Jos G. W. Kosterink

Biodistribution of 89Zr-trastuzumab and PET Imaging of HER2-Positive Lesions in Patients With Metastatic Breast Cancer

We performed a feasibility study to determine the optimal dosage and time of administration of the monoclonal antibody zirconium‐89 (89Zr)‐trastuzumab to enable positron emission tomography (PET) imaging of human epidermal growth factor receptor 2 (HER2)‐positive lesions. Fourteen patients with HER2‐positive metastatic breast cancer received 37 MBq of 89Zr‐trastuzumab at one of three doses (10 or 50 mg for those who were trastuzumab‐naive and 10 mg for those who were already on trastuzumab treatment). The patients underwent at least two PET scans between days 2 and 5. The results of the study showed that the best time for assessment of 89Zr‐trastuzumab uptake by tumors was 4–5 days after the injection. For optimal PET‐scan results, trastuzumab‐naive patients required a 50 mg dose of 89Zr‐trastuzumab, and patients already on trastuzumab treatment required a 10 mg dose. The accumulation of 89Zr‐trastuzumab in lesions allowed PET imaging of most of the known lesions and some that had been undetected earlier. The relative uptake values (RUVs) (mean ± SEM) were 12.8 ± 5.8, 4.1 ± 1.6, and 3.5 ± 4.2 in liver, bone, and brain lesions, respectively, and 5.9 ± 2.4, 2.8 ± 0.7, 4.0 ± 0.7, and 0.20 ± 0.1 in normal liver, spleen, kidneys, and brain tissue, respectively. PET scanning after administration of 89Zr‐trastuzumab at appropriate doses allows visualization and quantification of uptake in HER2‐positive lesions in patients with metastatic breast cancer.

Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents

There are currently a number of licensed azole antifungal drugs; however; only 4 (namely, fluconazole, itraconazole, posaconazole, and voriconazole) are used frequently in a clinical setting for prophylaxis or treatment of systemic fungal infections. In this article, we review the pharmacokinetic interactions of these azole antifungal drugs with other coadministered agents. We describe these (2-way) interactions and the extent to which metabolic pathways and/or other supposed mechanisms are involved in these interactions. This article provides an overview of all published drug-drug interactions in humans (either healthy volunteers or patients), and on the basis of these findings, we have developed recommendations for managing the specific interactions.

Development and Characterization of Clinical-Grade 89Zr-Trastuzumab for HER2/neu ImmunoPET Imaging

The anti–human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/neu-overexpressing breast cancer. Whole-body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible metastases. The aims of this study were to develop clinical-grade radiolabeled trastuzumab for clinical HER2/neu immunoPET scintigraphy, to improve diagnostic imaging, to guide antibody-based therapy, and to support early antibody development. The PET radiopharmaceutical 89Zr-trastuzumab was compared with the SPECT tracer 111In-trastuzumab, which we have tested in the clinic already. Methods: Trastuzumab was labeled with 89Zr and (for comparison) with 111In. The minimal dose of trastuzumab required for optimal small-animal PET imaging and biodistribution was determined with human HER2/neu-positive or -negative tumor xenograft–bearing mice. Results: Trastuzumab was efficiently radiolabeled with 89Zr at a high radiochemical purity and specific activity. The antigen-binding capacity was preserved, and the radiopharmaceutical proved to be stable for up to 7 d in solvent and human serum. Of the tested protein doses, the minimal dose of trastuzumab (100 μg) proved to be optimal for imaging. The comparative biodistribution study showed a higher level of 89Zr-trastuzumab in HER2/neu-positive tumors than in HER2/neu-negative tumors, especially at day 6 (33.4 ± 7.6 [mean ± SEM] vs. 7.1 ± 0.7 percentage injected dose per gram of tissue). There were good correlations between the small-animal PET images and the biodistribution data and between 89Zr-trastuzumab and 111In-trastuzumab uptake in tumors (R2 = 0.972). Conclusion: Clinical-grade 89Zr-trastuzumab showed high and HER2/neu-specific tumor uptake at a good resolution.

Indium-111-Labeled Trastuzumab Scintigraphy in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer

PURPOSE The cardiac and antineoplastic effects of trastuzumab may be related to specific uptake of trastuzumab in myocardium and tumor tissue, respectively. We evaluated whether indium-111 (111In)-labeled trastuzumab scintigraphy can predict cardiotoxicity and identify tumor lesions. In addition, we evaluated whether plasma markers for cardiac dysfunction can be used to predict cardiotoxicity. PATIENTS AND METHODS Patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer underwent gamma camera imaging from 15 minutes to 7 days after injection of 150 MBq 111In-diethylenetriamine penta-acetic acid anhydride (DTPA) -trastuzumab, after loading-dose trastuzumab, and after once-a-week trastuzumab doses for 11 weeks, and concomitant paclitaxel once every 3 weeks. Cardiac assessments were performed before treatment, and after four and six cycles. Plasma N-terminal probrain natriuretic peptide (NT-proBNP) and serum troponin I were measured with immunoassay. RESULTS Fifteen of the 17 patients were available for cardiac and tumor uptake analysis. On the first scan, myocardial 111In-DTPA-trastuzumab uptake was observed in one patient with pre-existing cardiac arrhythmias, who did not develop heart failure during treatment. Severe cardiotoxicity occurred in three patients, without initial myocardial uptake, whereas one showed weak myocardial uptake after four cycles. The detection rate of single tumor lesions was 45%. New tumor lesions were discovered in 13 of 15 patients. Pretreatment plasma NT-proBNP levels were higher in patients with than without heart failure (mean, 534 [standard deviation, 236] v 105 [standard deviation, 79] ng/L; P = .009). CONCLUSION Radiolabeled trastuzumab scintigraphy was not valuable in predicting trastuzumab-related cardiotoxicity in metastatic breast cancer patients, but can identify HER2-positive tumors. Measurement of plasma NT-proBNP is promising regarding prediction of trastuzumab-related cardiotoxicity.

