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Heteronanocrystals consisting of a CdSe core and a giant CdS shell have shown remarkable optical properties which are promising for applications in optoelectrical devices. Since these properties sensitively depend on the size and shape, a morphological characterization is of high interest. Here, we present a high angle annular dark field scanning transmission electron microscopy (HAADF-STEM) study of CdSe (core)/CdS (giant shell) heteronanocrystals. Electron tomography reveals that the nanocrystals have a bullet shape, either ending in a tip or a small dip, and that the CdSe core is positioned closer to the tip (or dip) than to the hexagonal base. Based on a high resolution HAADF-STEM study, we were able to determine all the surface facets. We present a heuristic model for the different growth stages of the CdS crystal around the CdSe core. [ABSTRACT FROM AUTHOR]

New, stable heterobidentate phosphane–olefin ligandsbased on the dibenzo[b,f]phosphepinebackbone are reported together with their redox properties and coordinationchemistry to rhodium(I). The X-ray crystal structures and DFT calculationsshow different conformations for the P-phenyl (6a) and P-mesityl (6b) derivatives.Cyclic voltammetry (vs Fc/Fc+) of 6asupportedby UV–vis spectroelectrochemistry showed two cathodic waves,a reversible one at E1/2= −2.62V (If/Ib=1.0) and a quasi-reversible (If/Ib≈ 1.2) one at E1/2= −3.03 V. Reduction with sodium afforded a mixtureof the radical anion [6a•]−, characterized by EPR spectroscopy, and dianion [6a]2–, for which an X-ray crystal structure was obtained.Both 6aand 6bbind to RhIcenters,giving rise to 3:1 (8a) and 2:1 (8b) ligand:Rhcomplexes, respectively. Two dibenzo[b,f]phosphepinesin 8aand 8bact as heterobidentate ligandsin which both the phosphorus atom and the olefinic double bond coordinateto rhodium, but the third ligand in 8abinds as a monodentateP-donor. The cyclic voltammogram of 8bshowed two close-lyingwaves, a one-electron reversible wave at −1.45 V and a two-electronquasi-reversible wave at −1.80 V (If/Ib≈ 1.3). 8ashoweda reversible wave at −1.71 V and irreversible waves at lowerpotentials. [ABSTRACT FROM AUTHOR]

The subcellular localization of the PDGF β-receptor was investigated in relation with PDGF-induced actin and membrane dynamics in mouse C3H10T1/2 fibroblasts. Serum-starved cells exhibit a nonhomogenous distribution of PDGF β-receptors. However, the observed pattern does not resemble the localization of PDGF-induced actin structures. Interestingly, the PDGF β-receptor showed a changed subcellular distribution in relation to the formation of PDGF-BB-induced actin structures. Upon PDGF exposure, PDGF β-receptors were found to accumulate in dorsal circular ruffles. The presence of both macropinosomes and clathrin in the induced circular ruffles suggests that the accumulation of PDGF β-receptors in circular ruffles results in the efficient internalization of PDGF β-receptors. [ABSTRACT FROM AUTHOR]

Abstract: Near-infrared (NIR) spectroscopy was employed as a process analytical technique in three steps of tabletting process: to monitor the blend homogeneity, evaluate the content uniformity of tablets and determine the tablets coating thickness. A diode-array spectrometer mounted on a lab blender (SP15 NIR lab blender) was used to monitor blend uniformity using a calibration-free model with drug concentration ranging from 2.98 to 9.25% (w/w). The method developed accurately depicted the changes in concentration of the drug during blending and the positive effect of a delumping step in the production process. Blend homogeneity was reached within 2min of the blending step post-delumping, with relative standard deviation (R.S.D.) values varying from 1.0 to 2.5% depending on the drug concentration of the blend. A Fourier-transform spectrometer (Bruker MPA) was used to analyze content uniformity and coating thickness with calibration based models. Prediction of a validation set with tablets compacted at pressures not present in the calibration set yielded an root mean square error of cross validation (RMSEP) of 1.94%; prediction of tablets compacted at pressures present in the calibration set yielded a RMSEP of 1.48%. Performance of the model was influenced by several physical tablet properties, which could be reduced by spectral pre-processing. A model based on reflectance spectra predicted coating thickness and its variation more accurately than the model based on transmission spectra. Inter-tablet coating variation was predicted with NIR and compared to reference thickness measurements. Both methods gave comparable results. Initial inter-tablet variation of tablets sampled in-process during coating was high, but stabilized after 30min into the process. [Copyright &y& Elsevier]

