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Purpose Reduced exposure to echinocandins has been reported in specific patient populations, such as critically ill patients; however, fixed dosing strategies are still employed. The present review examines the accumulated evidence supporting echinocandin therapeutic drug monitoring (TDM) and summarizes available assays and sampling strategies. Methods A literature search was conducted using PubMed® in December 2020, with search terms such as echinocandins, anidulafungin, caspofungin, micafungin, or rezafungin with pharmacology, pharmacokinetics, pharmacodynamics, drug-drug interactions, therapeutic drug monitoring, resistance, drug susceptibility testing, toxicity, adverse drug reactions, bioanalysis, chromatography, and mass spectrometry. Data on pharmacokinetic/pharmacodynamic (PK/PD) outcome markers, drug resistance, PK variability, drug-drug interactions, assays, and TDM sampling strategies were summarized. Results Echinocandins demonstrate drug exposure-efficacy relationships, and maximum concentration/minimal inhibitory concentration ratio (Cmax/MIC) and area under the concentration-time curve/MIC ratio (AUC/MIC) are proposed PK/PD markers for clinical response. The relationship between drug exposure and toxicity remains poorly clarified. TDM could be valuable in patients at risk of low drug exposure, such as those with critical illness and/or obesity. TDM of echinocandins may also be useful in patients with moderate liver impairment, drug-drug interactions, hypoalbuminemia, and those undergoing extracorporeal membrane oxygenation, as these conditions are associated with altered exposure to caspofungin and/or micafungin. Assays are available to measure anidulafungin, micafungin, and caspofungin concentrations. A limited-sampling strategy for anidulafungin has been reported. Conclusion Echinocandin TDM should be considered in patients at known risk of suboptimal drug exposure. However, for implementing TDM, clinical validation of PK/PD targets is needed.

Background & aims Survivorship is a well-established concept in the cancer care continuum with a focus on disease recurrence, quality of life, and minimizing competing risks for mortality; however, this has not been well studied in liver transplantation (LT). We aimed to investigate what survivorship means to LT patients and identify motivations and coping strategies for overcoming challenges after LT. Approach & results Twenty in-depth home interviews were conducted among adults 3 to 6 months after LT. Interviews were conducted by trained qualitative research experts, coded and analyzed using an inductive approach. A majority of LT recipients (75%) identified themselves as survivors. Integral to the definition of survivorship was overcoming hardship (including experiences on the waitlist) and the unique experience of being given a "second chance" at life. Motivations to survive included: 1) honoring a new chance at life (55%), 2) family (40%), 3) spirituality/faith (30%), and 4) fear of rejection (15%). LT recipients and caregivers identified multiple strategies to cope with post-LT challenges including relying on a large network of community, spiritual, and virtual support. These findings informed a conceptual model of LT survivorship based on socioecological theory, which identified the following variables influencing survivorship: 1) pre-transplant experiences, 2) individual attributes and challenges, 3) interpersonal relationships with caregivers and other social support, 4) community relationships, and, 5) largescale factors including neighborhood and financial issues. Conclusions LT recipients identify themselves as survivors, and post-LT identities were greatly influenced by pre-LT experiences. These perspectives informed an in depth conceptual model of survivorship after transplantation. We identified sources of motivation and coping strategies used in LT recovery that could be targets of survivorship interventions aimed at improving post-LT outcomes.

BACKGROUND Carbamazepine and oxcarbazepine are potent modulators of metabolic enzymes. Hence, potential drug-drug interactions (DDIs) may occur between these 2 drugs and antiretrovirals. Here, we aimed to assess the relevance of these drug-drug interactions in real-life clinical settings. METHODS Patients treated concomitantly with carbamazepine or oxcarbazepine and antiretrovirals for at least 3 months were considered. Data on therapeutic drug monitoring (TDM) of both antiepileptic and antiretrovirals as trough concentrations were collected. HIV-infected patients not concomitantly treated with antiepileptic drugs and who underwent TDM for antiretrovirals in the previous 2 years were considered as controls. RESULTS Eleven HIV-positive patients prescribed carbamazepine or oxcarbazepine were identified. All the TDM evaluations for carbamazepine and oxcarbazepine that resulted were within the therapeutic ranges. TDM results of darunavir measured in these patients were comparable with values usually measured in the control group. Conversely, the trough concentrations for atazanavir and dolutegravir demonstrated significantly lower values when compared with values usually measured in HIV-infected patients not treated with antiepileptic drugs (190 ± 91 versus 546 ± 380 ng/mL; -65%, P < 0.001; 191 ± 78 versus 1096 ± 510 ng/mL; -83%, P < 0.001, respectively). CONCLUSIONS Co-administration of carbamazepine or oxcarbazepine with atazanavir or dolutegravir should be avoided owing to the potential risk of virological failure; in case of these 2 drugs, the adoption of TDM is strongly advisable, eventually combining with increased antiretroviral doses.

