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Item does not contain fulltext PURPOSE: Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing. METHODS: A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated. RESULTS: A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436). CONCLUSION: We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing. CLINICAL TRIAL NUMBER: Clinicaltrials.gov identifier: NCT03655821. 01 januari 2023

A liquid chromatography–tandem mass spectrometry method was developed and validated to quantify the small-molecule inhibitors (SMIs) brigatinib, lorlatinib, pralsetinib and selpercatinib, which are used in patients with oncogenic-driven non-small cell lung cancer. Chromatographic separation was performed on a HyPURITY® C 18 analytical column with a gradient elution using ammonium acetate in water and in methanol, both acidified with formic acid 0,1%. Detection and quantification were performed using a triple quad mass spectrometer with an electrospray ionization interface. The assay was validated over a linear range of 50–2,500 ng/ml for brigatinib, 25–1,000 ng/ml for lorlatinib, 100–10,000 ng/ml for pralsetinib and 50–5,000 ng/ml for selpercatinib. All four SMIs were stable for at least 7 days under cool conditions (2–8°C), and at least 24 h at room temperature (15–25°C) in K2-EDTA plasma. Under freezing conditions (−20°C), all SMIs were stable for at least 30 days, except for the lowest quality control (QC LOW) of pralsetinib. The QC LOW of pralsetinib was stable for at least 7 days at −20°C. This method provides an efficient and simple way to quantify four SMIs with a single assay in clinical practice.

Introduction: Exposure to osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treatment of non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation, can be substantially below average. We evaluated whether plasma levels could be boosted by co-administration of cobicistat, a strong Cytochrome P450 3A-inhibitor. Methods: This was a pharmacokinetic, proof-of-concept clinical trial (the OSIBOOST trial, NCT03858491). NSCLC-patients with osimertinib were eligible if their steady state osimertinib plasma trough concentration was low (≤195 ng/mL). On day 1, the area under the plasma curve (AUC0-24,ss) of osimertinib and its metabolite (AZ5104) was calculated using a limited sampling strategy (four samples). Cobicistat co-treatment (150 mg, once daily) was started on day 2. Between day 22–26, a second AUC was determined. Cobicistat dose could be escalated if the osimertinib trough concentration was still ≤ 195 ng/mL, in the absence of toxicity. Primary endpoint was the increase in osimertinib exposure, secondary endpoint was toxicity. Cobicistat could be continued during the expanded access phase, with follow-up (2–4 months) of the boosting effect. Results: The mean baseline osimertinib trough concentration for the eleven enrolled patients was 154 ng/mL. In all patients, cobicistat addition led to an increase in osimertinib exposure. Mean increase in total AUC0-24ss (AUC osimertinib + AUC AZ5104) was 60%, (range 19%–192%). The boosting effect was consistent over time. No grade ≥ 2 toxicity was observed. Conclusion: Pharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable.

Contains fulltext : 292912.pdf (Publisher’s version ) (Open Access) 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.

The effect of intermittent hemodialysis (IHD) on nivolumab serum concentrations in patients with severe renal impairment is largely unknown. Here, we present a 79-year-old patient with metastatic melanoma and end-stage renal disease on IHD three times a week, treated with 480 mg nivolumab every 4 weeks. A serum trough concentration of nivolumab was determined before the start of the third cycle, and two samples were taken immediately before and after a hemodialysis session during this cycle. All nivolumab serum concentrations were within a similar range as those previously measured among patients without renal insufficiency, after a comparable duration of nivolumab treatment. Therefore, we conclude that IHD does not influence nivolumab exposure. Furthermore, nivolumab treatment was continued without complications and appears to be well tolerated for patients on IHD.

Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing.A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated.A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436).We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing.Clinicaltrials.gov identifier: NCT03655821.

ObjectivesLiposomal amphotericin B is widely used to treat life-threatening invasive fungal infections and has replaced conventional amphotericin B deoxycholate due to its more favourable toxicity profile. Despite the fact that liposomal amphotericin B has been licensed for several decades, there is still a paucity of clinical pharmacokinetic data. An assay for the quantification of amphotericin B is necessary to allow the study of its pharmacokinetics.MethodsA UPLC-photodiode array (PDA) analytical method was developed and validated (linearity, accuracy, precision, dilution integrity, carry-over, selectivity and stability) in accordance with EMA requirements.ResultsThe analytical method was validated over a concentration range of 0.5–50.0 mg/L. Accuracy ranged from 97.6% to 112.1% and within-day repeatability and between-day reproducibility from 1.0% to 6.6% and from 0.4% to 4.6%, respectively, dependent on the concentration. Originally, the goal was to develop an analytical method to separate the liposomal and free amphotericin B fractions, but this was not achieved. Difficulties and bottlenecks encountered are presented.ConclusionsA UPLC-PDA analytical method was developed to quantify total amphotericin B in plasma after the use of liposomal amphotericin B.

