Monoclonal antibody biosimilars for cancer treatment.

Monoclonal antibodies are important cancer medicines. The European Medicines Agency (EMA) approved 48 and the Food and Drug Administration (FDA) 56 anticancer monoclonal antibody-based therapies. Their high prices burden healthcare systems and hamper global drug access. Biosimilars could retain costs and expand the availability of monoclonal antibodies. In Europe, five rituximab biosimilars, six trastuzumab biosimilars, and eight bevacizumab biosimilars are available as anti-cancer drugs. To gain insight into the biosimilar landscape for cancer treatment, we performed a literature search and analysis. In this review, we summarize cancer monoclonal antibodies' properties crucial for the desired pharmacology and point out sources of variability. The analytical assessment of all EMA-approved bevacizumab biosimilars is highlighted to illustrate this variability. The global landscape of investigational and approved biosimilars is mapped, and the challenges for access to cancer biosimilars are identified.

Infliximab in paediatric inflammatory bowel disease: External evaluation of population pharmacokinetic models.

AIMS: Use of infliximab (IFX) has improved outcomes in children with inflammatory bowel disease (IBD). However, a proportion of patients does not respond to IFX or loses response over time. Population pharmacokinetic (PopPK) modelling is a promising approach for IFX dose optimization, but with the increasing number of PopPK models in literature, model evaluation is essential. The aims of this study are: (i) to validate the predictive performance of existing IFX PopPK models using a cohort of children with IBD; and (ii) to perform a Bayesian estimation of the most suitable model to predict the next IFX concentrations. METHODS: PubMed was searched for IFX PopPK models in children. Selected models were rebuilt and analysed using R. Model performance was assessed through goodness-of-fit-plots, residuals against time, prediction error and prediction-corrected visual predictive checks. The validation cohort consisted of 73 children with IBD who were treated with IFX in our centre between 2017 and 2023 (340 IFX measurements). RESULTS: We identified 9 PopPK models. Model bias for individual predicted values ranged from -9.29% to 8.01% compared to bias for population predicted values. The model by Vande Casteele et al. demonstrated superior performance (individual predicted bias 2.13, population predicted bias -6.11); upon Bayesian estimation, it predicted induction trough levels with median error of 12.95% but had a median error of -69% predicting maintenance concentrations. CONCLUSION: The model by Vande Casteele et al. displayed superior performance in initial evaluations but had a high error in estimating next IFX levels and can only be used in practice to predict induction levels.

Clinical Validation of a Capillary Blood Home-Based Self-Sampling Technique for Monitoring of Infliximab, Vedolizumab, and C-Reactive Protein Concentrations in Patients With Inflammatory Bowel Disease.

BACKGROUND: Therapeutic drug monitoring provides important guidance for treatment of patients with inflammatory bowel disease (IBD) and could help to early identify treatment failure. This study aimed to validate a finger prick-based capillary blood sampling technique to measure biological trough levels and C-reactive protein (CRP) and evaluate patient performance and -support. METHODS: In this prospective cohort study, patients with IBD receiving infliximab (IFX) or vedolizumab (VEDO) therapy performed finger prick-based capillary blood sampling at home. Additionally, blood was collected through routinely performed in-hospital venepuncture prior to biological infusion. IFX, VEDO, and CRP concentrations were measured by enzyme-linked immunosorbent assay. The concordance between methods was statistically evaluated and a survey was conducted to assess practicality and patient support. RESULTS: In total, 81 patients (46 IFX, 35 VEDO) were enrolled. Mean differences between both methods were 0.42 (95% confidence interval, -1.74 to 2.58) µg/mL for IFX and 0.72 (95% confidence interval, -5.50 to 6.94) µg/mL for VEDO. Passing-Bablok regressions demonstrated no evidence for systematic or proportional biases. Venous and capillary IFX (ρ = 0.96, P < .001) and VEDO (ρ = 0.97, P < .001) levels strongly correlated and showed high intermethod agreement (Cohen's kappa: IFX = 0.82; VEDO = 0.94). Similarly, venous and capillary CRP levels were strongly correlated (ρ = 0.99, P < .001). Most patients (>95%) were able to successfully perform the self-sampling at home without prior instructions. CONCLUSIONS: This study clinically validated a finger prick-based capillary blood self-sampling technique allowing concomitant home monitoring of biological levels and CRP for patients with IBD, who reported substantial support, tolerability, and practicality.

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.

