Prediction of the Intra-T Lymphocyte Tacrolimus Concentration after Kidney Transplantation with Population Pharmacokinetic Modeling.

The intracellular tacrolimus concentration in CD3 T lymphocytes is proposed to be a better representative of the active component of tacrolimus than the whole blood concentration. However, intracellular measurements are complicated. Therefore, the aim of this study was to describe the relationship between intracellular and whole blood tacrolimus concentrations in a population pharmacokinetic model.

Implementation of Pharmacogenetics in First-Line Care: Evaluation of Its Use by General Practitioners.

Pharmacogenetics (PGx) can explain/predict drug therapy outcomes. There is, however, unclarity about the use and usefulness of PGx in primary care. In this study, we investigated PGx tests ordered by general practitioners (GPs) in 2021 at Dept.

Irinotecan-Induced Toxicity: A Pharmacogenetic Study Beyond UGT1A1.

Background And Objective: Side effects of irinotecan treatment can be dose limiting and may impair quality of life. In this study, we investigated the correlation between single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in the irinotecan metabolism and transport, outside UGT1A1, and irinotecan-related toxicity. We focused on carboxylesterases, which are involved in formation of the active metabolite SN-38 and on drug transporters.

Modelling changes in the pharmacokinetics of tacrolimus during pregnancy after kidney transplantation: A retrospective cohort study.

Aims: Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole-blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics.

CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients.

Introduction: A genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The primary aim of this study was to investigate if the systemic exposure is non-inferior after a dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to patients without this SNP (i.e.

as a Predictor of Severe Fluoropyrimidine-Related Adverse Events.

Purpose: Around 20%-30% of patients treated with fluoropyrimidines develop severe treatment-related adverse events (AEs). These are mainly caused by deficiency of dihydropyrimidine dehydrogenase, its main metabolizing enzyme. The *7 variant allele contains a frameshift mutation that leads to absence of dihydropyrimidine dehydrogenase.

Donor-Derived Cell-Free DNA for the Detection of Heart Allograft Injury: The Impact of the Timing of the Liquid Biopsy.

In heart transplant recipients, donor-derived cell-free DNA (ddcfDNA) is a potential biomarker for acute rejection (AR), in that increased values may indicate rejection. For the assessment of ddcfDNA as new biomarker for rejection, blood plasma sampling around the endomyocardial biopsy (EMB) seems a practical approach. To evaluate the effect of the EMB procedure on ddcfDNA values, ddcfDNA values before the EMB were pairwise compared to ddcfDNA values after the EMB.

Genotyping in Clinical Practice: Ready for Implementation?

Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6 and opioids (codeine, tramadol and oxycodone).

The current Dutch Pharmacogenetics Working Group (DPWG) guideline, describes the gene-drug interaction between CYP2D6 and the opioids codeine, tramadol and oxycodone. CYP2D6 genotype is translated into normal metaboliser (NM), intermediate metaboliser (IM), poor metaboliser (PM) or ultra-rapid metaboliser (UM). Codeine is contraindicated in UM adults if doses >20 mg every 6 h (q6h), in children ≥12 years if doses >10 mg q6h, or with additional risk factors.

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

Investigate the potential role of (mu-opioid receptor) and (catechol-O-methyltransferase enzyme) polymorphisms in postoperative acute, chronic and experimental thermal pain. A secondary analysis of 125 adult cardiac surgery patients that were randomized between fentanyl and remifentanil during surgery and genotyped. Patients in the fentanyl group with the high-pain sensitivity haplotype required less postoperative morphine compared with the average-pain sensitivity haplotype (19.

Cytochrome P450 genotype and aggressive behavior on selective serotonin reuptake inhibitors.

Letter in reply to: Eikelenboom-Schieveld SJM, Fogleman JC. Letter to the Editor. Pharmcogenomics 19(14), 1095-1096 (2018) [ 1 ].

Increased Metformin Clearance in Overweight and Obese Adolescents: A Pharmacokinetic Substudy of a Randomized Controlled Trial.

Background: In view of the increased use of metformin in obese adolescents, the aim of this study was to determine the pharmacokinetics of metformin in overweight and obese adolescents.

Methods: In overweight and obese adolescents receiving metformin 500 or 1000 mg twice daily for 37 weeks during a clinical trial, blood samples were collected over 8 h during an oral glucose tolerance test. Population pharmacokinetic modeling was performed using NONMEM.

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.

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice.

Background: The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies.

CYP450 genotype and aggressive behavior on selective serotonin reuptake inhibitors.

Aim: Genetic variants for selective serotonin reuptake inhibitor (SSRI) metabolizing enzymes have been hypothesized to be a risk factor for aggression as adverse drug effect of SSRIs. Our aim was to assess the possible involvement of these polymorphisms on aggression when using SSRIs.

Materials & Methods: A retrospective noninterventional case-control study was performed on 18 cases.

Inter-Subject Variability in OCT1 Activity in 27 Batches of Cryopreserved Human Hepatocytes and Association with OCT1 mRNA Expression and Genotype.

Purpose: OCT1/3 (Organic Cation Transporter-1 and -3; SLC22A1/3) are transmembrane proteins localized at the basolateral membrane of hepatocytes. They mediate the uptake of cationic endogenous compounds and/or xenobiotics. The present study was set up to verify whether the previously observed variability in OCT activity in hepatocytes may be explained by inter-individual differences in OCT1/3 mRNA levels or OCT1 genotype.

A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients.

Background: Oral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.

Methods: Blood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).

Genetic variants associated with thermal pain sensitivity in a paediatric population.

Pain sensitivity is an inherited factor that varies strongly between individuals. We investigated whether genetic polymorphisms in the candidate genes COMT, OPRM1, OPRD1, TAOK3, TRPA1, TRPV1, and SCN9A are contributing to experimental pain variability between children. Our study included 136 children and adolescents (8-18 years).

Opioid treatment failure in cancer patients: the role of clinical and genetic factors.

Aim: To identify clinical and genetic factors associated with outcome of opioid treatment.

Patients & Methods: We performed an exploratory analysis in a cohort of 353 patients treated with fentanyl, morphine, oxycodone and/or hydromorphone for cancer-related pain, exploring selected clinical and pharmacogenetic factors for a correlation with treatment failure for all and per type of opioid.

Results: Use of adjuvant pain medication, intensity of pain at rest and age were associated with treatment failure in the various cohorts.