Contains fulltext : 249097.pdf (Publisher’s version ) (Open Access) Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.

A liquid chromatography-tandem mass spectrometry method was developed and validated to quantify alectinib, crizotinib, erlotinib and gefitinib. This assay can be combined with our method for osimertinib, allowing quantification of the most used ALK- and EGFR-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer with a single-assay setup. Chromatographic separation was performed on a HyPurity (R) C-18 analytical column using an elution gradient of ammonium acetate in water and in methanol, both acidified with formic acid 0.1%. Detection and quantification were performed using a triple quad mass spectrometer with an electrospray ionization interface. This method led to robust results, as the selectivity, carryover, precision and accuracy met all pre-specified requirements. The assay was validated over a linear range of 100-2,000 ng/ml for alectinib and erlotinib and 50-1,000 ng/ml for crizotinib and gefitinib. Alectinib, crizotinib, erlotinib and gefitinib were all stable for at least 4 h in whole blood (at room temperature and at 4 degrees C) and for at least 1 month in EDTA plasma when stored at -80 degrees C, while osimertinib proved to be unstable at room temperature. Although high-performance liquid chromatography was used, the run time was short and comparable with other methods using ultra-high performance liquid chromatography.

Purpose Immediate and proper implementation of a new and more potent therapy is important to ensure that the patient achieves the best possible outcome. This study aimed to examine whether the real-world overall survival (OS) has improved in patients with human epidermal growth factor receptor 2-positive (HER2 +) advanced breast cancer (ABC) since the market release of pertuzumab and T-DM1. Furthermore, we aimed to assess the implementation and survival rates per hormone receptor (HR) subtype. Patients and methods We included 493 systemically treated patients consecutively diagnosed with HER2 + ABC in 2008–2017 from the SOutheast Netherlands Advanced BREast cancer (SONABRE) Registry. Median OS was obtained using the Kaplan–Meier method and differences between periods (2008–2012 versus 2013–2017) were tested using multivariable Cox proportional hazards regression modeling. The 3-year implementation rates were estimated for any HER2-targeted therapy, pertuzumab, and T-DM1 by using the competing risk method and calculated from the date of diagnosis of ABC to start of HER2-targeted therapy of interest. Results The median OS in 2008–2012 versus 2013–2017 was 28.3 versus 39.7 months in all patients (adjusted hazard ratio (adjHR) 0.85, 95%CI 0.66–1.08), 29.9 versus 36.3 months in patients with HR + /HER2 + disease (adjHR 0.97, 95%CI 0.72–1.32), and 22.7 versus 40.9 months in patients with HR-/HER2 + disease (adjHR 0.59, 95%CI 0.38–0.92). Any HER2-targeted therapy was used in 79% of patients in 2008–2012 and in 84% in 2013–2017. The use of pertuzumab and T-DM1 in 2013–2017 was 48% and 29%, respectively. For patients diagnosed with HR + /HER2 + and HR-/HER2 + disease, implementation rates in 2013–2017 were , respectively, 77% and 99% for any HER2-targeted therapy, 38% and 69% for pertuzumab, and 24% and 40% for T-DM1. Conclusion The survival of patients with HER2 + ABC improved since the introduction of pertuzumab and T-DM1. There is room for improvement in implementation of these HER2-targeted therapies, especially in patients with HR + /HER2 + disease.

Purpose: We aimed to assess the implementation and effectiveness of exemestane plus everolimus treatment per hospital type in real-life, shortly after approval of everolimus.Methods: Advanced breast cancer patients treated with exemestane plus everolimus in 2012-2014 were included from the SONABRE registry. Progression-free survival (PFS) and a 12-week conditional PFS (post-hoc) were estimated by Kaplan-Meier method. The multivariable Cox proportional hazards model was performed by type of hospital and adjusted for patient, tumour and treatment characteristics.Results: We included 122 patients, comprising 48 patients treated in academic (N = 1), 56 in teaching (N = 4), and 18 in non-teaching (N = 2) hospitals. The median PFS was 6.3 months (95% Confidence Interval (CI) 4.0-8.6) overall, and 8.5 months (95% CI 7.7-9.3), 4.2 months (95% CI 2.0-6.3), and 5.5 months (95% CI 4.2-6.7) for the patients treated in academic, teaching and non-teaching hospitals, respectively. The adjusted Hazard Ratio (HR) for PFS-events was 1.5 (95% CI 1.0-2.2) and 1.0 (95% CI 0.5-1.9) respectively for patients treated at teaching and non-teaching hospitals versus the academic hospital. The adjusted HR for 12-week conditional PFS-events was not different between hospital types. In the first 12-week treatment period, treatment was discontinued due to early progression in one out of 48 patients in the academic versus nine out of 74 patients in the non-academic hospitals, confirmed by imaging in one and two patients, respectively.Conclusions: In our study, the median PFS was borderline significantly different between hospital types, possibly the result of a different assessment approach in the first 12-week treatment period. (C) 2019 Elsevier Ltd. All rights reserved.

