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BACKGROUND: Urine drug testing (UDT) is a useful tool in monitoring compliance to prescribed medication and can also help identify behaviors of drug misuse, abuse, and diversion. Mass spectrometry (MS)-based screening is recommended as the first-line of UDT for pain management patients; however, this testing comes with an inherent lack of standardization in methodologies and various analytical challenges. The objective of this study was to assess the current state of UDT for pain management in a cross-section of clinical laboratories in North America. MATERIALS AND METHODS: A total of 10 blinded urine samples were sent to 6 laboratories across the United States and Canada. Urine samples containing drugs and/or metabolites of interest were included to represent different clinical scenarios commonly seen in pain management settings. Assessment was based on the ability of the laboratories to correctly identify drugs and provide a meaningful interpretation of the findings (when offered by the performing laboratory). RESULTS: Across the laboratories involved in the study, 85% of tests correctly identified and appropriately reported the drugs present in the urine samples. Similarly, 84% of samples were considered to have an accurate interpretation included in the UDT report. Out of the total number of drugs included in the samples, 11% were not offered on every test menu. CONCLUSIONS: This study revealed the lack of standardization in pain management UDT performed in a limited cross-section of clinical laboratories across North America.

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The use and adherence monitoring of opioids in pain management is recommended by numerous clinical practice guidelines. Many physicians use urine immunoassay screening tests, which suffer from a lack of sensitivity and specificity, to verify compliance to pain medications. However, several immunoassay tests are required to comprehensively detect the synthetic, semisynthetic, and natural opioids due to the limited cross-reactivity of each assay. Superior testing strategies are required to specifically identify low concentrations of opioids found in adherent pain management patients. Therefore we present a method for the qualitative identification of 33 opioids and metabolites (codeine, codeine-6-ß-glucuronide, morphine, morphine-6-ß-glucuronide, 6-acetylmorphine, hydrocodone, norhydrocodone, dihydrocodeine, hydromorphone, hydromorphone-3-ß-glucuronide, oxycodone, noroxycodone, oxymorphone, oxymorphone-3-ß-glucuronide, noroxymorphone, meperidine, normeperidine, methadone, EDDP, propoxyphene, norpropoxyphene, tramadol, O-desmethyltramadol, tapentadol, tapentadol-ß-glucuronide, N-desmethyltapentadol, buprenorphine, norbuprenorphine, norbuprenorphine glucuronide, naloxone, naloxone glucuronide, fentanyl, and norfentanyl) in unhydrolyzed urine using a liquid chromatography tandem mass spectrometry (LC-MS/MS) with high-resolution, accurate-mass Orbitrap detection.

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Busulfan is a commonly used antineoplastic agent to condition/ablate bone marrow cells before hematopoietic stem cell transplant. While intravenous (IV) formulations of busulfan are now available and have lower incidences of toxicity and treatment related mortality compared to oral dosing, it still displays large pharmacokinetic variability. As a result, studies have shown that therapeutic drug monitoring is clinically useful to minimize graft failure, disease reoccurrence, and toxicities like veno-occlusive disease and neurologic toxicity. Current methods for assaying busulfan include the use of GC/MS, HPLC, and LC-MS/MS. The clinical need for faster turnaround times and increased testing volumes has required laboratories to develop faster methods of analysis for higher throughput of samples. Therefore, we present a method for the quantification of busulfan in plasma using an ultrafast SPE-MS/MS which has much faster sample cycle times (<20 s per sample) and comparable analytical results to GC/MS.

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BACKGROUND: Busulfan is an alkylating agent used to ablate bone marrow cells before hematopoietic stem cell transplantation. Because of its highly variable pharmacokinetics, studies have shown that therapeutic drug monitoring is clinically useful for patients undergoing bone marrow transplant so that toxic effects associated with high drug exposure could be reduced and improve clinical outcomes. Current methods for assaying busulfan include the use of gas chromatography mass spectrometry (GC/MS), high-performance liquid chromatography, and liquid chromatography mass spectrometry. The clinical need for faster turnaround times and increased testing volumes has required laboratories to develop faster methods of analysis for higher throughput of samples. Therefore, we present a method for the quantification of busulfan in plasma using an ultrafast solid-phase extraction/tandem mass spectrometry, which has much faster sample cycle times and similar analytical results to GC/MS. METHOD: Calibration standards, quality controls, and patient samples after addition of busulfan-d4 internal standard were extracted into n-butyl chloride from plasma. The organic fraction was dried and reconstituted in 600 µL of water containing ammonium acetate, trifluoroacetic acid, and formic acid. Sample analysis was performed at a rate of less than 20 seconds per sample using a Rapidfire 300 system coupled to an Agilent 6490 MS/MS using electrospray ionization in positive ion mode. Concentrations were calculated based on a 5-point calibration curve using a 1/x linear curve fit. RESULTS: The analytical method shows excellent precision, sensitivity, and specificity. Minimal ion suppression or enhancement due to the matrix effect was observed. No significant carryover was seen following a sample containing 15,000 ng/mL of busulfan. Seventy-two patient samples were cross-validated with a current GC/MS method. All patient results throughout the analytical range correlated within the acceptance criteria of ±20%. The linear regression demonstrated the following: slope = 1.0067, r = 0.9964, and intercept = -6.2. CONCLUSIONS: A simple, fast, and robust method was developed for the quantitation of busulfan in plasma with solid-phase extraction/tandem mass spectrometry cycle times of <20 seconds per sample.

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BACKGROUND: Ribavirin is a nucleoside analog used in treatment of chronic hepatitis C. It is associated with severe, dose-dependent toxicities, including hemolytic anemia. To facilitate therapeutic drug monitoring, a liquid chromatography-tandem mass spectrometry method was validated for quantitation of ribavirin in serum. METHODS: After protein precipitation, ribavirin is quantitated using a (13)C(5)-ribavirin internal standard, on a Hypercarb analytical column designed for retention of polar analytes. RESULTS: The analytical method shows excellent precision, sensitivity, and specificity. In vitro drug stability was also assessed. Interestingly, endogenous isobaric compounds were noted in both human and bovine serum; these could be chromatographically separated from the ribavirin peak. Addition of exogenous uridine and cytosine increases the size of the isobaric peaks, suggesting that these compounds are the source of the endogenous interference. CONCLUSIONS: This method uses mass spectrometric transitions that have been used in other published methods, but also separates ribavirin from isobaric peaks that were not described. These peaks were determined to be endogenous nucleosides. Laboratories quantitating ribavirin in biological matrices should be aware of the potential for isobaric interferences, and take steps to chromatographically separate them from the ribavirin peak for accurate quantitation.

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