Intraoperative Near-Infrared Fluorescence Tumor Imaging with Vascular Endothelial Growth Factor and Human Epidermal Growth Factor Receptor 2 Targeting Antibodies

Fluorescence imaging is currently attracting much interest as a method for intraoperative tumor detection, but most current tracers lack tumor specificity. Therefore, this technique can be further improved by tumor-specific detection. With tumor-targeted antibodies bound to a radioactive label, tumor-specific SPECT or PET is feasible in the clinical setting. The aim of the present study was to apply antibody-based tumor detection to intraoperative optical imaging, using preclinical in vivo mouse models. Methods: Anti–vascular endothelial growth factor (VEGF) antibody bevacizumab and anti–human epidermal growth factor receptor (HER) 2 antibody trastuzumab were labeled with the near-infrared (NIR) fluorescence dye IRDye 800CW. Tumor uptake of the fluorescent tracers and their 89Zr-labeled radioactive counterparts for PET was determined in human xenograft–bearing athymic mice during 1 wk after tracer injection, followed by ex vivo biodistribution and pathologic examination. Intraoperative imaging of fluorescent VEGF- or HER2-positive tumor lesions was performed in subcutaneous tumors and in intraperitoneal dissemination tumor models. Results: Tumor-to-background ratios, with fluorescent imaging, were 1.93 ± 0.40 for bevacizumab and 2.92 ± 0.29 for trastuzumab on day 6 after tracer injection. Real-time intraoperative imaging detected tumor lesions at even the submillimeter level in intraperitoneal dissemination tumor models. These results were supported by standard histology, immunohistochemistry, and fluorescence microscopy analyses. Conclusion: NIR fluorescence–labeled antibodies targeting VEGF or HER2 can be used for highly specific and sensitive detection of tumor lesions in vivo. These preclinical findings encourage future clinical studies with NIR fluorescence–labeled tumor-specific antibodies for intraoperative-guided surgery in cancer patients.

Preclinical characterisation of 111In-DTPA-trastuzumab

Trastuzumab (Herceptin®) is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), used for metastatic breast cancer treatment. Radiolabelled trastuzumab may have several future applications for diagnostic use. The aim of the present study was to develop clinical grade 111Indium (111In) radiolabelled trastuzumab, to evaluate the stability and immunoreactivity of the tracer and to perform a biodistribution study in human tumour‐bearing mice. Trastuzumab was radiolabelled with 111In using DTPA as a chelator. 111In‐DTPA‐trastuzumab (labelling yield 92.3±2.3%, radiochemical purity 97.0±1.5%) is stable in PBS when stored at 4°C for more than 14 days. The immunoreactive fraction determined by cell‐binding assays, using the HER2‐overexpressing human ovarian SK‐OV‐3 tumour cell line, was 0.87±0.06. Biodistribution and tumour targeting were studied in HER2 receptor‐positive and ‐negative tumour‐bearing athymic mice. The HER2‐positive tumour showed (9.77±1.14% injected dose per gram (ID g−1)) substantial uptake of the labelled antibody already after 5 h. The difference in uptake between HER2‐positive versus ‐negative tumours was even more pronounced 3 days after injection (16.30±0.64% ID g−1), and was visualised by radioimmunoscintigraphy. Liver, spleen and kidney showed marked tracer uptake. In summary, trastuzumab can be efficiently radiolabelled with 111In with high labelling yields and high stability. 111In‐DTPA‐trastuzumab selectively binds to the human HER2 receptor both in vitro and in vivo in animals. Therefore, 111In‐DTPA‐trastuzumab appears suitable for clinical use.

The influence that electronic prescribing has on medication errors and preventable adverse drug events : an interrupted time-series study

OBJECTIVE This study evaluated the effect of a Computerized Physician Order Entry system with basic Clinical Decision Support (CPOE/CDSS) on the incidence of medication errors (MEs) and preventable adverse drug events (pADEs). DESIGN Interrupted time-series design. MEASUREMENTS The primary outcome measurements comprised the percentage of medication orders with one or more MEs and the percentage of patients with one or more pADEs. RESULTS Pre-implementation, the mean percentage of medication orders containing at least one ME was 55%, whereas this became 17% post-implementation. The introduction of CPOE/CDSS has led to a significant immediate absolute reduction of 40.3% (95% CI: -45.13%; -35.48%) in medication orders with one or more errors. Pre-implementation, the mean percentage of admitted patients experiencing at least one pADE was 15.5%, as opposed to 7.3% post-implementation. However, this decrease could not be attributed to the introduction of CPOE/CDSS: taking into consideration the interrupted time-series design, the immediate change was not significant (-0.42%, 95% CI: -15.52%; 14.68%) because of the observed underlying negative trend during the pre-CPOE period of -4.04% [95% CI: -7.70%; -0.38%] per month. CONCLUSIONS This study has shown that CPOE/CDSS reduces the incidence of medication errors. However, a direct effect on actual patient harm (pADEs) was not demonstrated.