Contains fulltext : 238572.pdf (Publisher’s version ) (Closed access) Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]

Item does not contain fulltext BACKGROUND: Pemetrexed is an antifolate cytostatic drug that targets multiple enzymes involved in folate biosynthesis and is indicated for treatment of non-small-cell lung cancer and malignant pleural mesothelioma. As evidence for an exposure-response/toxicity relationship is accumulating, dose individualization using therapeutic drug monitoring may be a feasible strategy to optimize treatment. The purpose of this study was to develop a simple, sensitive, high-performance liquid chromatography method with UV detection for quantification of pemetrexed levels in human plasma. METHOD: The method involves a simple protein precipitation, followed by ultra-performance liquid chromatography with ultraviolet detection at a wavelength of 254 nm. Pemetrexed was separated using a mobile phase with a linear gradient and a run time of only 7 minutes. RESULTS: The assay has been validated over the concentration range 0.25-500 mg/L of pemetrexed. Accuracy for this assay ranged from -4.50% to 1.78%, and the within- and between-run coefficients of variation were

Contains fulltext : 218134.pdf (Publisher’s version ) (Closed access) A new method for quantification of osimertinib (OSIM) in human plasma using a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated. Methanol was used for protein precipitation and pazopanib as internal standard. Separation was performed on a HyPURITY(R)C18 analytical column (50 x 2.1 mm; 3 mum) using a gradient elution of ammonium acetate in water and ammonium acetate in methanol, both acidified with formic acid 0.1%. Detection and quantification of OSIM and pazopanib was performed using a triple quadruple mass spectrometer after electrospray ionization. This method led to robust results, as the selectivity, carryover, precision and accuracy all met pre-specified requirements. OSIM was stable in human serum when stored at -80 degrees C. Reduced stability was found when stored at 2-4 degrees C or room temperature. Degradation of OSIM slowed down in EDTA-plasma and acidified human serum. The limited stability of OSIM at room temperature should be considered for transport and sample preparation. Plasma samples should be frozen as soon as possible and sample preparation should be performed on dry-ice. In the future, EDTA-plasma and sample acidification may be used to improve OSIM stability at room temperature. However, more research and validation of such an approach are required.

Purpose Everolimus treatment is seriously hampered by its toxicity profile. As a relationship between everolimus exposure and effectiveness and toxicity has been established, early and ongoing concentration measurement can be key to individualize the dose and optimize treatment outcomes. Dried blood spot (DBS) facilitates sampling at a patients’ home and thereby eases dose individualization. The aim of this study is to determine the agreement and predictive performance of DBS compared to whole blood (WB) to measure everolimus concentrations in cancer patients. Methods Paired DBS and WB samples were collected in 22 cancer patients treated with everolimus and analyzed using UPLC-MS/MS. Bland-Altman and Passing-Bablok analysis were used to determine method agreement. Limits of clinical relevance were set at a difference of ± 25%, as this would lead to a different dosing advice. Using DBS concentration and Passing-Bablok regression analysis, WB concentrations were predicted. Results Samples of 20 patients were suitable for analysis. Bland-Altman analysis showed a mean ratio of everolimus WB to DBS concentrations of 0.90, with 95% of data points within limits of clinical relevance. Passing-Bablok regression of DBS compared to WB revealed no constant bias (intercept 0.02; 95% CI 0.93–1.35) and a small proportional bias (slope 0.89; 95% CI 0.76–0.99). Predicted concentrations showed low bias and imprecision and 90% of samples had an absolute percentage prediction error of

OBJECTIVES: To develop a reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for therapeutic drug monitoring (TDM) of unbound ciprofloxacin concentrations in critically ill patients. METHODS: Total and unbound ciprofloxacin concentrations of five randomly selected intensive care unit (ICU) patients were measured using UPLC-MS/MS. Method validation included accuracy, linearity, precision, repeatability, and limits of detection and quantification. RESULTS: The median unbound ciprofloxacin fraction was 74.8%, with a median area under the curve from 0-24 h (AUC0-24) and maximum serum concentration (Cmax) of 28.51 h·mg/L and 4.45 mg/L respectively. Median free AUC0-24 (fAUC0-24) and free Cmax (fCmax) were 21.57 h·mg/L and 3.53 mg/L respectively; 20% of patients reached the pharmacodynamic target. The UPLC-MS/ MS method was validated using an intra-assay and inter-assay precision < 3%. Recoveries were between 90-110% CONCLUSIONS: This UPLC-MS/MS method provided reliable unbound ciprofloxacin concentrations, allowing target attainment in critically ill patients and exploration of different dosing regimens.