Background A long-acting injectable (LAI) formulation of olanzapine has been developed as an alternative to oral regimens. A therapeutic range of 20 to 80 ng/mL for oral olanzapine trough concentrations has been proposed. Here, we sought to investigate the intraindividual and interindividual variability of olanzapine concentrations with time in patients on maintenance therapy with the LAI formulation carried out in the routine clinical practice. Methods To address this issue, we carried out a retrospective analysis of therapeutic drug monitoring of olanzapine concentrations in 21 schizophrenic patients on maintenance LAI olanzapine. Drug concentrations were correlated with LAI olanzapine doses, duration of treatment, and main clinical characteristics. Results Fifty percent of the patients had olanzapine trough concentrations lower than 20 ng/mL. Only drug doses significantly correlated with olanzapine exposure. Mean interindividual and intraindividual coefficients of variations of olanzapine concentrations were 56% (range, 21%-97%) and 34% (range, 15%-69%), respectively. Conclusions We have documented that, in a real-life setting, a large proportion of patients treated with olanzapine LAI had drug trough concentrations of less than 20 ng/mL; wide intraindividual and interindividual variability of olanzapine concentrations has been also observed. Our results could provide the rationale for the design of larger prospective, concentration-controlled clinical trials specifically designed with the goal to identify ad hoc therapeutic ranges of drug concentrations for olanzapine LAI.

Background An enzymatic immunoassay is under development by ARK Diagnostics, Inc for the quantification of plasma concentrations of linezolid (LZD). In this study, the authors aimed to assess the performance of this immunoassay using a validated high-performance liquid chromatography (HPLC) ultraviolet method as reference. Methods Within- and between-day in vitro inaccuracy and imprecision of the ARK LZD assay were firstly tested using spiked quality controls (QC) provided by the kit manufacturer. Subsequently, the performance of the immunoassay was verified in vivo by analyzing 170 trough LZD plasma samples from patients on antibiotic therapy. Results Imprecision of the spiked QCs resulted in every instance less than 7.0% and the inaccuracy ranged from -1.5% to 6.6%. The linear correlation between the 2 methods was documented by the Pearson analysis of plasma samples from patients on LZD therapy (coefficient = 0.9619). By Bland-Altman comparison, 8.2% of the patient samples resulted out of the limits ranging from -27.0% to +33.5%, with most of them having LZD concentrations exceeding 10 mg/L. Conclusions Acceptable analytical performance of the ARK LZD immunoassay has been demonstrated both with spiked QC and patients' samples, making it a viable alternative to HPLC for the therapeutic drug monitoring of LZD in clinical practice in laboratory hospitals that do not have HPLC equipment.

Background The application of Quality by Design (QbD) principles in clinical laboratories can help to develop an analytical method through a systematic approach, providing a significant advance over the traditional heuristic and empirical methodology. In this work, we applied for the first time the QbD concept in the development of a method for drug quantification in human plasma using elvitegravir as the test molecule. Methods The goal of the study was to develop a fast and inexpensive quantification method, with precision and accuracy as requested by the European Medicines Agency guidelines on bioanalytical method validation. The method was divided into operative units, and for each unit critical variables affecting the results were identified. A risk analysis was performed to select critical process parameters that should be introduced in the design of experiments (DoEs). Different DoEs were used depending on the phase of advancement of the study. Results Protein precipitation and high-performance liquid chromatography-tandem mass spectrometry were selected as the techniques to be investigated. For every operative unit (sample preparation, chromatographic conditions, and detector settings), a model based on factors affecting the responses was developed and optimized. The obtained method was validated and clinically applied with success. Conclusions To the best of our knowledge, this is the first investigation thoroughly addressing the application of QbD to the analysis of a drug in a biological matrix applied in a clinical laboratory. The extensive optimization process generated a robust method compliant with its intended use. The performance of the method is continuously monitored using control charts.

BACKGROUND The aim of this study was to analyze the relationships between quetiapine and N-desalkylquetiapine plasma levels and clinical improvement, particularly, in regard to depressive and anxious symptoms and to hostility. METHODS This was a prospective observational study that involved 37 outpatients diagnosed as having bipolar disorder I or II. All the patients were observed during a clinical acute and postacute phase. Patients were prescribed 50-800 mg of quetiapine. Patients were evaluated at baseline, after 15 days and after 3 months using the Brief Psychiatry Rating Scale with particular reference to the dimensions of depression, anxiety, and hostility. The plasma concentrations of quetiapine and N-desalkylquetiapine were determined after 3 months using blood samples taken at steady state. RESULTS There was a significant relationship between the N-desalkylquetiapine/quetiapine ratio and the improvement in the depression dimension, and there was not a significant relationship between the N-desalkylquetiapine/quetiapine ratio and anxiety and hostility improvement. Quetiapine treatment was well tolerated, and there were no extrapyramidal, anticholinergic, or other side effects to note. There was no relationship between plasma quetiapine or N-desalkylquetiapine concentrations and side effects. CONCLUSIONS Our findings confirm the efficacy of quetiapine on depressive symptoms, and the available data support that quetiapine's antidepressant activity is mediated by the active metabolite norquetiapine, and it exemplifies the case of an active metabolite that can make a drug like quetiapine originally introduced as an antipsychotic a useful antidepressant agent.