Background and Objective: Vancomycin is a glycopeptide antibiotic used for the treatment of severe gram-positive infections. Despite decades of clinical experience, optimized dosing for vancomycin in pediatric populations still warrants further investigation. Patients admitted to the pediatric intensive care unit (PICU) after cardiac surgery are often treated with vancomycin in case of (suspected) infection. However, vancomycin dosing in this population is often challenging due to fluctuations in volume status, (temporarily) compromised renal function or the use of diuretics or extracorporeal membrane oxygenation (ECMO). The main objective of this study was to describe vancomycin pharmacokinetics (PK) in pediatric cardiac surgery patients. Secondary objectives were to potentially optimize vancomycin dosing and to assess the suitability of the model to be used for model informed precision dosing (MIPD). Methods: A retrospective cohort study was performed with patients admitted to the PICU of the Leiden University Medical Center. Clinical data from post-cardiac surgery PICU patients receiving intravenous vancomycin between January 2020 and December 2023 were included in the analysis. Patients received vancomycin 10 mg/kg 4 times daily (qid), after which a trough concentration was generally sampled just before the fourth dose. Pharmacokinetic data were used to develop a population PK model by using a non-linear mixed effects modeling approach (NONMEM). In addition, potential covariates such as renal function, body weight (BW) and post-menstrual age were tested. The final model was used for vancomycin dose optimization using Monte Carlo simulations. Results: In total, 193 pediatric post-cardiac surgery patients, contributing a total of 706 vancomycin blood samples were included. The 2-compartmental population PK model best described the data. Renal function and BW were identified as significant and clinically relevant covariates on vancomycin PK. Model parameters were: elimination clearance: 4.01 L/min at 70 kg; intercompartmental clearance: 0.425 L/min at 70 kg; central volume of distribution: 56.1 L/70 kg; and peripheral volume of distribution: 21.7 L/70 kg (fixed). Dose simulations suggested a non-linear dosing algorithm, with relatively lower per kg dose for increasing BW to be optimal for our population. Furthermore, the model was considered to be suitable for the (a posteriori) prediction of future vancomycin serum concentrations. Conclusion: We successfully developed a population PK model for vancomycin in post-cardiac surgery children. Vancomycin PK were shown to be significantly influenced by serum creatinine and BW. Furthermore, we suggest a new vancomycin dosing regimen based on allometric scaling. The developed PK model can be used for model informed precision dosing of vancomycin in pediatric post-cardiac surgery patients. [ABSTRACT FROM AUTHOR]

Background: After liver transplantation (LT), tacrolimus and ciclosporin treatment can lead to, partially concentration‐dependent, chronic kidney disease. Monitoring ciclosporin with two‐hour levels reduced overexposure and led to better renal function than trough‐monitoring (C0). For tacrolimus, a 4‐hour level (C4) can give a reasonable approximation of total drug exposure. We evaluated whether monitoring tacrolimus in stable patients after LT by C4 was superior to C0 regarding renal function, rejection and metabolic parameters. Methods: This open label randomized controlled trial compared C4 monitoring of tacrolimus BID (Prograft) to trough (C0) monitoring in stable LT recipients. The target range for C4 of 7.8–16 ng/ml was calculated to be comparable with target C0 of 4–8 ng/ml. Primary endpoint was the effect on renal function and secondary endpoints were the occurrence of treated biopsy‐proven acute rejection, blood pressure and metabolic parameters, during 3 months of follow‐up. Results: Fifty patients were randomized to C0 (n = 25) or C4 (n = 25) monitoring. There was no difference in renal function between the C0 and the C4 group (p =.98 and p =.13 for CG and MDRD at 3 months). Also, the amount of proteinuria was similar (p =.59). None of the patients suffered from graft loss or was treated for rejection. Metabolic parameters did not differ between the two groups. Conclusion: Tacrolimus 4‐hour monitoring in stable LT patients is not superior to trough monitoring, regarding the effect on renal function, but is safe for use to facilitate tacrolimus monitoring in an afternoon outpatient clinic. [ABSTRACT FROM AUTHOR]

