Optimising pharmacotherapy in older cancer patients with polypharmacy

Objective Polypharmacy is frequent among older cancer patients and increases the risk of potential drug-related problems (DRPs). DRPs are associated with adverse drug events, drug-drug interactions and hospitalisations. Since no standardised polypharmacy assessment methods for oncology patients exist, we aimed to develop one that can be integrated into routine care. Methods Based on the Systematic Tool to Reduce Inappropriate Prescribing (STRIP), we developed OncoSTRIP, which includes a polypharmacy anamnesis, a concise geriatric assessment, a polypharmacy analysis taking life expectancy into account and an optimised treatment plan. Patients >= 65 years with >= 5 chronic drugs visiting our outpatient oncology clinic were eligible for the polypharmacy assessment. Results OncoSTRIP was integrated into routine care of our older cancer patients. In 47 of 60 patients (78%), potential DRPs (n = 101) were found. In total, 85 optimisations were recommended, with an acceptance rate of 41%. It was possible to reduce the number of potential DRPs by 41% and the number of patients with at least one potential DRP by 30%. Mean time spent per patient was 71 min. Conclusions Polypharmacy assessment of older cancer patients identifies many pharmacotherapeutic optimisations. With OncoSTRIP, polypharmacy assessments can be integrated into routine care

Cobicistat as a Potential Booster of Ponatinib and Dasatinib Exposure in a CML Patient:A Case Study

The authors present a case of a 57-year-old patient with chronic myeloid leukemia who was treated with ponatinib and subsequently treated with dasatinib. The patient showed a major molecular response; however, the BCR-ABL1 signal increased with low ponatinib and dasatinib trough concentrations. Cobicistat was used as a pharmacokinetic booster to increase ponatinib and dasatinib exposure, as opposed to increasing the dose. However, ponatinib exposure was not sufficiently increased by cobicistat. The peak dasatinib concentration was successfully increased with cobicistat treatment. Dasatinib and cobicistat cotreatment induced a response in BCR-ABL1 PCR signal, was well tolerated, and led to a substantial reduction in drug costs.</p

Representation of older patients in the safety analysis of protein kinase inhibitor registration studies

INTRODUCTION: Older patients (≥65 years old) make up the majority of the cancer population. Older patients seem to experience more adverse events (AEs) from protein kinase inhibitors (PKIs) in clinical practice. Yet they are underrepresented in clinical trials. We aimed to evaluate whether age-related safety differences were described at authorization of PKIs. Representation of older patients in registration studies was also evaluated.MATERIALS AND METHODS: European Public Assessment Reports (EPARs) of PKIs authorized between 2010 and 2015 were evaluated for the description of age-related safety- and pharmacokinetic differences. The International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use (ICH) E7 guideline was applied to EPARs to assess the representation of older patients. Study results were presented descriptively.RESULTS: Eighteen PKIs with 19 EPARs were analyzed. Age-related safety differences were described in 14 out of 19 EPARs, and age-related pharmacokinetic differences in 1 out of 19 EPARs. More than 100 older patients were included in half of the studies. Older patients were not excluded solely by age, although other inclusion and exclusion criteria negatively influenced enrollment of older patients. None of the PKIs met all criteria from the ICH E7 guideline.DISCUSSION: Age-related safety differences are described for most PKIs. Older patients were underrepresented in PKI registration studies. Adequate representation of older patients in clinical trials for PKIs is vital, since they make up most of the cancer population.</p

Validation of an LC-MS/MS assay for rapid and simultaneous quantification of 21 kinase inhibitors in human plasma and serum for therapeutic drug monitoring

Kinase inhibitors have revolutionized cancer treatment in the past 25 years and currently form the cornerstone of many treatments. Due to the increasing evidence for therapeutic drug monitoring (TDM) of kinase inhibitors, the need is growing for new assays to rapidly evaluate kinase inhibitor plasma concentrations. In this study, we developed an LC-MS/MS assay for the rapid and simultaneous quantification of 21 kinase inhibitors. First, a literature search was conducted to ensure that the linear ranges of the analytes were in line with the reported therapeutic windows and/or TDM reference values. Subsequently, the assay was validated according to FDA and EMA guidelines for linearity, selectivity, carry-over, accuracy, precision, dilution integrity, matrix effect, recovery, and stability. The assay was fast, with a short run-time of 2 min per sample. Sample pre-treatment consisted of protein precipitation with methanol enriched with stable isotope-labeled internal standards (SIL-IS), and the mixture was vortexed and centrifuged before sample injection. Separation was achieved using a C18 column (3 μm,50 × 2.1 mm) with a gradient of two mobile phases (ammonium formate buffer pH 3.5 and acetonitrile). Analyte detection was conducted in positive ionization mode using selected reaction monitoring. The assay was accurate and precise in plasma as well as in serum. Extraction recovery ranged between 95.0% and 106.0%, and the matrix effect was 95.7%-105.2%. The stability of the analytes varied at room temperature and in refrigerated conditions. However, all drugs were found to be stable for 7 days in the autosampler. The clinical applicability of the analytical method (486 analyzed samples between 1 July 2022-1 July 2023) as well as external quality control testing results were evaluated. Taken together, the results demonstrate that the analytical method was validated and applicable for routine analyses in clinical practice.</p