Capsules with Ileocolonic-Targeted Release of Vitamin B2, B3, and C (ColoVit) Intended for Optimization of Gut Health: Development and Validation of the Production Process.

The ileocolonic-targeted delivery of vitamins can establish beneficial alterations in gut microbial composition. Here, we describe the development of capsules containing riboflavin, nicotinic acid, and ascorbic acid covered with a pH-sensitive coating (ColoVit) to establish site-specific release in the ileocolon. Ingredient properties (particle size distribution, morphology) relevant for formulation and product quality were determined. Capsule content and the in vitro release behaviour were determined using a HPLC-method. Uncoated and coated validation batches were produced. Release characteristics were evaluated using a gastro-intestinal simulation system. All capsules met the required specifications. The contents of the ingredients were in the 90.0-120.0% range, and uniformity requirements were met. In the dissolution test a lag-time in drug release of 277-283 min was found, which meets requirements for ileocolonic release. The release itself is immediate as shown by dissolution of the vitamins of more than 75% in 1 h. The production process of the ColoVit formulation was validated and reproducible, it was shown that the vitamin blend was stable during the production process and in the finished coated product. The ColoVit is intended as an innovative treatment approach for beneficial microbiome modulation and optimization of gut health.

Pharmacokinetic Boosting of Kinase Inhibitors.

(1) Introduction: Pharmacokinetic boosting of kinase inhibitors can be a strategy to enhance drug exposure and to reduce dose and associated treatment costs. Most kinase inhibitors are predominantly metabolized by CYP3A4, enabling boosting using CYP3A4 inhibition. Kinase inhibitors with food enhanced absorption can be boosted using food optimized intake schedules. The aim of this narrative review is to provide answers to the following questions: Which different boosting strategies can be useful in boosting kinase inhibitors? Which kinase inhibitors are potential candidates for either CYP3A4 or food boosting? Which clinical studies on CYP3A4 or food boosting have been published or are ongoing? (2) Methods: PubMed was searched for boosting studies of kinase inhibitors. (3) Results/Discussion: This review describes 13 studies on exposure boosting of kinase inhibitors. Boosting strategies included cobicistat, ritonavir, itraconazole, ketoconazole, posaconazole, grapefruit juice and food. Clinical trial design for conducting pharmacokinetic boosting trials and risk management is discussed. (4) Conclusion: Pharmacokinetic boosting of kinase inhibitors is a promising, rapidly evolving and already partly proven strategy to increase drug exposure and to potentially reduce treatment costs. Therapeutic drug monitoring can be of added value in guiding boosted regimens.

Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial.

OBJECTIVES: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis. METHODS: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. RESULTS: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001). CONCLUSIONS: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT00893555.

Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients.

INTRODUCTION: The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease. METHODS: Open-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation. RESULTS: A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39-0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9-28) in the standard arm versus 9 days (IQR 5-14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98; p = 0.042). CONCLUSIONS: This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone. TRIAL REGISTRATION: https://www.trialregister.nl/trial/8504.

Population Pharmacokinetic Modelling and Limited Sampling Strategies for Therapeutic Drug Monitoring of Pyrazinamide in Patients with Tuberculosis.

Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration-time curve (AUC24) to MIC. The objective of this study was to develop and validate a limited sampling strategy (LSS) based on a population pharmacokinetic (popPK) model to predict AUC24. A popPK model was developed using an iterative two-stage Bayesian procedure and was externally validated. Using data from 20 treatment-naive adult tuberculosis (TB) patients, a one compartment model with transit absorption and first-order elimination best described pyrazinamide pharmacokinetics and fed state was the only significant covariate for absorption rate constant (ka). External validation, using data from 26 TB patients, showed that the popPK model predicted AUC24 with a slight underestimation of 2.1%. LSS were calculated using Monte Carlo simulation (n = 10,000). External validation showed LSS with time points 0 h, 2 h, and 6 h performed best with RMSE of 9.90% and bias of 0.06%. Food slowed absorption of pyrazinamide, but did not affect bioavailability, which may be advantageous in case of nausea or vomiting in which food can be used to diminish these effects. In this study, we successfully developed and validated a popPK model and LSS, using 0 h, 2 h, and 6 h postdose samples, that could be used to perform therapeutic drug monitoring (TDM) of pyrazinamide in TB patients.

Population pharmacokinetic model and limited sampling strategy for clozapine using plasma and dried blood spot samples.

