medicine; and, finally, we will discuss the Posters and Awards that were presented at the conference.

Genetic variation in the PPARA gene is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study.

AIM: Recently, minor alleles of two strongly linked polymorphisms in the PPARA gene, rs4253728 G>A and rs4823613 A>G, were related to decreased CYP3A4 expression and activity. We studied whether they were associated with the cholesterol-lowering effect of simvastatin. MATERIALS & METHODS: We identified 123 incident users with cholesterol measurements before and after starting statin therapy in a prospective population-based cohort study. Associations between PPARA polymorphisms and change in total and low-density lipoprotein (LDL)-cholesterol levels were analyzed using linear regression. RESULTS: The minor G allele of the rs4823613 A>G polymorphism was associated with a 0.258 mmol/l (95% CI: -0.470 to -0.046) and a 0.294 mmol/l (95% CI: -0.495 to -0.093) larger reduction in total and LDL-cholesterol, respectively, after starting simvastatin therapy. Results were similar for the rs4253728 G>A polymorphism. CONCLUSION: The minor alleles of the PPARA rs4253728 and rs4823613 polymorphisms are associated with a better total and LDL-cholesterol-lowering response to simvastatin, possibly through influence on CYP3A4.

CYP3A4*22 and CYP3A combined genotypes both correlate with tacrolimus disposition in pediatric heart transplant recipients.

BACKGROUND: Tacrolimus metabolism depends on CYP3A4 and CYP3A5. We aimed to determine the relationship between the CYP3A4*22 polymorphism and combined CYP3A genotypes with tacrolimus disposition in pediatric heart transplant recipients. METHODS: Sixty pediatric heart transplant recipients were included. Tacrolimus doses and trough concentrations were collected in the first 14 days post-transplantation. CYP3A phenotypes were defined as extensive (CYP3A5*1 + CYP3A4*1/*1 carriers), intermediate (CYP3A5*3/*3 + CYP3A4*1/*1 carriers) or poor (CYP3A5*3/*3 + CYP3A4*22 carriers) metabolizers. RESULTS: CYP3A4*22 carriers needed 30% less tacrolimus (p = 0.016) to reach similar target concentrations compared with CYP3A4*1/*1 (n = 56) carriers. Poor CYP3A metabolizers required 17% (p = 0.023) less tacrolimus than intermediate and 48% less (p < 0.0001) than extensive metabolizers. Poor metabolizers showed 18% higher dose-adjusted concentrations than intermediate (p = 0.35) and 193% higher than extensive metabolizers (p < 0.0001). CONCLUSION: Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.

Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside?

The 118A>G single nucleotide polymorphism (SNP) in the µ-opioid receptor (OPRM1) gene has been the most described variant in pharmacogenetic studies regarding opioid drugs. Despite evidence for an altered biological function encoded by this variant, this knowledge is not yet utilized clinically. The aim of the present review was to collect and discuss the available information on the 118A>G SNP in the OPRM1 gene, at the molecular level and in its clinical manifestations. In vitro biochemical and molecular assays have shown that the variant receptor has higher binding affinity for ß-endorphins, that it has altered signal transduction cascade, and that it has a lower expression compared with wild-type OPRM1. Studies using animal models for 118A>G have revealed a double effect of the variant receptor, with an apparent gain of function with respect to the response to endogenous opioids but a loss of function with exogenous administered opioid drugs. Although patients with this variant have shown a lower pain threshold and a higher drug consumption in order to achieve the analgesic effect, clinical experiences have demonstrated that patients carrying the variant allele are not affected by the increased opioid consumption in terms of side effects.