Objectives: To describe the population pharmacokinetics and protein-binding characteristics of unbound ceftriaxone administered as continuous or intermittent infusion. Additionally, to determine the optimal dosing regimen in critically ill patients.Methods: A pharmacokinetic study was performed in the ICU of a tertiary teaching hospital. Patients were treated with ceftriaxone as continuous or intermittent infusion. A population pharmacokinetic model was developed with non-linear mixed-effects analysis. Subsequently, the PTA of a 100% T>MIC was assessed for influential patient characteristics using Monte Carlo simulation.Results: Fifty-five patients were included. The pharmacokinetics of ceftriaxone was best described by a one-compartment model with non-linear saturable protein binding including the following covariates: body weight, estimated CLCR, serum albumin concentration and mode of administration. For pathogens with an MIC of 1 mg/L, the simulation demonstrated that intermittent infusion of 2 g/24 h only resulted in a ≥90% PTA in patients with a reduced CLCR (0-60 mL/min). Intermittent infusion of 2 g/12 h led to sufficient exposure if CLCR was 0-90 mL/min and continuous infusion of 2 g/24 h led to a ≥90% PTA in all simulations (CLCR 0-180 mL/min).Conclusions: In the critically ill, the clearance of unbound ceftriaxone is closely related to CLCR. Furthermore, ceftriaxone protein binding is saturable, variable and dependent on serum albumin concentration. Intermittent dosing of 2 g/24 h ceftriaxone leads to subtherapeutic exposure in patients with a normal or increased CLCR. Treating these patients with continuous infusion of 2 g/24 h is more effective than an intermittent dosing regimen of 2 g/12 h. [ABSTRACT FROM AUTHOR]

The highly luminescent title nanorods are synthesized using the reverse micelle method. [ABSTRACT FROM AUTHOR]

In this work, we investigate the thermal evolution of CdSe–CdS–ZnS core–multishell quantum dots (QDs) in situ using transmission electron microscopy (TEM). Starting at a temperature of approximately 250 °C, Zn diffusion into inner layers takes place together with simultaneous evaporation of particularly Cd and S. As a result of this transformation, CdxZn1−xSe–CdyZn1−yS core–shell QDs are obtained. [ABSTRACT FROM AUTHOR]

Kidney transplant recipients (KTRs) are at increased risk of severe COVID-19 disease compared to the general population. This is partly driven by their use of immunosuppressive therapy, which influences inflammatory responses and viral loads. Current guidelines suggest to withdraw mycophenolate while calcineurin inhibitors are often continued during a COVID-19 infection. However, clinical signs of calcineurin toxicity have been described in multiple COVID-19 positive KTRs. In this report we describe the course of tacrolimus exposure prior to, during, and post COVID-19 in observations from three clinical cases as well as four KTRs from a controlled trial population. We postulate inflammation driven downregulation of the CYP3A metabolism as a potential mechanism for higher tacrolimus exposure. To mitigate the risk of tacrolimus overexposure and toxicity therapeutic drug monitoring is recommended in KTRs with COVID-19 both in the in-, outpatient and home monitoring setting. [ABSTRACT FROM AUTHOR]

ModraPac001 (MP1) and ModraPac005 (MP5) are novel oral paclitaxel formulations that are coadministered with the cytochrome P450 3A4 inhibitor ritonavir (r), enabling daily low‐dose metronomic (LDM) treatment. The primary aim of this study was to determine the safety, pharmacokinetics and maximum tolerated dose (MTD) of MP1/r and MP5/r. The second aim was to establish the recommended phase 2 dose (RP2D) as LDM treatment. This was an open‐label phase 1 trial. Patients with advanced solid tumors were enrolled according to a classical 3+3 design. After initial employment of the MP1 capsule, the MP5 tablet was introduced. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.02. Pharmacokinetic sampling was performed on days 1, 2, 8, and 22 for determination of paclitaxel and ritonavir plasma concentrations. In this study, 37 patients were treated with up to twice‐daily 30‐mg paclitaxel combined with twice‐daily 100‐mg ritonavir (MP5/r 30‐30/100‐100) in 9 dose levels. Dose‐limiting toxicities were nausea, (febrile) neutropenia, dehydration and vomiting. At the MTD/RP2D of MP5/r 20‐20/100‐100, the maximum paclitaxel plasma concentration and area under the concentration‐time curve until 24 hours were 34.6 ng/mL (coefficient of variation, 79%) and 255 ng • h/mL (coefficient of variation, 62%), respectively. Stable disease was observed as best response in 15 of 31 evaluable patients. Based on these results, LDM therapy with oral paclitaxel coadministrated with ritonavir was considered feasible and safe. The MTD and RP2D were determined as MP5/r 20‐20/100‐100. Further clinical development of MP5/r as an LDM concept, including potential combination treatment, is warranted. [ABSTRACT FROM AUTHOR]