Background: To improve efficacy, therapeutic drug monitoring is often used in clozapine therapy. Trough level monitoring is regular, but trough levels provide limited information about the pharmacokinetics of clozapine and exposure in time. The area under the concentration time curve (AUC) is generally valued as better marker of drug exposure in time but calculating AUC needs multiple sampling. An alternative approach is a limited sampling scheme in combination with a population pharmacokinetic model meant for Bayesian forecasting. Furthermore, multiple venepunctions can be a burden for the patient, whereas collecting samples by means of dried blood spot (DBS) sampling can facilitate AUC-monitoring, making it more patient friendly. Objective: Development of a population pharmacokinetic model and limited sampling strategy for estimating AUC0-12h (a twice-daily dosage regimen) and AUC0-24h (a once-daily dosage regimen) of clozapine, using a combination of results from venepunctions and DBS sampling. Method: From 15 schizophrenia patients, plasma and DBS samples were obtained before administration and 2, 4, 6, and 8 h after clozapine intake. MwPharm® pharmacokinetic software was used to parameterize a population pharmacokinetic model and calculate limited sampling schemes. Results: A three-point sampling strategy with samples at 2, 6, and 8 h after clozapine intake gave the best estimation of the clozapine AUC0-12h and at 4, 10, and 11 h for the AUC0-24h. For clinical practice, however, a two-point sampling strategy with sampling points at 2 and 6 h was sufficient to estimate AUC0-12h and at 4 and 11 h for AUC0-24h. Conclusion: A pharmacokinetic model with a two-time point limited sampling strategy meant for Bayesian forecasting using DBS sampling gives a better prediction of the clozapine exposure in time, expressed as AUC, compared to trough level monitoring. This limited sampling strategy might therefore provide a more accurate prediction of effectiveness and occurrence of side effects compared to trough level monitoring. The use of DBS samples also makes the collection of clozapine samples easier and wider applicable.

Association between TNF Receptors and KIM-1 with Kidney Outcomes in Early-Stage Diabetic Kidney Disease.

BACKGROUND AND OBJECTIVES: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. TNF receptor-1, TNF receptor-2, and kidney injury marker-1 (KIM-1) are known to be associated with kidney disease progression in patients with micro- or macroalbuminuria. We assessed the value of TNF receptor-1, TNF receptor-2, and KIM-1 as prognostic biomarkers for CKD progression in patients with type 2 diabetes and normoalbuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: TNF receptor-1, TNF receptor-2, and KIM-1 were measured using immunoassays in plasma samples from patients with type 2 diabetes at high cardiovascular risk participating in the Canagliflozin Cardiovascular Assessment Study trial. We used multivariable adjusted Cox proportional hazards analyses to estimate hazard ratios per doubling of each biomarker for the kidney outcome, stratified the population by the fourth quartile of each biomarker distribution, and assessed the number of events and event rates. RESULTS: In patients with normoalbuminuria (n=2553), 51 kidney outcomes were recorded during a median follow-up of 6.1 (interquartile range, 5.8-6.4) years (event rate, 3.5; 95% confidence interval, 2.6 to 4.6 per 1000 patient-years). Each doubling of baseline TNF receptor-1 (hazard ratio, 4.2; 95% confidence interval, 1.8 to 9.6) and TNF receptor-2 (hazard ratio, 2.3; 95% confidence interval, 1.5 to 3.6) was associated with a higher risk for the kidney outcome. Baseline KIM-1, urinary albumin-creatinine ratio, and eGFR were not associated with kidney outcomes. The event rates in the highest quartile of TNF receptor-1 (≥2992 ng/ml) and TNF receptor-2 (≥11,394 ng/ml) were 5.6 and 7.0 events per 1000 patient-years, respectively, compared with 2.8 and 2.3, respectively, in the lower three quartiles. CONCLUSIONS: TNF receptor-1 and TNF receptor-2 are associated with kidney outcomes in patients with type 2 diabetes and normoalbuminuria. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629.

Improving the aseptic transfer procedures in hospital pharmacies part C: evaluation and redesign of the transfer process.