Contains fulltext : 176996.pdf (Publisher’s version ) (Closed access) BACKGROUND: Tacrolimus and mycophenolic acid (MPA) are the backbone of immunosuppressive therapy after pediatric kidney transplantation. Dosing of these drugs is individualized by therapeutic drug monitoring. Dried blood spot (DBS) sampling may prove beneficial over conventional venous sampling. We aimed to develop and clinically validate a DBS method for tacrolimus and MPA in children. METHODS: A joint DBS liquid chromatography-mass spectrometry assay for tacrolimus and MPA was developed. DBS-specific items included the hematocrit effect and influence of spot volume. Subsequently, a clinical validation study among children aged 2-18 years was performed to assess the agreement between observed and DBS-predicted venous concentrations. Agreement of the methods was assessed with Passing-Bablok regression, Bland-Altman plots, and quantification of the DBS predictive performance in terms of bias (median percentage prediction error) and precision (median absolute percentage prediction error), both should be

Contains fulltext : 202592.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Pemetrexed is indicated for non-small cell lung cancer and mesothelioma. Dosing is based on body surface are (BSA), while renal function is the only determinant for exposure and thus toxicity. BSA-based dosing introduces large variability in exposure and may lead to (hemato)toxicity in patients with impaired renal function. Therefore, pemetrexed is contraindicated in renal impairment. The presented cases provide proof-of-concept for pharmacokinetically-guided dosing of pemetrexed in a haemodialysis patient and a patient with mild renal impairment. METHODS: The pharmacokinetic target was an area under the concentration-time curve (AUC) of 123-205 mg.h/L. Using a previously developed population pharmacokinetic model, individual pharmacokinetics were estimated. RESULTS: Both patients had an exposure above target after the initial dose, but a proportional dose reduction resulted in a therapeutic exposure in both patients (185 and 166 mg.h/L, respectively), that was well-tolerated. Interestingly, a threefold increase in systemic clearance of pemetrexed was observed during hemodialysis (from 1.00 L/h to 3.01 L/h), which approximates the population clearance of pemetrexed. CONCLUSION: Altogether, we showed that pharmacokinetically-guided dosing of pemetrexed may be a feasible strategy for patients with lung cancer and renal impairment.

Nitrofurantoin is an antimicrobial drug that has been used in the treatment of lower urinary tract infections for more than 50 years. Despite its long use, surprisingly little is known of the pharmacokinetics of nitrofurantoin, whereas this is essential to optimize patient treatment. We developed a novel analytical method for the quantification of nitrofurantoin in plasma and urine using ultra-high performance liquid chromatography and diode array detection to allow pharmacokinetic studies in these two matrices. The sample preparation method consisted of protein precipitation for plasma and liquid-liquid extraction for urine. 100 mu L was needed for the sample preparation. Furazolidone was used as internal standard. Gradient chromatographic separation was performed on a HSS-T3 column. UV detection was performed at a wavelength of 369 nm. The analysis time was 5 min. The method was successfully validated according to the FDA-guidelines (2018). Linearity was confirmed over a concentration range from 50 to 1250 mu g/L in plasma and from 4 to 200 mg/L in urine (r(2) > 0.95). Validation results of five QC concentrations for plasma and urine, respectively, are for within-day accuracy

Background: The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.Objectives: To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs. Patient and Methods: A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012–March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex.Results: In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 (95% confidence interval [CI] 5.0–6.9) months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone (adjusted hazard ratio [HRa] 2.37; 95% CI 0.97–5.76), which became statistically significant in a sensitivity analysis (HRa 4.56; 95% CI 1.51–13.75).Conclusions: There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation. [Figure not available: see fulltext.]

Crizotinib is an orally available tyrosine kinase inhibitor, approved for treatment of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement-positive non-small cell lung cancer (NSCLC). According to the product leaflet, crizotinib capsules should be swallowed whole, and should not be crushed, dissolved or opened. However, this manner of administration is not always possible. At present, literature is lacking regarding the absorption of crizotinib via percutaneous endoscopic jejunostomy (PEJ) tube. We report a case of a patient with ALK+ NSCLC who was administered crizotinib via PEJ tube. An adequate steady state crizotinib trough concentration was reached, resulting in a metabolic response. Safety for the caregiver was ensured since the administration of crizotinib was made without crushing or opening the capsule. This case supports the option for providing crizotinib via PEJ tube in patients who have ALK+ NSCLC and are unable to swallow whole capsules. This option might also apply to the administration of other ALK inhibitors. Keywords Crizotinib, ALK inhibitor, percutaneous endoscopic jejunostomy tube, pharmacokinetics, non-small cell lung cancer.