An involvement of selective serotonin reuptake inhibitors (SSRIs) in increasing the risk of malformations, neonatal withdrawal syndrome, has been suggested recently. Here, we aimed to investigate the contribution of individual pharmacogenetics of SSRI on infants' outcome. We also estimated the umbilical/maternal plasma SSRI concentration ratio in the pregnant women still on SSRI therapy at the time of delivery.Thirty-four pregnant women, referred to our hospital from January 2011 to July 2015, who were given SSRIs in the third trimester, and related children, were considered. The umbilical/maternal plasma SSRI concentration ratio was estimated in 15 mothers still on SSRI therapy at the time of delivery. For patients with pharmacokinetic analyses, blood samples were collected for pharmacogenetic analyses.Nineteen newborns presented clinical signs possibly related to drug toxicity. A high umbilical/maternal plasma ratio of SSRI was observed in 10 of the 15 evaluated newborns. Five mothers were intermediate metabolizers and 1 a poor metabolizer for the major CYP enzyme involved in pharmacokinetic pathway.Individualized psychopharmacologic treatment that takes into account the mother's exposure to SSRI concentrations and eventually her genetic background may become the standard of care to maximize drug benefit and minimize risks to the newborn.

BACKGROUND We have developed and validated a high-performance liquid chromatographic method for the simultaneous quantification, in human plasma, of dolutegravir, a new human immunodeficiency virus (HIV) integrase inhibitor, and rilpivirine, a novel HIV nonnucleoside reverse transcriptase inhibitor. METHODS An internal standard (quinoxaline) was added to plasma aliquots (500 μL), and a simple solid-phase extraction procedure was applied. Chromatographic separation of the drugs and internal standard was achieved with a gradient of acetonitrile and acetate buffer, and with an analytical run time of 25 minutes using an XBridge C18 column. The column eluate was monitored at 260 nm for dolutegravir and the internal standard and at 305 nm for rilpivirine. RESULTS The method was linear in the range of 20-8000 and 20-2000 ng/mL for dolutegravir and rilpivirine, respectively (mean r ≥ 0.993 on 10 replicates for both analytes). Mean intraday and interday precision and inaccuracy were

BACKGROUND Recently, a turbidimetric immunoassay method has been developed for use in the form of a QMS lamotrigine (LTG) commercial immunoassay. This study was designed to evaluate the performance of this immunoassay using a validated high-performance liquid chromatography-ultraviolet (HPLC-UV) method as the reference. METHODS The performance of QMS was initially tested using drug-free plasma spiked with different amounts of LTG and, subsequently, by analyzing 61 trough plasma samples from epileptic patients given the drug as part of their maintenance antiepileptic therapies. RESULTS The correlation between LTG concentrations measured by QMS and HPLC was good, with a Pearson coefficient of 0.968 (P < 0.0001). The Bland-Altman approach showed that LTG concentrations measured with QMS exceeded HPLC on an average by 15.6% (limits of agreement, -18% to +63%), with a concentration-dependent performance (mean percent bias, 49.5 ± 8.2% and 0.6 ± 12.7% for concentrations less than 2 mg/L and greater than 14.9 mg/L, respectively). CONCLUSIONS The QMS provided acceptable analytical performance across a wide concentration range for routine LTG measurements, being at least comparable with the other commercial immunoassays. It could be, therefore, considered as a viable alternative to HPLC methods for routine LTG monitoring in the clinical practice, although its suitability for accurate analysis of samples with low concentration is limited.

BACKGROUND Recently, the European Medicines Agency (EMA) has released new guidelines on the validation of bioanalytical methods. In this work, we compared the analytical performance of 2 high-performance liquid chromatography with tandem mass spectrometry methods designed for the quantification of the antiretroviral drug raltegravir (RAL) that fully accomplish the criteria according to the new EMA guidelines. METHODS The first method was developed with the goal of separating RAL from its main metabolite, whereas in the second method, we deliberately did not discriminate the parent drug from its metabolite. After validation, both methods were used for the quantification of plasma samples from HIV-infected patients on RAL-based maintenance antiretroviral therapy. RESULTS Incurred reanalysis of samples obtained from patients receiving RAL as therapy evidenced optimal performance for both methods. Similarly, the comparison of both methods performed by the Deming test showed that they correlate significantly with each other (Pearson coefficient of regression 0.97, P < 0.0001) with no significant deviation from linearity according to the Cusum test. The Bland-Altman test, however, showed a mean difference between the 2 methods of 54.1% (limits of agreements of ±1.96 SD ranged from -163.3% to +271.5%). Such differences were significantly affected by interindividual variations in the production of RAL metabolites. CONCLUSIONS We conclude that the recently released EMA guidelines on bioanalytical method validation present some limitations related to the process of method development. To have confidence in the drug-concentration measurements, laboratories must demonstrate their performance through the participation in international proficiency testing schemes that must include patient samples.