OBJECTIVES: To transfer sterile medical devices (SMD), infusion bags (IB), ampoules (A), injection vials (V) and infusion bottles (B) into a laminar airflow cabinet (LAF) or safety cabinet (SC) with a surface bioburden as low as possible. METHODS: Surface bioburden of the outer layer of SMD, IB, A, V and B was determined by contact plates. Surface bioburden determination of critical spots on A, V and B (ampoule necks and stoppers) was determined by high-recovery swabs and contact plates. Particle emission from white cardboard boxes was determined by a particle counter. RESULTS: The chances of a contaminated outer layer of SMD is negligible as long as they stay in their original boxes. The outer layer of double-packed IB can contain a considerable number of micro-organisms. As found in previous studies, the surface bioburden of A, V and B is low as long as they stay in their original cardboard boxes. Particle emission from white boxes is low. The necessity of a final disinfection step inside LAF/SC of critical sspots of A, V and B cannot be proven. SmallSMD, ampoules and injection vials can be transferred into the background areain their original white boxes. Other materials have to be unpacked in front ofthe lock while the operator wear disposable gloves. Disinfection of the outerlayer of IB, before transfer trough the lock, is advised. Tohave materials with a low chance of contamination in LAF/SC, transfer bypresentation for SMD and IB and using a sterile tray for disinfected materialsis an effective procedure. Wiping of ampoule necks and stoppers inside LAF/SC isadvised based on risk assessment.Small SMD, ampoules and injection vials can be transferred into the background areain their original white boxes. Other materials have to be unpacked in front ofthe lock while the operator wear disposable gloves. Disinfection of the outerlayer of IB, before transfer trough the lock, is advised. CONCLUSION: When SMD, ampoules, injection vials and infusion bottles stay in their original boxes as long as possible, the aseptic transfer and the disinfection procedure can be maintained effectively and efficiently.

Safe use of radiopharmaceuticals in patients with chronic kidney disease: a systematic review.

BACKGROUND: Patients with chronic kidney disease (CKD) may need to have their radiopharmaceutical dosage adjusted to prevent adverse effects and poor outcomes, but there are few recommendations on radiopharmaceutical dosing for this group of patients. The aim of this study is to provide an overview of the available information on radiopharmaceutical dose recommendations for patients with CKD. METHODS: We performed a systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We conducted a literature search in the MEDLINE (PubMed) and Embase databases and screened potentially relevant studies using inclusion and exclusion criteria. We independently assessed the included observational studies' methodologies and extracted relevant data. RESULTS: Of the 5795 studies first identified, 34 were included in this systematic review. These studies described three radiopharmaceuticals: [131I]sodium iodine, [18F]fludeoxyglucose, and [131I]iobenguane. Twenty-nine studies (85.3%) reported data on patients with CKD stage 5, while only three studies mentioned CKD patients in other stages (8.8%). CONCLUSION: We found no consistent recommendations for radiopharmaceutical dosing in patients with CKD. Although some studies do mention dosing difficulties in patients with CKD, information is available for only a few radiopharmaceuticals, and recommendations are sometimes contradictory. Further research on radiopharmaceutical dosing in patients with CKD is needed to determine whether these patients require specific dosing, especially for therapeutic radiopharmaceuticals where a non-optimised dose may lead to an increased risk of toxicity for non-targeted organs. Including patients with CKD in studies and providing specific information about dosing in these patients should be a priority for the radiopharmaceutical community.

Improving the aseptic transfer procedures in hospital pharmacies. Part B: evaluation of disinfection methods for materials with a non-sterile surface.

OBJECTIVES: To improve the disinfection methods for materials with a non-sterile surface to be used in aseptic handling. METHODS: The surface bioburden on ampoules (A) and injection vials (IV) is determined by contact plates and total immersion. The occurrence of spore-forming bacteria is determined by strain colouring and matrix-assisted laser desorption ionisation-time of flight mass spectrometry. The disinfection procedures of non-sterile materials in 10 hospital pharmacies are judged by observing. RESULTS: After wiping according to local disinfection methods, the mean surface bioburden determined by contact plates in 10 hospital pharmacies is 0.36 (plastic A), 0.50 (glass A) and 0.29 colony-forming unit (cfu) (IV). The observers found great differences in accuracy of wiping and degree of wetting the sterile gauzes.After improved wiping with commercially available alcohol impregnated sterile wipes and a two-towel technique (one-step TT disinfection), the mean surface bioburden determined by contact plates is 0.03 (plastic A), 0.2 (glass A) and 0.13 cfu (IV). Further improvement can be reached by submerging A and IV in ethanol 70% followed by improved wiping (two-step TT disinfection), but still micro-organisms will remain (mean surface bioburden determined by total immersion is 0 (plastic A) and 0.3 cfu (IV); glass A not determined). Two-step TT disinfection is more labour intensive. Spilling of alcohol is another disadvantage. However, we presume one-step TT disinfection is effective enough in daily practice. Routine surface bioburden determinations have to prove this.The effectiveness of the combination of spray and wipe is not examined because we observed a quick disappearance of alcohols from vertical as well as horizontal surfaces, which shortens the contact time to far below the advised 2 min.Spore-forming bacteria disappear as quickly as other micro-organisms during disinfection by alcohols. CONCLUSION: Local disinfection procedures can be improved. Complete removal of micro-organisms from materials with a non-sterile surface, even after two-step TT disinfection, is impossible. Routine surface bioburden determinations have to prove if one-step TT disinfection is effective enough.