CYP2C19*2 and CYP2C19*17 might influence tamoxifen metabolism and clinical outcome. Our aim was to investigate the effect of CYP2C19 genotypes on tamoxifen concentrations and metabolic ratios (MRs) and breast cancer recurrence in a large cohort of Caucasian women. Genetic variants (CYP2D6 and CYP2C19 genotypes), tamoxifen and metabolites concentrations, baseline characteristics, and breast cancer recurrence from the CYPTAM study (NTR1509) were used. CYP2C19*2 and CYP2C19*17 genotypes were evaluated as alleles and as groups based on CYP2D6 genotypes (high, intermediate and low activity). Log-rank test and Kaplan–Meier analysis were used to evaluate differences in recurrence defined as relapse-free survival (RFS). Classification tree analyses (CTAs) were conducted to assess the levels of interactions per polymorphism (CYP2D6 and CYP2C19 genotypes) on endoxifen concentrations. No differences in mean concentrations and MRs were observed when comparing CYP2C19 genotypes (CYP2C19*1/*1; CYP2C19*1/*2; CYP2C19*2/*2; CYP2C19*1/*17; CYP2C19*17/*17; CYP2C19*2/*17). Only significant differences (p value < 0.05) in mean concentrations and MRs were observed when comparing tamoxifen activity groups (high, intermediate and low activity). A log-rank test did not find an association across CYP2C19 genotypes (p value 0.898). CTAs showed a significant relationship between CYP2D6 and endoxifen (p value < 0.0001), but no association with CYP2C19 genotypes was found. CYP2C19 polymorphisms do not have a significant impact on tamoxifen metabolism or breast cancer relapse. [ABSTRACT FROM AUTHOR]

Aims: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. Methods: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. Results: A 2‐compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model‐based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. Conclusions: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3‐point LSM allows for accurate and precise estimation of treosulfan exposure. [ABSTRACT FROM AUTHOR]

Aims: The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each patient. Methods: Data on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed‐effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. Results: A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two‐compartment model. The mean absorption rate was 3.6 h−1, clearance was 23.0 l h–1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: Dosemg=222nghml–1*22.5lh–1*1.0ifCYP3A5*3/*3or1.62ifCYP3A5*1/*3orCYP3A5*1/*1*1.0ifCYP3A4*1or unknownor0.814ifCYP3A4*22*Age56−0.50*BSA1.930.72/1000Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model. Conclusions: For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation. [ABSTRACT FROM AUTHOR]

Aims: Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of dosing, as the optimal immunosuppressive dose in calcineurin‐free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment‐limiting toxicity. Methods: We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens. Results: We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75–1 mg twice daily (BID) results in subtherapeutic trough levels (<6 μg l–1) and that a higher starting dose of 2.25–3 mg BID is required. Conclusion: For oncological indications, our results encourage the investigation of dosing everolimus 3.75 mg BID in terms of superiority in safety and noninferiority in efficacy. [ABSTRACT FROM AUTHOR]

Introduction Two solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored. Methods Adult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0. Results ModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1–2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration–time curve (AUC 0–48 ) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment. Conclusion Oral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising. [ABSTRACT FROM AUTHOR]

Background: Everolimus is a mTOR inhibitor used for the treatment of different solid malignancies. Many patients treated with the registered fixed 10 mg dose once daily are in need of dose interruptions, reductions or treatment discontinuation due to severe adverse events. This study determined the correlation between systemic everolimus exposure and toxicity. Additionally, the effect of different covariates on everolimus pharmacokinetics (PK) was explored.Methods: Forty-two patients with advanced thyroid carcinoma were treated with 10 mg everolimus once daily. Serial pharmacokinetic sampling was performed on days 1 and 15. Subsequently, a population PK model was developed using NONMEM to estimate individual PK values used for analysis of an exposure-toxicity relationship. Furthermore, this model was used to investigate the influence of patient characteristics and genetic polymorphisms in genes coding for enzymes relevant in everolimus PK.Results: Patients who required a dose reduction (n = 18) due to toxicity at any time during treatment had significant higher everolimus exposures [mean AUC0-24 (SD) 600 (274) vs. 395 (129) µg h/L, P = 0.008] than patients without a dose reduction (n = 22). A significant association between everolimus exposure and stomatitis was found in the four-level ordered logistic regression analysis (P = 0.047). The presence of at least one TTT haplotype in the ABCB1 gene was associated with a 21 % decrease in everolimus exposure.Conclusion: The current study showed that dose reductions and everolimus-induced stomatitis were strongly associated with systemic everolimus drug exposure in patients with cancer. Our findings confirm observations from another study in patients with cancer and show us that everolimus is a good candidate for individualized dosing in patients with cancer. CLINICALTRIAL.Gov Number: NCT01118065. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the implementation of a multicomponent lifestyle intervention at two different worksites. Methods: Data on eight process components were collected by means of questionnaires and interviews. Data on the effectiveness were collected using questionnaires. Results: The program was implemented partly as planned, and 84.0% (max 25) and 85.7% (max 14) of all planned interventions were delivered at the university and hospital, respectively. Employees showed high reach (96.6%) and overall participation (75.1%) but moderate overall satisfaction rates (6.8 ± 1 .1 ). Significant intervention effects were found for days of fruit consumption (P = 0.44 days/week, 95% Cl: 0.02 to 0.85) in favor of the intervention group. Conclusions: The study showed successful reach, dose, and maintenance but moderate fidelity and satisfaction. Mainly relatively simple and easily implemented interventions were chosen, which were effective only in improving employees' days of fruit consumption. [ABSTRACT FROM AUTHOR]

