Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods for the therapeutic drug monitoring of cytotoxic anticancer drugs: An update.

In the era of precision medicine, there is increasing evidence that conventional cytotoxic agents may be suitable candidates for therapeutic drug monitoring (TDM)- guided drug dosage adjustments and patient's tailored personalization of non-selective chemotherapies. To that end, many liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) assays have been developed for the quantification of conventional cytotoxic anticancer chemotherapies, that have been comprehensively and critically reviewed. The use of stable isotopically labelled internal standards (IS) of cytotoxic drugs was strikingly uncommon, accounting for only 48 % of the methods found, although their use could possible to suitably circumvent patients' samples matrix effects variability. Furthermore, this approach would increase the reliability of cytotoxic drug quantification in highly multi-mediated cancer patients with complex fluctuating pathophysiological and clinical conditions. LC-MS/MS assays can accommodate multiplexed analyses of cytotoxic drugs with optimal selectivity and specificity as well as short analytical times and, when using stable-isotopically labelled IS for quantification, provide concentrations measurements with a high degree of certainty. However, there are still organisational, pharmacological, and medical constraints to tackle before TDM of cytotoxic drugs can be more largely adopted in the clinics for contributing to our ever-lasting quest to improve cancer treatment outcomes.

A battery of tandem mass spectrometry assays with stable isotope-dilution for the quantification of 15 anti-tuberculosis drugs and two metabolites in patients with susceptible-, multidrug-resistant- and extensively drug-resistant tuberculosis.

OBJECTIVE: Anti-tuberculosis (antiTB) drugs are characterized by an important inter-interindividual pharmacokinetic variability poorly predictable from individual patients' characteristics. Therapeutic drug monitoring (TDM) may therefore be beneficial for patients with Mycobacterium tuberculosis infection, especially for the management of multidrug/extensively drug resistant- (MDR/XDR)-TB. Our objective was to develop robust HPLC-MS/MS methods for plasma quantification of 15 antiTB drugs and 2 metabolites, namely rifampicin, isoniazid plus N-acetyl-isoniazid, pyrazinamide, ethambutol (the conventional quadritherapy for susceptible TB) as well as combination of agents against MDR/XDR-TB: bedaquiline, clofazimine, delamanid and its metabolite M1, levofloxacin, linezolid, moxifloxacin, pretomanid, rifabutin, rifapentine, sutezolid, and cycloserine. METHODS: Plasma protein precipitation was used for all analytes except cycloserine, which was analyzed separately after derivatization with benzoyl chloride. AntiTB quadritherapy drugs (Pool1) were separated by Hydrophilic Interaction Liquid Chromatography (column Xbridge BEH Amide, 2.1 × 150 mm, 2.5 µm, Waters®) while MDR/XDR-TB agents (Pool 2) and cycloserine (as benzoyl derivative) were analyzed by reverse phase chromatography on a column XSelect HSS T3, 2.1 × 75 mm, 3.5 µm (Waters®). All runs last <7 min. Quantification was performed by selected reaction monitoring electrospray tandem mass spectrometry, using stable isotopically labelled internal standards. RESULTS: The method covers the clinically relevant plasma levels and was extensively validated based on FDA recommendations, with intra- and inter-assay precision (CV) < 15% over the validated ranges. Application of the method is illustrated by examples of TDM for two patients treated for drug-susceptible- and MDR-TB. CONCLUSION: Such convenient extraction methods and the use of stable isotope-labelled drugs as internal standards provide an accurate and precise quantification of plasma concentrations of all major clinically-used antiTB drugs regimens and is optimally suited for clinically efficient TDM against tuberculosis.

[Sexual dysfunction and depression: Validity of a French version of the ASEX scale]. / Validation française de l'échelle psychométrique ASEX d'évaluation des troubles sexuels dans la dépression.

BACKGROUND: Since the Beck study (1967), it is well known that sexual dysfunction is particularly prevalent in depressive patients compared to the general population, at 70% and 30% respectively. Depression, psychotropics and antidepressants are responsible for altering sexuality, and patients are considerably affected by these symptoms that dramatically decrease their quality of life. Screening for sexual dysfunctions seems essential, and a scale such as the Arizona Sexual Experience Scale (ASEX) may help practitioners. The English version of this scale was validated in 2000 (McGahuey et al. [9]), and is widely used in scientific research. The aim of this study was to assess the validity of the French version of the ASEX scale. METHODS: Following authorization from the University of Arizona, the ASEX scale was translated into French by our team at the University hospital of Besançon (France), by the back translation technique, and then checked by a professional translator. ASEX, Mini International Neuropsychiatric Interview (MINI), Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) were filled out by 37 depressed inpatients, and ASEX and PHQ-9 by 64 controls (hospital employees, residents and students at the University of Besançon), and again one to two weeks later. Bivariate correlations were performed using total ASEX scores to determine the test-retest reliability. Internal consistency of the ASEX scale was assessed using Cronbach's alpha analysis. Analyses of variance (Anova) were performed to determine the validity of the ASEX scale to compare patients to controls for total ASEX score and for individual ASEX item scores. In order to determine whether the ASEX criteria accurately reflect sexual dysfunction (determined by the HDRS rating or self-report), positive and negative predictive value and sensitivity and specificity were measured. To determine how well the total ASEX score differentiates between individuals with sexual dysfunction and those without, a Receiver Operating Characteristic (ROC) analysis was performed. We expected similar results between the French version of the ASEX scale and the original one (McGahuey and al., 2000). RESULTS: Patients and controls were similar in terms of sex and age. The test-retest reliability was good, and the internal consistency was excellent using Cronbach's alpha analysis (alpha=0.9451). Analyses of variance (Anova) showed strong differences between the two groups, confirming the validity of the ASEX scale to compare patients to controls for total ASEX score and individual ASEX item scores. Positive and negative predictive values were respectively 89.66% (PPV) and 85.33% (NPV). Specificity and sensitivity were respectively 95.31% (Sp) and 70.27% (Se). The ROC analysis showed the area under the curve (AUC=0.8457) and the best ASEX criteria to demonstrate that sexual dysfunction had been correctly identified (total ASEX score ≥ 18). CONCLUSION: This study assessed the validity and reliability of the French version of the ASEX scale. These findings demonstrate the highly acceptable psychometric properties of ASEX in patients with depression.