Improving the aseptic transfer procedures in hospital pharmacies part A: methods for the determination of the surface bioburden on ampoules and vials.

OBJECTIVES: To develop methods for surface bioburden determination of ampoules and vials to be used in the validation of the disinfection procedures and in routine monitoring of ampoules and vials. METHODS: The surface bioburdens of ampoules and vials are determined before and after disinfection by contact plates and total immersion. RESULTS: The mean surface bioburdens of non-disinfected ampoules and vials taken straight from the original boxes are 2.4 and 5.01 cfu (total immersion; n = 20), and 0.97 and 0.94 cfu (contact plates; n = 60). The mean surface bioburdens of ampules and vials after disinfection by wiping are 1.15 and 7.50 cfu (total immersion; n = 20), and 0.12 and 0.10 cfu (contact plates; n = 60). The high number of cfu on vials (total immersion) indicate hidden cfu around the neck not removable by wiping and not detected by contact plates. Total immersion needs special laboratory facilities and is expensive (about €50 a sample). Therefore, it is less appropriate for use in routine monitoring. However, because of the high recovery, it is the method of choice for the validation of the disinfection procedure. Surface bioburden determination by contact plates is relatively simple. Non-flat surfaces cannot be reached, but the recovery from the touched flat part of the surface is high (around 50%). The recovery from swabs is low (around 10%). Another disadvantage of swabs is the laboratory work after sampling. We therefore advise contact plates for routine monitoring. To get a reliable value of the mean surface bioburden at least 30 samples need to be examined. CONCLUSION: Total immersion is the method of choice for the determination of the effectiveness of a disinfection procedure for ampoules and vials. Contact plate is the method of choice for routine monitoring of the surfaces of ampoules and vials.

First-in-Human Phase I Clinical Trial of an SFV-Based RNA Replicon Cancer Vaccine against HPV-Induced Cancers.

A first-in-human phase I trial of Vvax001, an alphavirus-based therapeutic cancer vaccine against human papillomavirus (HPV)-induced cancers was performed assessing immunological activity, safety, and tolerability. Vvax001 consists of replication-incompetent Semliki Forest virus replicon particles encoding HPV16-derived antigens E6 and E7. Twelve participants with a history of cervical intraepithelial neoplasia were included. Four cohorts of three participants were treated per dose level, ranging from 5 × 105 to 2.5 × 108 infectious particles per immunization. The participants received three immunizations with a 3-week interval. For immune monitoring, blood was drawn before immunization and 1 week after the second and third immunization. Immunization with Vvax001 was safe and well tolerated, with only mild injection site reactions, and resulted in both CD4+ and CD8+ T cell responses against E6 and E7 antigens. Even the lowest dose of 5 × 105 infectious particles elicited E6/E7-specific interferon (IFN)-γ responses in all three participants in this cohort. Overall, immunization resulted in positive vaccine-induced immune responses in 12 of 12 participants in one or more assays performed. In conclusion, Vvax001 was safe and induced immune responses in all participants. These data strongly support further clinical evaluation of Vvax001 as a therapeutic vaccine in patients with HPV-related malignancies.

Patient-Reported Adverse Events of Radiopharmaceuticals: A Prospective Study of 1002 Patients.

