Sunitinib for the treatment of metastatic gastrointestinal stromal tumors: the effect of TDM-guided dose optimization on clinical outcomes.

BACKGROUND: Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposure-response relationship at the standard dose, and minimum target levels of drug exposure have been defined above which better treatment outcomes are observed. Therapeutic drug monitoring (TDM) could be used as a tool to optimize the individual dose, aiming at sunitinib trough concentrations ≥37.5 ng/ml for continuous dosing. Nonetheless, data on the added value of TDM-guided dosing on clinical endpoints are currently lacking. Therefore, we evaluate the effect of TDM in patients with advanced and metastatic GIST treated with sunitinib in terms of efficacy and toxicity. PATIENTS AND METHODS: A TDM-guided cohort was compared to a non-TDM-guided cohort in terms of median progression-free survival (mPFS) and overall survival (mOS). Also, mPFS between patients with and without dose-limiting toxicities (DLTs) was compared. Patients in the prospective cohort were included in two studies on TDM-guided dosing (the DPOG-TDM study and TUNE study). The retrospective cohort consisted of patients from the Dutch GIST Registry who did not receive TDM-guided dosing. RESULTS: In total, 51 and 106 patients were included in the TDM-guided cohort and non-TDM-guided cohort, respectively. No statistical difference in mPFS was observed between these two cohorts (39.4 versus 46.9 weeks, respectively; P = 0.52). Patients who experienced sunitinib-induced DLTs had longer mPFS compared to those who did not (51.9 versus 28.9 weeks, respectively; P = 0.002). CONCLUSIONS: Our results do not support the routine use of TDM-guided dose optimization of sunitinib in patients with advanced/metastatic GIST to improve survival.

Towards a farmer-feasible soil health assessment that is globally applicable.

Globally, agriculture has had a significant and often detrimental impact on soil. The continued capacity of soil to function as a living ecosystem that sustains microbes, plants, and animals (including humans), its metaphorical health, is of vital importance across geographic scales. Healthy soil underpins food production and ecosystem resilience against a changing climate. This paper focuses on assessing soil health, an area of increasing interest for farming communities, researchers, industry and policy-makers. Without accessible and reliable soil assessment, any management and interventions to improve soil health are likely to be sub-optimal. Here we explore available soil health assessments (SHAs) that may be feasible for farmers of varying income levels and suitable for broad geographic application. Whilst there is a range of existing approaches to SHA, we find that no one framework currently meets these broad aims. Firstly, reliance on expensive and logistically complex laboratory methods reduces viability and accessibility for many farmers. Secondly, lack of defined indicator baselines and associated thresholds or gradients for soil health prevents the assessment of soil measurements against achieving optima for a given set of local soil-climate conditions. Since soils vary greatly, these baselines and thresholds must be defined considering the local biogeographic context; it is inappropriate to simply transfer calibrated information between contexts. These shortcomings demand progress towards a feasible, globally applicable and context-relevant SHA framework. The most feasible SHAs we identified were developed locally in conjunction with farmers, who have been repeatedly found to assess the health of their soils accurately, often using relatively simple, observable indications. To progress, we propose assessment of which indicators add information to a SHA in local contexts, with a focus on sufficiency, to reduce data burden. Provision of a standardised protocol for measurement and sampling that considers the reliability and accuracy of different methods would also be extremely valuable. For greatest impact, future work should be taken forward through a cross-industry collaborative approach involving researchers, businesses, policy makers, and, above all, farmers, who are both experts and users.

The impact of endoxifen-guided tamoxifen dose reductions on endocrine side-effects in patients with primary breast cancer.

BACKGROUND: Tamoxifen is important in the adjuvant treatment of hormone-sensitive breast cancer and substantially reduces recurrence; however, almost 50% of patients are non-compliant mainly due to side-effects. The aim of this study was to investigate whether endoxifen-guided tamoxifen dose reduction could lead to fewer side-effects. MATERIALS AND METHODS: Effects of tamoxifen dose reduction were investigated in patients with bothersome side-effects and endoxifen levels ≥32 nM and compared to patients with side-effects who remained on tamoxifen 20 mg. Endocrine symptoms and health-related quality of life (HR-QOL) were assessed after 3 months with the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire. RESULTS: Tamoxifen dose was reduced in 20 patients, 17 of whom were assessable for side-effect analyses. A clinically relevant improvement of >6 points was observed in endocrine symptoms and HR-QOL in 41% and 65% of the patients, respectively. In total, there was a significant and clinically relevant improvement in endocrine symptoms [5.7, 95% confidence interval (CI) -0.5-11.5] and HR-QOL (8.2, 95% CI 0.9-15.4) after dose reduction. This was not seen in patients whose doses were not reduced (n = 60). In 21% of patients, endoxifen dropped slightly below the 16-nM threshold (12.8, 15.5, 15.8, 15.9 nM). CONCLUSIONS: Endoxifen-guided dose reduction of tamoxifen significantly improved tamoxifen-related side-effects and HR-QOL. Nearly 80% of patients remained above the most conservative endoxifen threshold.

