Real World Effectiveness of Durvalumab in Stage III Unresectable Non-small Cell Lung Cancer: What is the Role of PD-L1 Expression?

Purpose: Although the European Medicines Agency approved durvalumab post-chemoradiation (CRT) only for stage III unresectable non-small cell lung cancer (UR-NSCLC) patients with PD-L1 tumor proportion scores (TPS) ≥ 1%, the Netherlands offers reimbursement irrespective of PD-L1 status. This real-world study compares survival between durvalumab-treated patients with PD-L1 TPS < 1% vs. ≥ 1%, and also evaluates its effectiveness against a historic-cohort.

The role of the gut microbiota in chemotherapy response, efficacy and toxicity: a systematic review.

There is growing evidence for the relationship between the gut microbiota and the effect of chemotherapy. Therefore, this systematic review provides an overview of the current evidence on the effects of the gut microbiota on chemotherapy response, efficacy and toxicity in patients with cancer. PubMed, Web of Science, and EMBASE were searched to collect studies on cancer patients treated with chemotherapy that evaluated tumor response, efficacy, or toxicity, and included microbiome analysis through fecal samples.

Pharmacogenetic Implementation Studies-Lessons Learned From the PREPARE Study.

The Ubiquitous Pharmacogenomics consortium (www.upgx.eu) has recently completed and published the Preemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE) study on the implementation of panel-based pharmacogenetic testing.

Real-world study on fluoropyrimidine-related toxicity outcomes in cancer patients with select DPYD variant alleles that received DPYD genotype-guided dosing.

DPYD gene variations are associated with severe fluoropyrimidine toxicity, and an initial 50% dose reduction is widely recommended for heterozygous carriers of relevant DPYD variants, including DPYD*2A, DPYD*13, c.2846A>T, and c.1236G>A.

Reporting Adverse Drug Events: A Comparison of an Online Patient Tool Versus Telephone-Based Monitoring in Community Pharmacy Patients in the Netherlands.

Background: Adverse drug events (ADEs) are events occurring after the administration of a drug. Several authorities are involved in capturing these ADEs to improve pharmacovigilance. These ADEs are reported directly to healthcare professionals or via the telephone, online, or e-mail and are crucial for maintaining drug safety.

Dose-individualisation of fluoropyrimidines based on pre-treatment serum uracil levels: the Alpe2U study.

Background: DPYD-guided dosing enhances safety of fluoropyrimidine-based chemotherapy. However, approximately 23 % of patients still experience severe toxicity unexplained by the four commonly tested DPYD-variant alleles. Elevated pre-treatment uracil levels have been proposed as a surrogate marker for reduced DPD activity and an independent predictor of toxicity.

Improved Prediction of CYP2D6 Catalyzed Drug Metabolism by Taking Variant Substrate Specificities and Novel Polymorphic Haplotypes into Account.

The polymorphic CYP2D6 enzyme plays a pivotal role in the metabolism of approximately 25% of clinically prescribed drugs. However, the impact of specific genetic variants on the interindividual variability in CYP2D6-mediated drug metabolism remains insufficiently quantified. This translational study sought to address this gap by analyzing the genotypes and phenotypes of patients in two large clinical cohorts, focusing on the metabolism of the CYP2D6 substrates risperidone and desmethyltamoxifen.

Severe fluoropyrimidine toxicity in older adults with cancer with DPYD wild type.

Background: Despite the implementation of DPYD genotype-guided dosing, approximately 1 in 3 patients receiving fluoropyrimidine-containing chemotherapy continues to experience severe toxicity. While clinical studies have demonstrated a favorable tolerance among highly selected fit older adults, real-world studies have shown an increased risk of toxicity.

Objective: To identify predictors of severe toxicity or treatment deintensification in older DPYD wild-type adults receiving fluoropyrimidine-containing chemotherapy.

The association between the number of HLA risk alleles and drug allergy and its implications for HLA screening - a case-control study.

Patients carrying specific HLA risk alleles are at higher risk for developing drug hypersensitivity reactions, yet pre-therapeutic screening is uncommon. We examined whether patients with a history of drug allergies have more HLA risk alleles to assess whether these patients are potential candidates for pre-therapeutic HLA screening. We performed a case-control study with patients who had a self-reported history of drug allergy (N = 94) and patients without such a history (N = 185).

Pharmacokinetic modeling of prenatal vitamin D exposure and the impact on offspring asthma and pulmonary function.

