New metabolic insights into the mechanism of ifosfamide encephalopathy.

Ifosfamide causes neurotoxicity, including sometimes fatal encephalopathy, in a small number of patients. Why and how this occurs is not fully understood. It is generally believed that N-dechloroethylation of ifosfamide to 2-chloroacetaldehyde is the cause.

Body Weight Gain Associated With Alectinib in Patients With ALK+ Non-Small Cell Lung Cancer: Pooled Analysis of Individual Patient Data From Four Prospective Clinical Trials.

Purpose: Weight gain is a known adverse event (AE) of alectinib. This study evaluates the progression of actual weight gain over time and explores its association with baseline characteristics.

Methods: A pooled analysis of individual patient data from four clinical trials (ALEX, J-ALEX, ALUR, and ML29453) was conducted.

Effects of tamoxifen on cognitive function in patients with primary breast cancer.

Introduction: Tamoxifen may adversely affect cognitive function by interfering with estrogen action in the brain. Despite growing evidence for a relationship between tamoxifen and cognitive problems, findings remain inconclusive. While some tamoxifen-related side effects seem exposure-dependent with concentrations of tamoxifen or its main metabolite, endoxifen, this has never been investigated for cognitive function.

Selecting the Best Pharmacokinetic Models for a Priori Model-Informed Precision Dosing with Model Ensembling.

Background And Objective: When utilizing population pharmacokinetic (popPK) models for a priori dosage individualization, selecting the best model is crucial to obtain adequate doses. We developed and evaluated several model-selection and ensembling methods, using external evaluation on the basis of therapeutic drug monitoring (TDM) samples to identify the best (set of) models per patient for a priori dosage individualization.

Methods: PK data and models describing both hospitalized patients (n = 134) receiving continuous vancomycin (26 models) and patients (n = 92) receiving imatinib in an outpatient setting (12 models) are included.

Optimizing the Dosing Regimen During Rotation From Subcutaneous to Transdermal Administration of Fentanyl.

Context: Subcutaneous (SC) administration of fentanyl allows for rapid dose titration to treat urgent cancer-related pain. After establishing the optimal fentanyl dose, patients typically rotate towards transdermal (TD) fentanyl patches. Continuing the SC fentanyl up to 12h after application of the patch led to elevated fentanyl concentrations and fentanyl-related toxicities.

Systematic Evaluation of Tyrosine Kinase Inhibitors as OATP1B1 Substrates Using a Competitive Counterflow Screen.

Unlabelled: Although the primary elimination pathway for most tyrosine kinase inhibitors (TKI) involves CYP3A4-mediated metabolism, the mechanism by which these agents are brought into hepatocytes remains unclear. In this study, we optimized and validated a competitive counterflow (CCF) assay to examine TKIs as substrates of the hepatic uptake transporter OATP1B1. The CCF method was based on the stimulated efflux of radiolabeled estradiol-17β-glucuronide under steady-state conditions in HEK293 cells engineered to overexpress OATP1B1.

Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD.

Background: The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.

Systemic Treatment Strategies and Outcomes of Patients With Synchronous Peritoneal Metastases of Gastric Origin: A Nationwide Population-Based Study.

Background: Palliative systemic treatment is currently standard of care for metastatic gastric cancer. However, patients with peritoneal metastases of gastric origin are often underrepresented in clinical studies due to unmeasurable radiologic disease. This study describes the systemic treatment strategies and outcomes in patients with peritoneal metastases in a nationwide real-world setting.

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.

Introduction And Objective: Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.

The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine: A Crossover Pharmacokinetic Study.

Background And Objectives: Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug-drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine.

Methods: In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C).

Market Entry Agreements for Innovative Pharmaceuticals Subject to Indication Broadening: A Case Study for Pembrolizumab in The Netherlands.

Objectives: Managed entry agreements and especially financial-based agreements are commonly used in European countries for innovative cancer pharmaceuticals. These agreements facilitate access to innovative treatments while mitigating financial risks for payers. This study focuses on the confidential price agreement made by the Dutch government for the reimbursement of pembrolizumab, the implications of broadening indications on cost-effectiveness, and the viability or desirability of said agreement.

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.

Intraperitoneal pharmacokinetics of systemic oxaliplatin, 5-fluorouracil and bevacizumab in patients with colorectal peritoneal metastases.

Background: Peritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that traditional systemic chemotherapy is not very effective for this patient population.

Levels of circulating tumor DNA correlate with tumor volume in gastro-intestinal stromal tumors: an exploratory long-term follow-up study.

Patients with gastro-intestinal stromal tumors (GISTs) undergoing tyrosine kinase inhibitor therapy are monitored with regular computed tomography (CT) scans, exposing patients to cumulative radiation. This exploratory study aimed to evaluate circulating tumor DNA (ctDNA) testing to monitor treatment response and compare changes in ctDNA levels with RECIST 1.1 and total tumor volume measurements.

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin: a systematic review and meta-analysis.

Background: Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy.

Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRAS-Mutated NSCLC Treated With Sotorasib.

Introduction: For patients with KRAS-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression.

Methods: Patients with KRAS-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372).

Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced -Mutated NSCLC.

Introduction: Brain metastases (BM) are common in patients with advanced -mutated (m+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (C) and consequently limited intracranial osimertinib exposure.

Staging laparoscopy in gastric cancer patients: From a Dutch nationwide Delphi consensus towards a standardized protocol.

Background: Staging laparoscopy is a common diagnostic tool in gastric cancer, but its performance varies widely. The aim of this study was to gain Dutch nationwide consensus regarding the indications for and execution of staging laparoscopy in patients with gastric cancer.

Methods: All surgeons in the Netherlands specialized in gastric cancer surgery (n = 52) were asked to participate in a Delphi consensus study.

Paclitaxel therapeutic drug monitoring - International association of therapeutic drug monitoring and clinical toxicology recommendations.

Paclitaxel, one of the most frequently used anticancer drugs, is dosed by body surface area, which leads to substantial inter-individual variability in systemic drug exposure. We evaluated clinical evidence regarding the scientific rationale and clinical benefit of individualized paclitaxel dosing based on measured systemic concentrations, known as therapeutic drug monitoring (TDM). In retrospective studies, higher systemic exposure is associated with greater toxicity and efficacy of paclitaxel treatment across several disease types and dosing regimens.