Therapeutic drug monitoring-based precision dosing of oral targeted therapies in oncology: a prospective multicenter study.

BACKGROUND: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems. PATIENTS AND METHODS: Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug-drug interactions, concomitant intake with food, splitting intake moments or dose increments). RESULTS: In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had ≥1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had ≥1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%). CONCLUSIONS: Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably.

Pemetrexed exposure predicts toxicity in advanced non-small-cell lung cancer: A prospective cohort study.

BACKGROUND: We explored whether total exposure to pemetrexed predicts effectiveness and toxicity in advanced non-small-cell lung cancer (NSCLC). Furthermore, we investigated alternative dosing schedules. METHODS: In this prospective cohort study, patients with advanced NSCLC receiving first- or second-line pemetrexed(/platinum) were enrolled. Plasma sampling was performed weekly (cyclePK) and within 24 h (24hPK) after pemetrexed administration. With population pharmacokinetic/pharmacodynamic modelling, total exposure to pemetrexed during cycle 1 (area under the curve during chemotherapy cycle 1 [AUC1]) was estimated and related to progression-free survival (PFS)/overall survival (OS). We compared mean AUC1 (mg·h/L) in patients with and without severe chemotherapy-related adverse events (AEs) during total treatment. Second, different dosing schedules were simulated to minimise the estimated variability (coefficient of variation [CV]) of AUC. RESULTS: For 106 of 165 patients, concentrations of pemetrexed were quantified (24hPK, n = 15; cyclePK, n = 106). After adjusting for prognostic factors, sex, disease stage and World Health Organisation performance score, AUC1 did not predict PFS/OS in treatment-naive patients (n = 95) (OS, hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.00-1.11; PFS, HR = 1.03, 95% CI: 0.98-1.08). Patients with severe chemotherapy-related AEs (n = 55) had significantly higher AUC1 values than patients without them (n = 51) (226 ± 53 vs 190 ± 31, p < 0.001). Compared with body surface area-based dosing (CV: 22.5%), simulation of estimated glomerular filtration rate (eGFR)-based dosing (CV 18.5%) and fixed dose of 900 mg with 25% dose reduction, if the eGFR<60 mL/min (CV: 19.1%), resulted in less interindividual variability of AUC. CONCLUSIONS: Higher exposure to pemetrexed does not increase PFS/OS but is significantly associated with increased occurrence of severe toxicity. Our findings suggest that fixed dosing reduces interpatient pharmacokinetic variability and thereby might prevent toxicity, while preserving effectiveness.

Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

A new method for the determination of total and released docetaxel from docetaxel-entrapped core-crosslinked polymeric micelles (CriPec®) by LC-MS/MS and its clinical application in plasma and tissues in patients with various tumours.

A sensitive, high-performance liquid chromatographic method was developed and validated, for determination of docetaxel from docetaxel-entrapped core-crosslinked polymeric micelles (CriPec®) in human potassium EDTA plasma and released docetaxel to support the clinical development of Cripec® docetaxel. CriPec® docetaxel is a novel formulation of docetaxel - covalently conjugated via a linker agent in a nanoparticle. The analytical characterization of CriPec® docetaxel comprises determination of both released and total docetaxel, the first being the already deconjugated docetaxel, whereas total is representative of all docetaxel (deconjugated as well as CriPec® nanoparticle conjugated material). Total docetaxel was determined by incubation of human plasma with 0.5 M ammonium acetate buffer pH 7.4 for 3-days at 37 °C. Hereafter, a liquid-liquid extraction with 1-chlorobutane was performed using paclitaxel as internal standard. Released docetaxel from CriPec® docetaxel nanoparticles was determined in human plasma stabilized with 5 M ammonium acetate, pH 5.0. Hereafter, a liquid-liquid extraction with 1-chlorobutane was performed using docetaxel-d5 in acetonitrile as internal standard. Released docetaxel and its internal standard were eluted. The validated ranges for total docetaxel were 2,000-100,000 ng/mL for the high concentrations and 2-500 ng/mL for the low concentrations and 0.250-100 ng/mL for released docetaxel. In conclusion the newly developed assay met the required standards for validation and was applied successfully to support pharmacokinetic analysis in both serum and tissue in patients treated with Cripec®.