Background Incretin-based therapies (Dipeptidyl Peptidase 4 inhibitors and Glucagon-Like Peptide-1 Receptor Agonists) are effective new agents for the treatment of Type 2 Diabetes Mellitus (T2DM). While incretin-based therapies have been associated with pancreatitis, evidence is conflicting for acute pancreatitis and lacks for chronic pancreatitis. Objective To determine the association between the use of incretin agents and the risk of any, acute and chronic pancreatitis. Research design and methods A population-based cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD 2007–2012). 182,428 adult patients with ≥1 Non-Insulin Antidiabetic Drug (NIAD) prescriptions were matched to non-diabetic controls. Cox regression estimated adjusted hazard ratios (HRa) and 95% Confidence Intervals (CI) of pancreatitis in incretin-users (N = 28,370) compared to controls and to other NIAD users. Adjustments were made for lifestyle, disease and drug history. In a sensitivity analysis, a new user design was used. Results Current incretin users had a 1.5-fold increased risk of any pancreatitis versus NIAD users (HRa 1.47; 95% CI 1.06–2.04). In incident current incretin users the risk of any and acute pancreatitis was increased by 2.1 and 2.0-fold versus NIAD users (HRa 2.12; 95% CI 1.31-3.43 and HRa 1.96; 95% CI 1.13-3.41), whereas there was no increased risk found for chronic pancreatitis. Conclusions Incretin use was associated with an increased risk of any pancreatitis. Moreover, risk of any and acute pancreatitis was higher when applying a new user design. We could not detect an association with chronic pancreatitis, but numbers in this subgroup were small.

In their Review, Roelof van Leeuwen and colleagues1 recommend various dose adjustments during concomitant use of tyrosine-kinase inhibitors and drugs that inhibit or induce cytochrome P450 3A4 (CYP3A4).1 Most information is taken from the US Food and Drug Administration (FDA)'s drug label or the European Medicines Agency (EMA)'s Summary of Product Characteristics. However, we could not find support for their advice regarding concomitant use of pazopanib and strong CYP3A4 inducers such as carbamazepine. They suggested to gradually increase the pazopanib dose in 200 mg steps depending on patient's tolerance,1 whereas both the FDA and EMA recommend that concomitant use should be avoided, and that the dose of pazopanib should not exceed 800 mg.2 and 3 We are unaware of clinical evidence for safety and efficacy of dose enhancement. By contrast, concomitant use and enhancement might result in carbamazepine toxic effects, because pazopanib can also act as a CYP3A4 inhibitor,2, 3 and 4 whereas carbamazepine is not only a CYP3A4 inducer, but also a CYP3A4 substrate with a narrow therapeutic index. We wonder which evidence supports the dosing guidelines that have been recommended by the authors.1 The Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (employers of FV) has received unrestricted research funding from the Netherlands Organisation for Health Research and Development, the Dutch Health Insurance Board, the Royal Dutch Association for the Advancement of Pharmacy, the private–public funded Top Institute Pharma (EU Innovative Medicines Initiative, EU 7th Framework Program), the Dutch Medicines Evaluation Board, the Dutch Ministry of Health, and industry (GlaxoSmithKline, Pfizer, and others).

OBJECTIVE: To determine the association between the use of incretin agents and the risk of pancreatic Cancer. Incretins (dipeptidyl peptidase 4 [DPP-4] inhibitors and glucaconlike peptide 1 [GLP-1] receptor analogues] are effective new agents for the treatment of type 2 diabetes mellitus (T2DM). Incretins have been associated with pancreatic Cancer, but evidence is limited and conflicting. DESIGN AND METHODS: A retrospective population-based cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD, 2007-2012). 182.428 adult patients with at least one non-insulin antidiabetic drug INIAD] prescription were matched to non-diabetic controls. Multivariable Cox proportional hazard ratios (HRa) and 95% confidence intervals (CI95) were used to estimate the risk of pancreatic Cancer in incretin users (N = 28,3701 as compared to controls and to other NIAD users. Adjustments were made for lifestyle, disease and drug history. In a sensitivity analysis, a new user design was used. RESULTS: The main duration of follow up was 4.1 years for incretin users. Current NIAD use was associated with a 4-fold increased risk of pancreatic Cancer and this risk almost doubled among current incretin users as compared to controls. Incretin use was not associated with pancreatic Cancer when compared to diabetic controls (HRa 1.36; CI95 0.94-1.961. However, the new user design did show an association between incretin use and pancreatic Cancer. CONCLUSION: Incretin use was not associated with pancreatic Cancer after adjustment for the severity of the underlying T2DM. The presence of confounding by disease severity and the lack of duration of use relationship do not support a causal explanation for the association between incretin agents and pancreatic Cancer.

