Drug-drug interactions in Neonatal Intensive Care Units: how to overcome a challenge

INTRODUCTION: Critically ill patients in neonatal intensive-care units (NICU) are exposed to a large number of drugs. Clinical trials for safety, dosing and efficacy are lacking although age-dependent alterations of pharmacokinetics (PK), drug-drug-interactions (DDIs), as well as intravenous admixture incompatibilities (IAI) may impact drug efficacy and trigger side-effects in this vulnerable population. Consequently, implementation of a routinely used DDIs checking regimen may help guide in decision making and will assist clinicians to avoid serious and preventable events. Therefore, the goal of the present work is to identify and assess the risk of relevant DDIs of drugs commonly used in the NICU. EVIDENCE ACQUISITION: A literature review study was performed to identify and further assess the risk of relevant DDIs of 48 drugs frequently used in the tertiary care NICU of the University Hospital of Cologne. DDIs were categorized into five different classes according to their severity (contraindicated, minor, moderate, and major DDI, IAI), based on the classification used in the Micromedex database. In the database a major interaction is defined as any interaction that can be life threatening and/or demands medical intervention to avoid severe adverse effects. Moderate interactions can lead to a degradation of the patient's status and demand an adjustment in the therapy, and minor interactions only have a limited clinical effect. All identified DDIs in the present study are presented as a Visual Interaction Triangle (VIT) and recommendations on the management of clinically significant DDIs are provided. EVIDENCE SYNTHESIS: According to the classification used in the Micromedex database: a total of 160 (13.2%) possible interactions (DDI, IAI) were found. Fifty-five (4.9%) cases were categorized as serious interactions (DDI-major), 48 (4.2%) were less severe (DDI-moderate/minor) and in 52 (4.6%) cases an intravenous admixture drug interaction was found. Five (0.4%) drug-combinations were contraindicated. CONCLUSIONS: In this web-based study, a total of 160 DDIs were identified. Although only 4.9% were classified as clinically relevant, practitioners can use the presented VIT as a unique clinical reference to avoid possible predictable adverse effects and to uncover possible drug-interaction potential

Pharmacodynamic Monitoring of Mycophenolic Acid Therapy: Improved Liquid Chromatography-Tandem Mass Spectrometry Method for Measuring Inosin-5 '-Monophosphate Dehydrogenase Activity

Background: Mycophenolic acid (MPA), a powerful inhibitor of lymphocyte proliferation, is widely used in transplantation medicine and as a glucocorticoid-sparing agent in rheumatic and inflammatory diseases. As inosine-5 '-monophosphate dehydrogenase (IMPDH), the target enzyme of MPA, shows high interindividual variability in its basal activity, the assessment of IMPDH activity in addition to pharmacokinetic monitoring has emerged as a strategy to individualize MPA pharmacotherapy. Methods: A liquid chromatography-tandem mass spectrometry method was developed to measure IMPDH activity in peripheral blood mononuclear cells from lithium-heparinized blood. Stable isotope-labeled analogs of analytes were used as internal standards for the quantitative analyses of xanthosine-5 '-monophosphate (XMP) and adenosine-5 '-monophosphate (AMP). IMPDH activity was expressed as enzymatic production of XMP per time normalized to the AMP concentration. Validation and evaluation of the new method were performed by using blood samples from healthy volunteers (n = 10). Results: Linearity was demonstrated over the concentration ranges of 0.25-80 mu M for XMP and 4-80 mu M for AMP (R-2 > 0.99). Between-day and within-day assay precisions and accuracies were within the acceptance criterion of +/- 15%. Matrix effects were fully compensated by the coelution of internal standards. Specific and linear XMP production (R-2 > 0.99) and the inhibition of IMPDH activity by MPA at clinically relevant doses were demonstrated. Conclusions: In this study, a liquid chromatography-tandem mass spectrometry method to measure IMPDH activity was established and fully evaluated for matrix and ion suppression effects. The method enabled precise quantification of IMPDH activity for the improvement of pharmacokinetic/pharmacodynamic therapeutic drug monitoring approaches to optimize immunosuppressive treatment with MPA

Reliable and Easy-To-Use Liquid Chromatography-Tandem Mass Spectrometry Assay for Quantification of Olorofim (F901318), a Novel Antifungal Drug, in Human Plasma and Serum

A fast and easy-to-use liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination and quantification of a novel antifungal drug, olorofim (F901318), a member of the novel class of orotomides, in human plasma and serum was developed and validated. Sample preparation was based on protein precipitation with acetonitrile and subsequent centrifugation. An isotopelabeled analogue of F901318 was employed as an internal standard. Chromatographic separation was achieved using a 50-mm by 2.1-mm, 1.9-mu m, polar Hypersil Gold C-18 column and isocratic mobile phase consisting of 0.1% formic acid-acetonitrile (60%-40%, vol/vol) at a flow rate of 330 mu l/min. The analyte was detected using a triple-stage quadrupole mass spectrometer operated in selected reaction monitoring (SRM) mode with positive heated electrospray ionization (HESI*) within a single runtime of 2.00 min. The present LC-MS/MS method was validated according to the international guidelines of the International Conference on Harmonisation (ICH) and the U.S. Food and Drug Administration (FDA). Linearity of F901318 concentration ranges was verified by the Mandel test. The calibration curve was tested linear across the range and fitted using least-squares regression with a weighting factor of the reciprocal concentration. The limit of detection was 0.0011 mg/liter, and the lower limit of quantitation was 0.0033 mg/liter. Intraday and interday precisions ranged from 1.17% to 3.23% for F901318, and intraday and interday accuracies (percent bias) ranged from 0.75% to 5.01%. In conclusion, a method was established for the rapid quantitation of F901318 concentrations in serum and plasma samples in patient trials, and it optimizes therapeutic drug monitoring in applying an easy-to-use single method

