Cancer Chemotherapy and Pharmacology最新文献

Afatinib, an irreversible ErbB family inhibitor, is approved for the treatment of non-small cell lung cancer (NSCLC) with both common and selected uncommon EGFR mutations. Evidence in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) is scarce, especially with pharmacokinetic (PK) data. Here, we report the case of a patient with metastatic NSCLC harboring an EGFR G719C mutation who was successfully treated with afatinib during regular hemodialysis. Afatinib was initiated at 20 mg once daily under fasting conditions and later escalated to 30 mg once daily. PK sampling was conducted on two consecutive HD days at each dose level. At 20 mg, the trough concentration (C_trough) was 4.02 ng/mL, with peak concentrations (C_max) of 6.09 and 8.75 ng/mL, both lower than reported values in patients with normal renal function. At 30 mg, C_trough increased to 26.3 ng/mL, while C_max values of 48.2 and 55.5 ng/mL were comparable to steady-state exposures in patients with preserved renal function. Notably, no adverse events were observed, and the patient has maintained a partial response for over eight months. This case suggests that afatinib can be administered without major dose modification in HD patients, with PK data indicating minimal impact of dialysis and underscoring the importance of accumulating real-world evidence in this underrepresented population.

The transient receptor potential melastatin (TRPM) family consists of eight members (TRPM1-8), which play a pivotal role in regulating cation fluxes, including K⁺, Na⁺, Ca²⁺, and Mg²⁺. While these channels are integral to various physiological functions, emerging evidence links TRPM dysregulation to the pathogenesis of colorectal cancer (CRC), one of the most prevalent and deadly malignancies worldwide. This review highlights the multifaceted roles of TRPM channels in CRC pathogenesis, their potential as diagnostic and prognostic biomarkers, and their therapeutic applications. Recent research has revealed that certain types of TRPM channels and specific noncoding RNAs within TRPM loci are implicated in critical oncogenic processes such as proliferation, migration, invasion, and epithelial-mesenchymal transition. Specific members, including TRPM4, TRPM7, and TRPM8, exhibit diverse effects in CRC, ranging from modulating metastasis to influencing chemoresistance. Despite their significant role in CRC, conflicting findings on TRPM expression levels in patient tissues highlight the complexity of their involvement and necessitate further research. TRPM modulators show therapeutic potential as anticancer agents. However, challenges in specificity and off-target effects currently limit their clinical application. Advancing our understanding of TRPM function in CRC could hold promise for novel treatment strategies to improve patient outcomes.

Background: Fluoropyrimidines (e.g., 5-fluorouracil, capecitabine) are antineoplastic agents commonly used in the setting of gastrointestinal cancer. Dihydropyridine dehydrogenase (DPD), encoded by the DPYD gene, is the enzyme responsible for up to 85% of 5-FU catabolism into inactive metabolites. Decreased or no function genetic variations in DPYD are rare but increase risk of potentially fatal adverse effects (e.g., myelosuppression) due to decreased metabolism of 5-FU. The extent of which DPD enzyme activity is impaired varies among individual decreased function DPYD variants.

Case presentation: A 75-year-old female was diagnosed with stage III squamous cell carcinoma of the anal canal. She was scheduled to receive therapy consisting of mitomycin C (8 mg/m2) administered over 30 min and continuous infusion 5-FU (4000 mg/m2) over 96 h for 2 cycles with concurrent radiotherapy. Prior to treatment, the patient underwent DPYD genotyping which revealed she was a heterozygous carrier of the decreased function allele, c.2846 A > T. In accordance with Clinical Pharmacogenomics Implementation Consortium (CPIC) guideline recommendations, the dose of 5-FU for cycle 1 was reduced by 50%. Despite the dose reduction, she still experienced mucositis (G3), neutropenia (G3), diarrhea (G2), nausea and vomiting (G2), and dyspnea (G2).

Conclusion: This case report supports the clinical utility of pre-emptive DPYD genotyping to guide initial 5-FU dosing in intermediate metabolizers, and it suggests that all patients still require close monitoring and some (particularly carriers of c.2846 A > T) may require an initial dose reduction greater than the recommended 50% to prevent severe toxicity.

Purpose: The healthcare sector, and especially laboratory diagnostics, is a major contributor to climate change, accounting for an estimated 8 to 10% of France's total greenhouse gas emissions. This study aims to assess plastic waste associated with the validation of a LC-MS/MS method for monitoring tamoxifen and its active metabolite endoxifen in plasma.

Method: A dedicated container was used to collect all plastic consumables employed throughout the method validation. At the end of the study, the total amount of waste was weighed to determine the environmental burden of the process. Method validation was performed according to ICH M10 guidelines.

Results: The method met all EMA/ICH acceptance criteria, showing good linearity, accuracy within ± 15% (± 20% at LLOQ), precision ≤ 15%, and negligible carry-over. Recovery was moderate but reproducible, and analytes were stable for 24 h at room temperature in different matrices. Inter-laboratory comparison confirmed robustness with deviations < 15%. Plastic waste generated during the 39-day validation amounted to 5.7 kg (≈ 146 g/day).

Conclusion: The daily plastic packaging waste generated solely from method validation was approximately 1.5 times higher than the average daily plastic consumption per capita in the European Union. Certain stability studies, especially those assessing the stability of analytes in whole blood or plasma under well-controlled storage conditions, could probably be avoided or reduced.

Purpose: Treatment with the Bruton tyrosine kinase inhibitor ibrutinib carries a significant risk of bleeding; therefore, the risk-benefit assessment regarding withholding ibrutinib pre- and post-surgery should be considered based on the type of surgery being planned. However, there is no optimal rationale regarding ibrutinib withdrawal during the perioperative period. This exploratory study aimed to generate hypotheses regarding perioperative management of ibrutinib therapy by simulating individual pharmacokinetic profiles using a previously reported population pharmacokinetic (PopPK) model.