INTRODUCTION: Adverse events of radiopharmaceuticals may be underreported or remain undetected. Patients can provide information about these adverse events to enable healthcare professionals to detect, understand, and manage them more efficiently. OBJECTIVE: In this study, we aimed to (a) determine the type, causality, and frequency of patient-reported adverse events of radiopharmaceuticals and to (b) assess the onset, outcome, and follow-up of these adverse events from the patient's perspective. METHODS: We performed a prospective cohort study of 1002 patients who underwent a nuclear medicine examination. Using a validated questionnaire, we collected patient-reported information on adverse events that occurred immediately after administration of the radiopharmaceutical as well as those that occurred later. Adverse events were analysed, coded and assessed for causality by two independent researchers. RESULTS: A total of 187 (18.7%) patients reported 379 adverse events. Most patient-reported adverse events of radiopharmaceuticals belonged to the 'general disorder and administration site conditions' (42.0%) and 'nervous system disorders' (16.9%) system organ classes. Of the patient-reported adverse events, 43.0% were possibly or probably causally related to radiopharmaceuticals. We found the frequency of patient-reported adverse drug reactions to diagnostic radiopharmaceuticals to be 2.8%. No important medical events were related to the administrations of diagnostic radiopharmaceuticals. Most adverse events (80.0%) occurred shortly after administration of the radiopharmaceutical and were resolved within a few hours. Some events (20.0%) emerged after patients had left the nuclear medicine department, took longer to resolve, and sometimes prompted the patient to consult a healthcare professional. CONCLUSION: Adverse reactions to diagnostic radiopharmaceuticals can occur, and the frequency reported by patients was found to be 2.8%, which is higher than reported in the existing literature. We hope that the results of this study increase awareness of these adverse reactions among patients and healthcare professionals.

Practical Barriers and Facilitators Experienced by Patients, Pharmacists and Physicians to the Implementation of Pharmacogenomic Screening in Dutch Outpatient Hospital Care-An Explorative Pilot Study.

Pharmacogenomics (PGx) can provide optimized treatment to individual patients while potentially reducing healthcare costs. However, widespread implementation remains absent. We performed a pilot study of PGx screening in Dutch outpatient hospital care to identify the barriers and facilitators to implementation experienced by patients (n = 165), pharmacists (n = 58) and physicians (n = 21). Our results indeed suggest that the current practical experience of healthcare practitioners with PGx is limited, that proper education is necessary, that patients want to know the exact implications of the results, that healthcare practitioners heavily rely on their computer systems, that healthcare practitioners encounter practical problems in the systems used, and a new barrier was identified, namely that there is an unclear allocation of responsibilities between healthcare practitioners about who should discuss PGx with patients and apply PGx results in healthcare. We observed a positive attitude toward PGx among all the stakeholders in our study, and among patients, this was independent of the occurrence of drug-gene interactions during their treatment. Facilitators included the availability of and adherence to Dutch Pharmacogenetics Working Group guidelines. While clinical decision support (CDS) is available and valued in our medical center, the lack of availability of CDS may be an important barrier within Dutch healthcare in general.

Discontinuation of metformin to prevent metformin-induced high colonic FDG uptake: is 48 h sufficient?

OBJECTIVE: In this retrospective, single-center observational study, we investigated whether discontinuing metformin for at least 48 h prevents metformin-induced [18F]fluorodeoxyglucose (FDG) uptake in all segments of the colon. METHODS: Patients with type 2 diabetes who were using metformin before undergoing an FDG PET/CT scan were included. Two groups were created: patients who discontinued metformin for less than 48 h (< 48 h group) and patients who discontinued metformin for between 48 and 72 h (≥ 48 h group). A control group comprised non-diabetic patients who were not using metformin before undergoing an FDG PET/CT. We visually scored the uptake of FDG in four segments of the colon-the ascendens, transversum, descendens, and rectosigmoid-using a four-point scale (1-4) and considered scores of 3 or 4 to be clinically significant. RESULTS: Colonic FDG uptake in the ≥ 48 h group (n = 23) was higher than uptake in the control group (n = 96) in the colon descendens [odds ratio (OR) 14.0; 95% confidence interval (CI) 4.8-40.9; p value: 0.001] and rectosigmoid (OR 11.3; 95% CI 4.0-31.9; p value: 0.001), and there was no difference in the colon ascendens and transversum. Colonic FDG uptake in the < 48 h group (n = 25) was higher than uptake in the ≥ 48 h group (n = 23) in the colon transversum (OR 4.8; 95% CI 1.3-18.5; p value: 0.022) and rectosigmoid (p value: 0.023), and there was no difference in the colon ascendens and descendens. CONCLUSIONS: Discontinuing metformin for 48 h before undergoing an FDG PET/CT still gives a high uptake in the distal parts of the colon when compared with non-diabetic patients who are not using metformin. Discontinuing metformin for 48 h seems to be useful for scanning the more proximal segments of the colon.