Measurement of the DNA alkylating agents busulfan and melphalan in human plasma by mass spectrometry.

Busulfan and melphalan are cytotoxic DNA alkylating agents that are used in many hematopoietic stem cell transplantation (HCT) conditioning regimens. We report the development of an assay using turbulent flow liquid chromatography (TFLC) and tandem mass spectrometry to simultaneously measure the concentration of busulfan (Bu) and melphalan (Mel) in human plasma. The method involves precipitating proteins in the plasma specimen with an organic solvent containing deuterated internal standards of both compounds. Following centrifugation, an aliquot of the supernatant was injected into the TFLC mass spectrometry system operated in the positive ion mode. The analytical measurement range for both compounds was 10-5000 ng/mL, and with validated dilutions the reportable range was extended to 25,000 ng/mL. Intra-day and inter-day (n = 20 day) precision studies showed a coefficient of variation (CV) of <7% at several concentrations across the measurement range. To determine accuracy recovery studies were performed at several concentrations spanning the measurement range. Recoveries for both compounds were between 98 and 103%. Additionally, busulfan was compared with an existing assay and showed excellent correlation. Experiments were conducted to rule out matrix effects, carryover and interference from endogenous substances. The validated clinically reportable range (CRR) and assay precision will allow this assay to be used clinically to monitor and adjust Mel and Bu levels to ensure better therapeutic outcomes and also to support clinical trials aimed at better defining therapeutic ranges.

A comparison of preferences for two GLP-1 products--liraglutide and exenatide--for the treatment of type 2 diabetes.

OBJECTIVE: To use time trade-off (TTO) to compare patient preferences for profiles of two glucagon-like peptide (GLP-1) products for the treatment of type 2 diabetes (liraglutide and exenatide) that vary on four key attributes - efficacy (as measured by hemoglobin A(1C)), incidence of nausea, incidence of hypoglycemia, and dosing frequency (QD vs. BID) - and measure the contribution of those attributes to preferences. METHODS: A total of 382 people with T2DM were recruited to participate in an internet-based survey consisting of a series of health-related questions, a conjoint exercise and a set of time trade-off items. In the conjoint exercise, respondents were presented with eight pairs of hypothetical GLP-1 profiles, and completed a time-tradeoff exercise for each pair. RESULTS: The product profile representing liraglutide was preferred by 96% of respondents and resulted in significantly higher health utilities (0.038) than the product profile representing exenatide (0.978 vs. 0.94, p < 0.05). Estimated preference scores from the conjoint analysis revealed that efficacy measured by hemoglobin A(1C) is the most important attribute, followed by nausea, hypoglycemia, and dosing schedule. LIMITATIONS: On-line participants may not represent 'typical' type 2 diabetes patients, and brief product profiles represented results from clinical trials, not clinical practice CONCLUSION: Based on the four attributes presented, patients prefer liraglutide over exenatide. Preference is based on superior efficacy and less nausea more than less hypoglycemia and once-daily dosing.

Matching With Doses in an Observational Study of a Media Campaign Against Drug Abuse.

Multivariate matching with doses of treatment differs from the treatment-control matching in three ways. First, pairs must not only balance covariates, but also must differ markedly in dose. Second, any two subjects may be paired, so that the matching is nonbipartite, and different algorithms are required. Finally, a propensity score with doses must be used in place of the conventional propensity score. We illustrate multivariate matching with doses using pilot data from a media campaign against drug abuse. The media campaign is intended to change attitudes and intentions related to illegal drugs, and the evaluation compares stated intentions among ostensibly comparable teens who reported markedly different exposures to the media campaign.