Cryogenic transmission electron microscopy(cryo-TEM) is utilizedto determine the second virial coefficient of osmotic pressure ofPbSe quantum dots (QDs) dispersed in apolar liquid. Cryo-TEM imagesfrom vitrified samples provide snapshots of the equilibrium distributionof the particles. These snapshots yield radial distribution functionsfrom which second virial coefficients are calculated, which agreewith second virial coefficients determined with analytical centrifugationand small-angle X-ray scattering. The size dependence of the secondvirial coefficient points to an interparticle interaction that isproportional to the QD surface area. A plausible cause for this attractionis the interaction between the surface ions on adjacent QDs. [ABSTRACT FROM AUTHOR]

The 3D distribution of nanocrystals at the liquid-air interface is imaged for the first time on a single-particle level by cryogenic electron tomography, revealing the equilibrium concentration profile from the interface to the bulk of the liquid. When the surface tension of the liquid is decreased, the interaction of the nanocrystals with the liquid-air interface shifts from adsorption to desorption. Macroscopic surface tension measurements do not detect this transition, due to the presence of surface-active molecular species. [ABSTRACT FROM AUTHOR]

Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK). Even though exposure has been linked to efficacy and toxicity for many of these drugs, they are still dosed using a one-size-fits-all approach. Consequently, individual patients (pts) have a high probability to be either underdosed or overdosed, potentially leading to decreased antitumor efficacy or increased toxicity. Therapeutic drug monitoring (TDM), which is personalised dosing based on measured drug levels, can be used to address these problems and thereby optimize treatment outcomes. This prospective clinical study (www.trialregister.nl, NL6695) evaluates the feasibility, tolerability and efficacy of TDM of oral anticancer drugs. In total, 600 pts will be included for 23 different drugs. Pts starting regular treatment with one of these drugs at the approved dose are included. PK sampling is performed 4, 8, and 12 weeks after start of treatment and every 12 weeks thereafter. Drug concentrations are measured and trough concentrations (C min) are estimated. In case of C min below the predefined target and acceptable toxicity, a PK-guided intervention is recommended. This may include emphasizing compliance, adaptations in concomitant medication (due to drug-drug interactions), concomitant intake with food, splitting intake moments or dose increments. In total, 274 pts were included (trametinib (n = 43), abiraterone (n = 38), enzalutamide (n = 35), imatinib (n = 33), pazopanib (n = 23), other (n = 102)), of whom 246 pts had available PK data. 83 pts (34%) were underdosed and had ≥ 1 PK samples below the predefined target. In 48 of 246 pts (20%) a PK-guided intervention was performed, which was successful (i.e. target attainment without additional toxicities) in 39 pts (81%). In 35 pts, a PK-guided intervention could not be performed, due to toxicity (17 pts), logistical reasons (13 pts) or lack of physician adherence (5 pts). This prospective study shows that PK-guided dose optimization of oral anticancer drugs is feasible in clinical practice. A PK-guided intervention was recommended in 20% of the patients and resulted in target attainment without additional toxicities in 81% of these patients. NL6695; release date: 6 December 2017. Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital. Unrestricted research grant of Novartis, Pfizer and Roche. S.L. Koolen: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. D.J.A.R. Moes: Advisory / Consultancy: Sandoz; Advisory / Consultancy, Research grant / Funding (institution): Chiesi Pharmaceuticals. I.M.E. Desar: Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Eisai. D.J. Touw: Advisory / Consultancy: Sanguin; Research grant / Funding (institution): Chiesi Pharmaceuticals. N.P. van Erp: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Gilead. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (institution), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier. N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]