Method for therapeutic drug monitoring of azole antifungal drugs in human serum using LC/MS/MS

Fungal infections occur in immunocompromised patients. Azole antifungal agents are used for the prophylaxis and treatment of these infections. The interest in therapeutic drug monitoring azole agents has increased over the last few years. Inter- and intra-patient variability of pharmacokinetics, drug-drug interactions, serum concentration related toxicity and success of therapy has stressed the need of frequently therapeutic drug monitoring of the drugs, belonging to the group of azoles. Therefore a simple, rapid and flexible method of analysis is required. This method is based on the precipitation of proteins in human serum with LC/MS/MS detection. Validation was performed according to the guidelines for bioanalytical method validation of the food and drug administration agency. The four most used azole drugs can be detected in human serum within the clinical relevant serum levels with good accuracy and reproducibility at the limit of quantification. Intra- and inter-day validation demonstrated good accuracy and reproducibility. A rapid, sensitive and flexible LC/MS/MS method has been developed and validated to measure voriconazole (VRZ), fluconazole (FLZ), itraconazole (ITZ) and posaconazole (PSZ) in human serum. This new method is suitable for clinical pharmacokinetic studies and routine monitoring in daily practice.

Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings.

Conventional pH-responsive coatings used for oral drug delivery to the lower parts of the gastro-intestinal tract often show a poor performance. A new system for site-specific pulsatile delivery in the ileo-colonic regions is described. The system is based on the non-percolating incorporation of disintegrants in a coating which consists further of a continuous matrix of pH-responsive polymer (Eudragit S). Extensive in vitro release studies were performed in which coatings with different concentrations and disintegrants were studied and compared to non-disintegrant containing coatings. In vitro data show that the incorporation of swelling agents in an Eudragit S-coating still allows delayed release in the simulated terminal ileum. The pulse time and the robustness could be improved compared to conventional Eudragit S-coatings. The augmented pH-responsiveness of the new coating was related to the swelling index of the applied disintegrant. Based on the in vitro data comparing different swelling agents, Ac-di-sol appears to be the best performing swelling agent. A proof-of-concept study in human subjects was performed to investigate the performance of the new system in vivo. Coated capsules containing the stable isotope (13)C(6)-glucose as the test compound were administered and the occurrence of (13)CO(2) in the breath of the subjects was measured. It could be shown that the coating is able to resist the environmental conditions in the stomach and duodenum and delay release until deeper parts of the intestines are reached. Furthermore, the capsule is able to maintain a pulsatile release profile. It is concluded that the structured incorporation of swelling agents in pH-responsive polymers improves the delayed, pulsatile release kinetics of coated capsules. In a proof-of-concept in vivo study it was shown that the newly developed coating enables pulsatile delivery of the content to the lower parts of the intestines.

Medication errors: the impact of prescribing and transcribing errors on preventable harm in hospitalised patients

Background: Medication errors (MEs) affect patient safety to a significant extent. Because these errors can lead to preventable adverse drug events (pADEs), it is important to know what type of ME is the most prevalent cause of these pADEs. This study determined the impact of the various types of prescribing (administrative, dosing and therapeutic) and transcribing errors on pADEs in hospitalised patients. Methods: During a 5-month period, data for patients admitted to a total of five internal medicine wards of one university and one teaching hospital in The Netherlands were prospectively collected by chart review. In each hospital, MEs were detected and classified by the same pharmacist, using the classification scheme for MEs developed by The Netherlands Association of Hospital Pharmacists. The primary outcome measure was the prevalence of pADEs during hospital stay. In consensus meetings, five pharmacists assessed the causal relationship between MEs and pADEs. The association between type of ME and pADEs was determined by a multivariate regression analysis taking into account potential confounders. Results: The study included 592 hospital admissions with 7286 medication orders (MOs), of which 60% contained at least one prescribing or transcribing error. 1.4% of all MOs led to pADEs, concerning 14.8% of all admitted patients. The total number of pADEs was 103, and in 92 of these cases patients experienced temporary harm, in eight cases hospital admission was prolongued, two cases were life-threatening, and one was fatal. Therapeutic errors were most strongly associated with pADEs (OR 1.98; 95% CI 1.53 to 2.56). Conclusions: Although many prescribing and transcribing errors occur in the process of medication use of hospitalised patients, a minority lead to pADEs. In particular, therapeutic errors are the cause of these pADEs and are therefore clinically relevant. Intervention and prevention programmes should primarily focus on this type of medication error.