Methods: Plasma levels of ibrutinib were measured in patients receiving ibrutinib and at high risk of bleeding at Saga University Hospital. Using Phoenix NLME, Bayesian estimation, based on a previously reported PopPK model incorporating actual plasma concentrations measured in individual patients, was employed to simulate perioperative withdrawal scenarios.

Results: Five patients were enrolled. After a withdrawal period of 3-7 days there were no bleeding events in patients that underwent surgery with a low bleeding risk; however, bleeding events occurred in one patient that underwent gastrectomy with moderate or higher bleeding risk. The AUC_0-24 for ibrutinib in a patient also receiving isavuconazole, a moderate CYP3A4 inhibitor, was 1,979 ng*h/mL, a value 2.4-4.8 times higher than that in the patients not receiving isavuconazole.

Conclusion: Perioperative withdrawal of ibrutinib was explored using a previously reported PopPK model in combination with sparse plasma concentration data obtained from patients in real-world clinical settings, including those undergoing surgery. This exploratory study suggests that reliance on plasma concentration data alone might be inadequate for determining the optimal perioperative withdrawal period of ibrutinib.

Background and aims: Trophoblast cell-surface antigen 2 (TROP2) is a cell surface glycoprotein that plays a significant role in the self-renewal, proliferation, invasion and transformation of tumor cells, and is highly expressed in a variety of tumors. At present, TROP2 has become an important target for the research and development of Antibody-drug conjugates (ADCs) in the field of lung cancer. Although sacituzumab govitecan, datopotamab deruxtecan and sacituzumab tirumotecan are all TROP2-targeted ADCs, there are certain differences in their drug structures. These differences may have led to the distinctions in their anti-tumor activity and safety. This study aims to review the similarities and differences among these three drugs, with the expectation of providing some assistance for the selection of clinical medication.

Methods: The key words Sacituzumab govitecan/IMMU-132, Datopotamab deruxtecan/DS-1062a and Sacituzumab tirumotecan/SKB264 retrieved Medline/PubMed, Google Scholar, Web of Science and ScienceDirect databases until September 25, 2025. Articles about pharmacokinetics, pharmacodynamics, drug safety and other aspects were selected to systematically summarize.

Results: These three TROP2 ADCs have many similarities in terms of pharmacokinetics, pharmacodynamics and common treatment-related adverse events. However, there are some differences in the efficacy of combination with immunotherapy drugs and treatment-related adverse events over grade 3.

Conclusion: There are differences in pharmacological effects, efficacy, and incidence of adverse events among sacituzumab govitecan, datopotamab deruxtecan, and sacituzumab tirumotecan. For patients with EGFR-mutated progression after targeted therapy or driver gene negative advanced non-small cell lung cancer, the individualized optimization of TROP2 ADCs treatment can obtain the greatest benefit.

Purpose: The combination of lazertinib and amivantamab has shown superior efficacy over first line osimertinib in EGFR-mutated metastatic non-small cell lung cancer, but is associated with significant toxicity and high costs. Lazertinib exposure varies widely due to genetic polymorphisms of the encoding for GSTM1, with almost 50% of Caucasians having a non-functional enzyme resulting in an approximate twofold higher systemic drug exposure. Despite this, all patients receive a fixed 240 mg once-daily dose irrespective of GSTM1 status, leading to avoidable toxicity without additional clinical benefit. Our purpose was to develop alternative dosing regimens based on GSTM1 status.

Methods: We conducted pharmacokinetic simulations using an existing validated population pharmacokinetic model to evaluate genotype-guided alternative dosing strategies in GSTM1 null individuals.

Results: Two regimens- 160 mg once daily (QD) and 240 mg every other day-were predicted to provide systemic exposures comparable to or exceeding those seen in GSTM1 non-null patients on the standard dose. The 160 mg QD dose resulted in a geometric mean ratio in GSTM1 null patients (GMR) for the trough (Ctrough) and average (Caverage) concentration relative tot he approved dose in GSTM1 non-null patients of 1.43 and 1.19, respectively. The respective GMRs for Ctrough and Caverage associated with 240 mg every-other-day dosing were 0.90 and 0.89, and this dosing regimen could reduce drug expenses up to 50% ($132.860 per year per patient) based on current pricing.

Conclusion: Our findings support the feasibility of individualized lazertinib dosing based on GSTM1 status to reduce toxicity and healthcare costs without compromising effective exposure.

Purpose: Tropomyosin receptor kinase (TRK) inhibitors have emerged as a promising class of targeted therapies for patients with tumors containing neurotrophic tyrosine receptor kinase (NTRK) gene fusions. While not noted in early clinical studies, about one-third of patients can experience diffuse arthralgias, myalgias, and allodynia in the contexts of missed, delayed, or discontinued therapy, resembling withdrawal-like symptoms. Here we report a case of a patient who had daily withdrawal-like symptoms which resolved after starting semaglutide.

Case presentation: A 35-year old male with metastatic/recurrent ETV6-NTRK3 fusion parotid gland cancer was enrolled on a clinical study investigating the efficacy of larotrectinib. He had a rapid complete response to therapy, and has continued on therapy for more than seven years. Early after starting therapy he experienced twice a day diffuse myalgias, arthralgias, and light sensitivity starting 30 to 45 min before his next dose was due. This continued until he was started on semaglutide, a GLP-1 receptor agonist, after which his symptoms completely resolved.

Conclusion: GLP-1 receptor agonists may have a role in improving side effects from larotrectinib. Possible mechanisms for this effect are discussed, with further research needed.