Enhanced Enterovirus D68 Replication in Neuroblastoma Cells Is Associated with a Cell Culture-Adaptive Amino Acid Substitution in VP1

Since its emergence in the United States in 2014, enterovirus D68 (EV-D68) has been and is associated with severe respiratory diseases and acute flaccid myelitis. Even though EV-D68 has been shown to replicate in different neuronal cells in vitro, it is currently poorly understood which viral factors contribute to the ability to replicate efficiently in cells of the central nervous system and whether this feature is a clade-specific feature. Here, we determined the replication kinetics of clinical EV-D68 isolates from (sub)clades A, B1, B2, B3, and D1 in human neuroblastoma cells (SK-N-SH). Subsequently, we compared sequences to identify viral factors associated with increased viral replication. All clinical isolates replicated in SK-N-SH cells, although there was a large difference in efficiency. Efficient replication of clinical isolates was associated with an amino acid substitution at position 271 of VP1 (E271K), which was acquired during virus propagation in vitro. Recognition of heparan sulfate in addition to sialic acids was associated with increased attachment, infection, and replication. Removal of heparan sulfate resulted in a decrease in attachment, internalization, and replication of viruses with E271K. Taken together, our study suggests that the replication kinetics of EV-D68 isolates in SKN-SH cells is not a clade-specific feature. However, recognition of heparan sulfate as an additional receptor had a large effect on phenotypic characteristics in vitro. These observations emphasize the need to compare sequences from virus stocks with clinical isolates in order to retrieve phenotypic characteristics from original virus isolates. IMPORTANCE Enterovirus D68 (EV-D68) causes mild to severe respiratory disease and is associated with acute flaccid myelitis since 2014. Currently, the understanding of the ability of EV-D68 to replicate in the central nervous system (CNS), and whether it is associated with a specific clade of EV-D68 viruses or specific viral factors, is lacking. Comparing different EV-D68 clad

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer

Background: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. Objective: We aimed to develop alternative dosing regimens to reduce drug expenses. Methods: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. Results: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. Conclusions: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.</p

PET imaging with zirconium-89 labeled antibodies to guid cancer therapy

Currently, chemotherapeutic drugs aiming directly or indirectly at DNA damage still most often form the cornerstone of systemic cancer treatment. Meanwhile, molecular targeted drugs of a new generation are increasingly used alone or combined with chemotherapy. Tumor biology research continues to identify new molecular targets involved in uncontrolled tumor growth, invasion and metastasis. For many tumor types, multiple molecular phenotypes have been identified and the next step is translating this rapidly expanding knowledge in tumor biology into new targeted systemic treatments. Tumor growth often depends on a few dysregulated growth signaling pathways and identifdng this 'tumor Achilles heel' might reveal the most relevant target for systemic therapy. Among the numerous drugs that target relevant pathways are drugs targeting human epidermal growth factor receptor-2 (HER2), the pro-angiogenic vascular endothelial growth factor (VEGF), the molecular chaperone heat shock protein-90 (HSP90) and the pro-metastatic transforming growth factor f3 (TGF-r3). It is of interest to identify the best drug candidate(s) in an earlly phase of development, to identify the patient (sub)populations most likely to benefit and to early predict response. Therefore the development of predictive biomarkers of antitumor efficacy is of releyance. In addition, there is a need for techniques that can rapidly and precisely elucidate the pharmacokinetic and pharmacodynamic profile of new agents, Molecular imaging can potentially fulfill all these tasks and is therefore explored for its use in translating cancer science, and in the discovery, development, evaluation and implementation of targeted anticancer agents. Molecular imaging can be performed in c1 whole body and repetitive setting, providing information about (changes in) all organs and tumor lesions, Techniques used for molecular imaging include radionuclide imaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI) and optical imaging. Of these techniques, PET currently is the most suitable for whole body imaging and has the best quantification properties. This thesis aimed at evaluating the role of molecular imaging with zirconium-89 ("'Zr) labeled antibodies in the guidance of targeted anticancer agents, with a focus on breast cancer.