The incidence of brain metastases of solid tumors is increasing. Local treatment of brain metastases is generally straightforward: cranial radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiosurgery) or resection when feasible. However, treatment becomes more complex when brain metastases occur while other metastases, outside of the central nervous system, are being controlled with systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies). It is known that some anticancer agents can increase the risk for neurotoxicity when used concurrently with radiotherapy. Increased neurotoxicity decreases quality of life, which is undesirable in this predominantly palliative patient group. Therefore, it is of utmost importance to identify the compounds that should be temporarily discontinued when cranial radiotherapy is needed.This review summarizes the (neuro)toxicity data for combining systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies) with concurrent radiotherapy of brain metastases. Because only a limited amount of high-level data has been published, a risk assessment of each agent was done, taking into account the characteristics of each compound (e.g., lipophilicity) and the microenvironment of brain metastasis. The available trials suggest that only gemcitabine, erlotinib, and vemurafenib induce significant neurotoxicity when used concurrently with cranial radiotherapy. We conclude that for most systemic therapies, the currently available literature does not show an increase in neurotoxicity when these therapies are used concurrently with cranial radiotherapy. However, further studies are needed to confirm safety because there is no high-level evidence to permit definitive conclusions. The Oncologist 2017;22:222-235Implications for Practice: The treatment of symptomatic brain metastases diagnosed while patients are receiving systemic therapy continues to pose a dilemma to clinicians. Will concurrent treatment with cranial radiotherapy and systemic therapy (chemotherapeutics, molecular targeted agents, and monoclonal antibodies), used to control intra- and extracranial tumor load, increase the risk for neurotoxicity? This review addresses this clinically relevant question and evaluates the toxicity of combining systemic therapies with cranial radiotherapy, based on currently available literature, in order to determine the need to and interval to interrupt systemic treatment.

Item does not contain fulltext AIM: To investigate the association between the use of incretin agents and the risk of pancreatic cancer. METHODS: A retrospective population-based cohort study, using data from the Clinical Practice Research Datalink, 2007-2012, was conducted. Patients (n = 182 428) with at least one non-insulin antidiabetic drug (NIAD) prescription and aged >/=18 years during data collection, were matched one-to-one to control patients without diabetes. Multivariable Cox proportional hazards models and a new user design were used to estimate the hazard ratio (HR) of pancreatic cancer in incretin users (n = 28 370) compared with control subjects without diabetes and other NIAD-treated patients. Time-dependent adjustments were made for age, sex, lifestyle, comorbidities and drug use. RESULTS: The mean duration of follow-up was 4.1 years for incretin users. Current NIAD use was associated with a fourfold increased risk of pancreatic cancer [HR 4.28, 95% confidence interval (CI) 3.49-5.24]. This risk was almost doubled among current incretin users as compared with control subjects. Incretin use was not associated with pancreatic cancer when compared with control subjects with diabetes (HR 1.36, 95% CI 0.94-1.96); however, the 'new user' design did show an association between incretin use and pancreatic cancer when compared with control subjects with diabetes. In both cohorts with prevalent and incident users of antidiabetic drugs, the risk of pancreatic cancer almost doubled in those who had recently initiated incretin therapy (up to seven prescriptions), whereas this elevated risk dropped to baseline levels with prolonged use. CONCLUSIONS: We found that incretin use was not associated with pancreatic cancer after adjustment for the severity of the underlying Type 2 Diabetes Mellitus (T2DM). The elevated risk of pancreatic cancer in those recently initiating incretin agents is likely to be caused by protopathic bias or other types of unknown distortion. The presence of considerable confounding by disease severity and the lack of a duration-of-use relationship do not support a causal explanation for the association between incretin agents and pancreatic cancer.

Therapeutic drug monitoring (TDM) of aminoglycosides has been a topic during the last thirty years. There is a tendency that - because of the once-daily regimen - TDM is considered not necessary anymore. Although once daily dosing has the potential for decreased toxicity, long-term usage can cause severe nephro- and ototoxicity. Furthermore, inadequate plasma concentrations can lead to treatment failure. This work is devoted to the development and application of the first mathematical model of aminoglycosides, which simulates in relation to the pharmacokinetics both their effects on bacteria as well as their nephrotoxicity and cochleotoxicity. Our software system is suitable for TDM. Based on theoretical considerations, a multi-compartment mathematical model in a numerical program in Matlab is derived that incorporates the antimicrobial effects of aminoglycosides, the saturable and active uptake into kidney cells, the reversible nephrotoxicity and the irreversible cochleotoxicity. Using fictitious person data, and an assumed pharmacokinetic and dynamic parameter set obtained from the literature, we simulated the drug concentrations, antibacterial effects, and toxicity over time in virtual patients to illustrate the benefits of optimized, efficacious dosage regimens that minimize (acceptable) nephro- and auditory ototoxicity. Our model confirms that extended-interval dosing seems the most appropriate to achieve this goal. By this manner, the present mathematical model contributes to an increase in our knowledge of how to obtain an optimized dosing strategy for individual patients. With the developed program, we are able to demonstrate that optimal aminoglycoside dosing still needs a sophisticated system of TDM. (C) 2011 Elsevier B.V. All rights reserved.

