Prospective Investigation of the Performance of 2 Gamma-Hydroxybutyric Acid Tests: DrugCheck GHB Single Test and Viva-E GHB Immunoassay

Background: Gamma-hydroxybutyric acid (GHB) is a recreational drug with central nervous system depressing effects that is often abused. A urine GHB point-of-care test can be of great diagnostic value. The objective of this prospective study was to determine the performance of the new DrugCheck GHB Single Test and the Viva-E GHB immunoassay for urine samples in emergency department patients. Methods: Patients presented to the emergency department of the OLVG hospital in Amsterdam with a Glasgow Coma Scale score ,15 and potential drug of abuse intoxication were included in the study. Between June 2016 and October 2017, 375 patients were included. Using the DrugCheck GHB Single Test (Express Diagnostics Int’l, Blue Earth, MN) and the Viva-E GHB immunoassay (Siemens Healthineers, The Hague, the Netherlands), patients’ urine samples were tested for GHB (cutoff for a positive result, 10 or 50 mcg/mL GHB). To ensure quality, the results obtained were compared with those generated using a validated gas chromatography method. The tests were considered reliable if specificity and sensitivity were both .90%. Possible cross-reactivity with ethanol was investigated by analyzing ethanol concentrations in patients’ samples. Results: Seventy percentage of the included patients was men, and the median age was 34 years old. The DrugCheck GHB Single Test’s specificity and sensitivity were 90.0% a

Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents

Due to variation in drug distribution, metabolism and elimination processes between patients, systemic exposure to chemotherapeutic agents may be highly variable from patient to patient after administration of similar doses. This pharmacokinetic variability may explain in part the large variability in therapeutic response seen in patients receiving chemotherapy. Patients receiving high exposures of a chemotherapeutic agent may show a better response to therapy but are also at higher risk for toxicity, while patients with lower exposures may have a reduced therapeutic response but also a lower risk of experiencing side-effects. The optimal exposure in a patient results in an adequate therapeutic response with low risk of adverse effects. Relationships between systemic exposure and toxic or therapeutic effects have been demonstrated for several anticancer drugs. These relationships may be used to optimize the administration of chemotherapeutic agents applying pharmacokinetically guided dosing (PKGD). However, measurement of plasma drug levels for dosing are not regularly performed with these agents. This thesis deals with PKGD of the four chemotherapeutic agents cyclophosphamide, thiotepa, carboplatin (as administered in the high-dose CTC regimen) and paclitaxel. To be able to implement this dosing strategy in clinical practice, we firstly worked on a fast and robust bioanalytical method for the quantification of cyclophosphamide and thiotepa and their relevant active metabolites using HPLC-MS/MS. Furthermore, we performed extensive population pharmacokinetic analysis to accurately describe the time-course of cyclophosphamide (and multiple metabolites), thiotepa (and its metabolite tepa), carboplatin and paclitaxel concentrations in plasma using non-linear regression methods. These models formed the basis for the Bayesian dosing strategy we applied for the PKGD strategy. Factors influencing the pharmacokinetic profile of cyclophosphamide, thiotepa and carboplatin were also established: Co-medicated agents such as phenytoin and aprepitant, as well as serum creatinine levels and obesity appeared to influence the pharmacokinetics of cyclophosphamide, thiotepa and/or carboplatin. Moreover, we established relationships between toxicity (irreversible alopecia and veno-occlusive disease of the liver (VOD)) and exposure to cyclophosphamide, thiotepa and carboplatin (or metabolites), which stress the importance of pharmacokinetically guided dosing in the CTC regimen in reducing or preventing the occurrence of these toxicities. Finally, pharmacokinetically guided dosing strategies for cyclophosphamide, thiotepa, carboplatin and paclitaxel were developed and validated in a prospective manner. In the CTC scheme, a total of 46 patients received adapted doses of cyclophosphamide, thiotepa and carboplatin based on their individual pharmacokinetic profile. A total of 25 patients with non-small cell lung cancer received multiple individualized paclitaxel administrations. The studies proved that the pharmacokinetically guided dosing strategy results in an effective reduction of interindividual variability in exposure to the compounds or their metabolites and is feasible in clinical practice. Whether the dosing strategy also results in reduction of toxicity and/or improvement of therapeutic outcome remains to be determined from larger studies, preferably in a randomized setting. In conclusion, a very significant therapeutic gain may be achievable by individualized dosing of chemotherapeutic agents to produce a uniformly high, effective yet safe drug exposure in each patient

Atazanavir in plasma-exchange treatment.

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Clinical value of drugs of abuse point of care testing in an emergency department setting

Objective: Toxicology screening tests for drugs-of-abuse and therapeutic drugs in urine (TST-U) are often used to assess whether a patient’s clinical condition can be explained by the use of drugs-of-abuse (DOA) and/or therapeutic drugs. TST-U have clinical value when they support clinical decision making by influencing diagnosis and patient care. We aim to quantify the influence of TST-U results on diagnosis and patient care in an emergency department. Our secondary objective is to identify specific patients for which a TST-U is most warranted or mostly unhelpful. Methods: This prospective observational study was performed at the emergency department of a middle-sized urban teaching hospital. A point of care TST-U has been used in this department for three years. When a TST-U is considered indicated by a physician, the influence of the TST-U result on diagnosis and patient care is quantified before and after the test results are available, by means of a questionnaire. Urgency and complaints upon admission have also been registered. Results: Of 100 TST-U results 37% were reported having a substantial influence on diagnosis and 25% on patient care. TST-U had a substantial influence on diagnosis in 48% of patients with decreased consciousness, 47% of patients with psychiatric symptoms and in 47% of patients with “other” complaints. In this last category patients with neurological symptoms benefited most. In patients who were already suspected to be intoxicated, only 18% of the TST-U results had substantial influence on diagnosis. Conclusions: The use of point of care TST-U in an Emergency Department helps physicians to understand the clinical condition of a patient. They influence the way a patient is treated to a lesser extent. These tests are most helpful in patients with decreased consciousness, psychiatric or neurological symptoms and mostly unhelpful in patients who, upon admission, are already known to be intoxicated. Keywords: Intoxications, Drug tests, Point of care testing, Drugs of abus