Monitoring in language perception in high-functioning adults with autism spectrum disorder: evidence from event-related potentials.

OBJECTIVES: Autism spectrum disorder (ASD) is characterized by impaired global language processing, whereas local language processing often appears intact. Recent psycholinguistic research suggests that the quality of language perception relies on monitoring, an aspect of executive control. The aim of the study was to examine monitoring in people with ASD of (a) local, orthographic violations, and (b) global, syntactic violations, when provided with single level versus dual level task instructions. METHODS: We recorded event-related potentials and compared P600 effects to the linguistic violations relative to correct words in 14 adults with ASD and 14 matched controls. RESULTS: In control participants, local errors elicited a monitoring response as tapped by the P600 effect in both conditions. For global errors, the P600 effect was present only at one centroposterior site in the single level condition, whereas in the dual level condition a broadly distributed effect was obtained. People with ASD, however, showed a monitoring response to local and global errors both in the single and dual level condition. CONCLUSIONS: The main ERP finding suggests that when instructed people with ASD monitor global aspects of language already under simple circumstances, whereas people without ASD mainly do so under more complex circumstances. SIGNIFICANCE: Results suggest that language problems in ASD should not be studied in terms of a linguistic dysfunction as such, but in light of the use of executive resources during language comprehension.

From mouse to man: predictions of human pharmacokinetics of orally administered docetaxel from preclinical studies.

Intravenously administered docetaxel is approved for the treatment of various types of cancer. An oral regimen, in combination with ritonavir, is being evaluated in clinical trials. The pharmacokinetics of docetaxel are determined by the activity of the metabolizing enzyme cytochrome P450 3A (CYP3A) and the drug efflux transporter P-glycoprotein (P-gp). The effects of these proteins on the pharmacokinetics of docetaxel were investigated in different mouse models that lack 1 or both detoxifying systems. Docetaxel was given to these mice orally or intravenously with or without a strong CYP3A inhibitor, ritonavir. The data of these 2 preclinical studies were pooled and analyzed using nonlinear mixed-effects modeling. The results of the preclinical studies could be integrated successfully, with only a small difference in residual error (33% and 26%, respectively). Subsequently, the model was used to predict human exposure using allometric scaling and this was compared with clinical trial data. This model led to adequate predictions of docetaxel exposure in humans.

Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001).

For use in chronic oral chemotherapeutic regimens, the potent anticancer drug docetaxel needs a solid oral dosage form. Because docetaxel has a very low permeability and a very low aqueous solubility (biopharmaceutical classification system class IV), a pharmacokinetic booster was combined with a newly developed solid dispersion formulation to improve the oral bioavailability of docetaxel. The best performing solid dispersion was a 1/9/1 w/w/w ternary mixture of docetaxel, polyvinylpyrrolidone (PVP)-K30 and sodium lauryl sulphate (SLS). In a phase I clinical trial, with ritonavir as pharmacokinetic booster, the docetaxel premix solution (TAXOTERE) was pharmacokinetically evaluated against the solid dispersion formulation filled into hard gelatin capsules (ModraDoc001 15 mg capsules). There were no significant differences between the pharmacokinetic parameters of docetaxel after administration of docetaxel premix solution or ModraDoc001 15 mg capsules, although there was a trend towards a higher and more variable exposure to docetaxel after oral administration of docetaxel premix solution (513 ± 219 vs. 790 ± 669 ngh/mL). The low inter-individual variability of docetaxel exposure (44%), the dosing accuracy, and the absence of ethanol and polysorbate are major advantages of ModraDoc001 15 mg capsules over docetaxel premix solution.

Intravenous-to-oral switch in anticancer chemotherapy: a focus on docetaxel and paclitaxel.

Oral administration of the taxanes docetaxel and paclitaxel is hampered by their affinity for drug transporters, especially ABCB1 (P-glycoprotein, Pgp); extensive first-pass metabolism by cytochrome P450 3A (CYP3A); and poor drug solubility. Preclinical studies in Pgp-deficient and wild-type mice demonstrated that modulation of either Pgp or CYP3A resulted in high systemic exposure to docetaxel or paclitaxel. This concept could successfully be translated to clinical trials.