Percutaneous (skin-penetrating) catheters such as central venous catheters (CVCs), are used ubiquitously in the treatment of critically ill patients, although it is known that the risks for serious complications, particularly bloodstream infection and thromboembolism, are high. Materials science and engineering offer important new perspectives regarding further improvement of CVCs. A promising approach is the use of synthetic biocompatible hydrogel coatings with both silver particles and heparin embedded therein. Such formulations combine the well-known broad-spectrum antimicrobial features of silver with the anticoagulant activity of immobilized heparin. Previous work revealed that heparin augments antimicrobial activity of silver, while maintaining its anticoagulant function. This study set out to investigate the synergy of heparin and silver in more detail. Exit-challenge tests, experiments on bacterial killing and adherence, as well as in vitro challenge tests with three Staphylococcus aureus strains (one reference strain, and two clinical isolates) consistently showed the synergistic effect. In addition, the impact of changing the coating's hydrophilicity, and changing the silver concentration in the coatings, were examined. The experimental results, taken together and combined with data from the literature, point out that synergy of heparin and silver is best explained by binding of Ag(+) ions to heparin within the swollen coating, followed by release of heparin-Ag(+) complexes upon immersion of the coatings in an aqueous environment such as blood. Possible implications of this work regarding the development of improved/safer CVCs are briefly discussed.

9540 Background: Vemurafenib is used for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The approved fixed vemurafenib dose of 960 mg twice daily may result in overexposure. Concomitant use of acid reducing agents (ARAs) may result in underexposure. Both situations are likely to affect treatment outcome. Therefore, the aim of this study was to determine the association between the use of vemurafenib (full-dose versus reduced dose) and/or concomitant ARA use (yes versus no) and the risk of disease progression. Methods: A retrospective cohort study was conducted using data from the electronic health record software of the Radboudumc pharmacy and medical records of the Radboudumc (March 17th 2012 to March 17th 2016). Patients (N = 112) using vemurafenib as first line treatment for melanoma were included. Multivariable cox regression estimated adjusted hazard ratios (HRa) and 95% confidence intervals (CI) of progression in vemurafenib users (full-dose N = 67 versus reduced dose N = 45) and/or concomitant ARA users (N = 38). Adjustments were made for age and sex. Results: The mean follow-up time was 3.5 months and 41 patients (36.6%) developed progression on first line vemurafenib. Co-treatment of ARAs in patients using full-dose vemurafenib was associated with a 4.6-fold increased risk of progression (HRa 4.56; 95% CI 1.51-13.75) as compared to full-dose vemurafenib users not co-treated with ARAs. No increased risk was found for users of vemurafenib in a reduced dose, regardless of concomitant ARA use. Conclusions: Concomitant use of ARAs in full-dose vemurafenib users was associated with an increased risk of progression. Physicians should be cautious to prescribe ARAs to patients tolerating full-dose vemurafenib. The presence of considerable confounding by disease severity, the small number of events and the hypothesis generating character of this study emphasize the need to prospective validate these results.

Background: To compare vancomycin pharmacokinetic parameters in patients with and without neutropenia. Methods: Patients >= 18 years admitted on general wards were included. Routinely vancomycin trough and peak plasma concentrations were measured with a fluorescence polarization immunoassay. Pharmacokinetic parameters of individual patients were determined with maximum a posterior Bayesian estimation (MW Pharm 3.60). Neutropenia was defined as neutrophils = 400 mgxh/L. Furthermore, 15 initially neutropenic patients in our study group received vancomycin for a second administration period. Ten patients received the second administration period during another neutropenic period and 5 patients during a non-neutropenic phase. All 5 patients with vancomycin during both neutropenic and non-neutropenic phase had higher CLva (91 (+/- 26) mL/min) during the neutropenic period and lower CLva (45 (+/- 10) mL/min) during the non-neutropenic phase (p = 0.009). Conclusion: This study shows that most patients with neutropenia have augmented CLva. In a small group of patients that received vancomycin during two episodes, the augmented CLva seems to be reversible in the non-neutropenic period. Our data indicate that it is important to increase the daily dose with one third in patients with neutropenia (from 15 mg/kg twice daily to 13 mg/kg three times daily). Frequent performance of therapeutic drug monitoring in patients with neutropenia may prevent both therapy failure due to low AUCs and overcomes toxicity due to high vancomycin trough concentrations during recovery from neutropenia.