Quantification of direct-acting oral anticoagulants: Application of a clinically validated liquid chromatography-tandem mass spectrometry method to forensic cases

In certain forensic cases, a quantification of direct-acting oral anticoagulants (DOACs) can be necessary. We evaluate the applicability of a previously described liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology for the determination of DOACs in plasma to postmortem specimen. Postmortem internal quality control (PIQC) samples were prepared in pooled blank postmortem heart blood, femoral blood, cerebrospinal fluid (CSF), and urine as well in plasma. To examine the application of the clinical method to forensic cases, the main validation parameters were reinvestigated using PIQC samples. Postmortem samples of 12 forensic cases with evidence of previous rivaroxaban intake and unknown bleeding disorders were analyzed. Interday variability remained within the acceptance criterion of +/- 15%. Matrix effects were comparable in blank plasma and postmortem matrix extracts. After 4 weeks of storage in the refrigerator, no relevant decrease of DOACs was evident. After 96 h of storage at room temperature, a slight decrease in edoxaban concentration was observed in CSF and urine, while plasma edoxaban decreased by about 50%. Median (range) rivaroxaban concentrations determined in specimen of forensic cases were as follows: heart blood (n = 6), 17.2 ng/ml (<LOQ, 56.6 ng/ml); femoral blood (n = 12), 27.6 ng/ml (<LOQ, 110.5 ng/ml); CSF (n = 7), 11.7 ng/ml (<LOQ, 17.5 ng/ml); urine (n = 6), 275.7 ng/ml (14.5-870.9 ng/ml). The median heart/femoral blood rivaroxaban ratio was 1.2 (n = 5). Exemplary, a forensic case with detection of edoxaban in femoral blood, CSF, and urine, is presented. DOACs can be detected in postmortem heart and femoral blood, CSF, and urine specimen by LC-MS/MS. Based on limited forensic cases, no significant redistribution was evident for rivaroxaban, which was found at highest concentrations in urine

West German Study PlanB Trial: Adjuvant Four Cycles of Epirubicin and Cyclophosphamide Plus Docetaxel Versus Six Cycles of Docetaxel and Cyclophosphamide in HER2-Negative Early Breast Cancer

PURPOSE The West German Study Group PlanB trial evaluated an anthracycline-free chemotherapy standard (six cycles of docetaxel and cyclophosphamide [TC]) in the routine treatment of human epidermal growth factor receptor 2-negative early breast cancer (EBC). PATIENTS AND METHODS Patients with pT1 to pT4c, all pN+, and pN0/high-risk EBC were eligible. High-risk pN0 was defined by one or more of the following: pT greater than 2, grade 2 to 3, high urokinase-type plasminogen activator/plasminogen activator inhibitor-1, hormone receptor (HR) negativity, and less than 35 years of age. After an early amendment, all HR-positive tumors underwent recurrence score (RS) testing, with chemotherapy omission recommended in RS less than or equal to 11 pN0 to pN1 disease. Patients were randomly assigned to four cycles of epirubicin (E)(90)/cyclophoshamide (C)(600) followed by four cycles of docetaxel (T)(100) or six cycles of T75C600 (administered once every 3 weeks). The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The protocol specified P = .05 for a noninferiority margin of 4.4% for all patients combined. RESULT Of the 3,198 registered patients, 348 (RS <= 11) omitted chemotherapy, and 401 were not randomly assigned. The intention-to-treat population included 2,449 patients (1,227 EC-T v 1,222 TC: postmenopausal, 62.2% v60.8%; pNO, 58.2% v59.5%; pT1, 57.6% v52.3%; HR positive, 81.4% v82.2%; RS greater than 25 [in H.R-positive patients], 26.2% v 27.5%). Within the safety population (1,167 v 1,178 patients), 87.5% v 93.0% completed therapy. After a 60-month median follow-up, 5-year outcomes were similar in the EC-T and TC arms (DFS, 89.6% [95% CI, 87.9% to 91.5%] v89.9% [95% CI, 88.1% to 91.8%]; OS, 94.5% [95% CI, 93.1% to 95.9%] v94.7% [95% CI, 93.3% to 96.1%]). The DFS difference was within the noninferiority margin of the original trial design. Five treatment-related deaths were reported for TC (one for EC-T), despite a trend toward more-severe adverse events in the latter. Interaction analysis revealed no predictive trends with respect to key factors, including triple-negative, luminal A/B-like, pN, age, and RS status. CONCLUSION In the West German Study Group PlanB trial, 5-year outcomes for TC and EC-T were equally excellent. Six cycles of TC is an effective/safe option in human epidermal growth factor receptor 2-negative EBC with pN0 high genomic risk or pN1 EBC with genomically intermediate- to high-risk disease. (C) 2019 by American Society of Clinical Oncolog