Gestational 25-hydroxyvitamin D (25[OH]D) is important in fetal lung development and may influence offspring respiratory outcomes, making accurate exposure assessment essential to understand clinical associations. Therefore, we used the combined data from two large RCTs investigating prenatal vitamin D supplementation, which included early and late prenatal 25(OH)D measurements, to refine a population pharmacokinetic model of vitamin D-25(OH)D and estimate individual area under the curve (AUC) Z-scores. The primary outcome was physician-diagnosed offspring asthma/wheezing at ages 3 and 6 years, and lung function, as a secondary outcome, was evaluated by spirometry at the ages 6 and 8 years.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between SLCO1B1 and statins and CYP2C9 and sulfonylureas.

Aligned with the mission of the Dutch Pharmacogenetics Working Group (DPWG) to promote the implementation of pharmacogenetics (PGx), this guideline is specifically designed to optimize pharmacotherapy of cholesterol lowering medication (statins) and glucose lowering medication (sulfonylureas). The SLCO1B1 c.521 T > C variant reduces the activity of the SLCO1B1 transporter involved in statin transport out of the blood into the liver.

Clinical Benefits and Utility of Pretherapeutic DPYD and UGT1A1 Testing in Gastrointestinal Cancer: A Secondary Analysis of the PREPARE Randomized Clinical Trial.

Importance: To date, the clinical benefit and utility of implementing a DPYD/UGT1A1 pharmacogenetic-informed therapy with fluoropyrimidines and/or irinotecan have not been prospectively investigated.

Objective: To examine clinically relevant toxic effects, hospitalizations, and related costs while preserving treatment intensity and efficacy outcomes in patients with gastrointestinal cancer.

Design, Setting, And Participants: This nonprespecified secondary analysis stems from Pre-Emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE), a multicenter, controlled, open, block-randomized, crossover implementation trial conducted from March 7, 2017, to June 30, 2020, and includes data from Italy according to a sequential study design.

Vitamin D beyond the blood: Tissue distribution of vitamin D metabolites after supplementation.

Vitamin D's role in mineral homeostasis through its endocrine function, associated with the main circulating metabolite 25-hydroxyvitamin D, is well characterized. However, the increasing recognition of vitamin D's paracrine and autocrine functions-such as cell growth, immune function, and hormone regulation-necessitates examining vitamin D levels across different tissues post-supplementation. Hence, this review explores the biodistribution of vitamin D in blood and key tissues following oral supplementation in humans and animal models, highlighting the biologically active metabolite, 1,25-dihydroxyvitamin D, and the primary clearance metabolite, 24,25-dihydroxyvitamin D.

The efficacy and safety of eculizumab in patients and the role of C5 polymorphisms.

Eculizumab is an orphan drug with indications for extremely rare autoimmune disorders. It is primarily prescribed for use in patients with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome; but is also highly effective in the treatment of myasthenia gravis, among others. By binding to the C5 protein in the complement system, eculizumab effectively inhibits cellular hemolysis and autoimmune reactions.

Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole.

Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion).

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP2C19 and non-SSRI/non-TCA antidepressants.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy based on pharmacogenetic test results. The current guideline describes the gene-drug interaction between CYP2D6 and venlafaxine, mirtazapine and duloxetine. In addition, the interaction between CYP2C19 and mirtazapine and moclobemide is presented.

Short-acting β-agonists (SABA) overuse in asthma and patients' perceptions for this behavior.

Background: Short-acting β-agonists (SABA) overuse is associated with poor asthma control. The Global Initiative for Asthma (GINA) 2019-updated strategy report has therefore taken a paradigm shift in reliever therapy recommendations.

Objectives: (I) To investigate the status of SABA overuse and medication dispensing patters in asthma in the Netherlands (II) validate dispensing data for SABA overuse identification and (III) understand patients' perspectives towards this SABA-taking behavior to inform future improvement strategies.

Model-Informed Development of a Cost-Saving Dosing Regimen for Sacituzumab Govitecan.

Background: The antibody-drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality.

Objective: The purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access.

Mapping the Pharmacogenetic Landscape in a Ugandan Population: Implications for Personalized Medicine in an Underrepresented Population.

Africans are extremely underrepresented in global genomic research. African populations face high burdens of communicable and non-communicable diseases and experience widespread polypharmacy. As population-specific genetic studies are crucial to understanding unique genetic profiles and optimizing treatments to reduce medication-related complications in this diverse population, the present study aims to characterize the pharmacogenomics profile of a rural Ugandan population.

Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort.

Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible.

Self-management support with the Respiratory Adherence Care Enhancer instrument in asthma and chronic obstructive pulmonary disease: An implementation trial.

Aim: Suboptimal self-management with controller inhalation therapy in asthma and COPD is frequently observed with poor treatment outcomes. The developed 'Respiratory Adherence Care Enhancer' (RACE) instrument identifies and addresses individual barriers to self-management with a theoretical underpinning. This study investigates the feasibility of pharmaceutical support with this instrument.