Central venous catheters (CVCs) have become indispensable in the treatment of neonates and patients undergoing chemotherapy or hemodialysis. A CVC provides easy access to the patient's circulation, thus enabling facile monitoring of hemodynamic parameters, nutritional support, or administration of (cytostatic) medication. However, complications with CVCs, such as bacterial bloodstream infection or thromboembolism, are common. Bloodstream infections, predominantly caused by Staphylococcus aureus, are notoriously difficult to prevent and treat. Furthermore, patients receiving infusion therapy through a CVC are at risk for deep-vein thrombosis, especially of the upper limbs. Several recent clinical trials have shown that prophylactic anticoagulation (low-molecular-weight heparin or vitamin K antagonists) is not effective. Here, we report on the systematic development of a new bifunctional coating concept that can -uniquely- be applied to make CVC surfaces antimicrobial and antithrombogenic at the same time. The novel coating consists of a moderately hydrophilic synthetic copolymer of N-vinylpyrrollidinone (NVP) and n-butyl methacrylate (BMA), containing embedded silver nanoparticles (AgNPs) and sodium heparin. The work demonstrates that the AgNPs strongly inhibit adhesion of S. aureus (reference strain and clinical isolates). Surprisingly, heparin not only rendered our surfaces practically non-thrombogenic, but also contributed synergistically to their biocidal activity.

The use of rifampin as an adjunct in biofilm-associated infections is based on the ability to penetrate into biofilms and a presumed activity against dormant bacteria. Yet, its efficacy remains contradictory, and rifampin-resistant strains frequently emerge during therapy. Therefore, the efficacy against rifampin-susceptible and isogenic rifampin-resistant methicillin-susceptible Staphylococcus aureus (MSSA) strains was evaluated. Biofilms were generated under static conditions using MSSA with various genetic backgrounds. Oxacillin alone or with rifampin at various concentrations was subsequently added, and after 24 h biomass and viable cell counts were determined. Upon rifampin addition, interstrain variations in viable count change, ranging from a tendency toward antagonism to synergy, were observed among all strains tested, irrespective of the genetic background of the strain. Similar variations were observed in changes in biomass. The decrease in viable count upon rifampin addition was negatively correlated to formation of large amounts of biomass, since strains embedded by more biomass showed a diminished reduction in viable count. Rifampin (1 μg/ml) as adjunct to oxacillin achieved greater reductions in biomass produced by most rifampin-susceptible isolates, ranging from 17 to 54%, compared to 4% for oxacillin alone. In contrast, rifampin had no additional value in reduction of biomass of isogenic rifampin-resistant mutants. At subinhibitory concentrations of rifampin (0.008 μg/ml), none of the strains tested yielded an extra reduction in biomass that was ≥40%. In conclusion, the effects of rifampin as adjunct on biomass and viable count were unpredictable, and the use of rifampin against biofilm containing rifampin-resistant strains seems unwarranted.

P>Since it is unknown whether beta-lactam antimicrobial agents can be used effectively against borderline oxacillin-resistant Staphylococcus aureus (BORSA) with oxacillin MICs >= 4 mg/L, the in vitro bactericidal activity and pharmacodynamic effect of oxacillin against clinical BORSA isolates was evaluated. Time-kill experiments with oxacillin were performed and the results compared with those obtained with vancomycin, daptomycin and linezolid against BORSA with oxacillin MICs >= 4 mg/L and BORSA with oxacillin MICs = 4 mg/L. pBORa53-like plasmid-containing BORSA with oxacillin MICs = 4 mg/L or (ii) beta-lactamase-hyperproducing BORSA (MICs

Background Since bacteria embedded in biofilms are far more difficult to eradicate than planktonic infections, it would be useful to know whether certain Staphylococcus aureus lineages are especially involved in strong biofilm formation. For this reason, in vitro biofilm formation of 228 clinical S. aureus isolates of distinct clonal lineages was investigated. Results At 0.1% glucose, more than 60% of the S. aureus strains associated with multilocus sequence typing (MLST) clonal complex (CC)8 produced large amounts of biomass, compared to 0-7% for various other clonal lineages. Additionally, S. aureus bloodstream isolates associated with MLST CC8 and CC7 had similar biofilm forming capacities as their commensal counterparts. Furthermore, strong biofilm formation could not be attributed to a specific accessory gene regulator (agr) genotype, as suggested previously. The agr genotypes were strictly associated with the clonal lineages. Moreover, strong biofilm formation was not related to slime formation. Congo red agar (CRA) screening is therefore not useful as a qualitative screening method for biofilm formation. Conclusion The adherence to polystyrene surfaces under physiologic glucose concentration (0.1%) was dependent on the clonal lineage. Strains associated with MLST CC8 were markedly more often classified as strong biofilm former at glucose concentrations of 0%, 0.1% and 0.25%. The present study reveals that the MLST CC8 associated genetic background was a predisposing factor for strong biofilm formation in vitro, under all tested glucose concentrations.