Narrow Therapeutic Margin Research Articles

Precision-cut lung slices in air-liquid interface (PCLS-ALI): A novel ex-vivo model for the study of Pulmonary Aspergillosis.

Pulmonary Aspergillosis is a respiratory infection with a high mortality rate, which affects patients with immunosuppression or structural lung defects. Antifungal treatment options are few and many have narrow therapeutic margins and potentially serious side effects. In recent years, there are growing numbers of reports of antifungal resistance. Thus, there is an urgent need for effective models to study fungal pathogenesis and test antifungal therapies in the respiratory system. Here, we present a novel ex-vivo model using precision-cut lung slices in an air-liquid interface platform to evaluate lung tissue responses to fungal infection and antifungal treatment. Readouts assessed were lactate dehydrogenase for tissue damage, release of inflammatory cytokines (TNF-α, IL-1β, CXCL1), and histology for confirmation of hyphal invasion. Overall, the PCLS-ALI model is a promising approach for understanding lung tissue responses to fungal infections, which fulfils the reduction and refinement components of the 3Rs guiding principles for ethical use of experimental animals.

Impact of Vancomycin trough levels monitoring on uncomplicated methilcillin-resistant Staphylococcus aureus bacteremia in chronic kidney disease on hemodialysis, retrospective cohort

BackgroundCKD patients on hemodialysis (HD) with Staphylococcus aureus (SA) bacteremia present high morbidity, mortality and increased risk of MRSA. Vancomycin is the antibiotic of choice in these cases, it has a narrow therapeutic margin and inadequate dosage generates a risk of toxicity, therefore, the recommendation is to dosage it through serum levels.MethodsThis is a retrospective cohort study in 3 hospitals of third level of complexity in the city of Medellin in which there were differences in the measurement and implementation of vancomycin25 dosage based on trough levels (VL) in patients with chronic kidney disease on hemodialysis (CKD- HD) with uncomplicated bacteremia based infection by methilcillin-resistant Staphyloccocus aureus (MRSA). The primary outcome was the composite of hospital mortality, clinical response (fever, hemodynamic instability and altered consciousness), complications associated with bacteremia, or bacteriological response failure (positive cultures at first week follow-up) at 7 days. The composite variables were analyzed individually as secondary outcomes.ResultsThe main unadjusted outcome (OR 1.3, CI 0.6 - 2.7) and adjusted for age, Charlson index, loading dose, initial dose, dosing frequency and MIC to vancomycin (OR 1.2, CI 0.5 - 2.7). Regarding adjusted secondary outcomes: clinical response (OR 1.4 CI 0.3 - 5.8), death (OR 1.3 CI 0.3 - 4.6) and complications (OR 0.9, CI 0.37 - 2.2).ConclusionsWe conclude that the measurement of trough levels in patients with HD-CKD does not modify the composite outcome. The main limitation is the sample size and type of study, randomized control trials may be required to confirm the results presented.

Existing and Emerging Technologies for Therapeutic Monitoring of Lithium: A Scoping Review.

Lithium is an effective psychoactive drug. It has a narrow therapeutic margin, with subtherapeutic levels or intoxication commonly occurring. Therapeutic drug monitoring (TDM) of lithium has several barriers. This scoping review aims to describe and analyze existing and emerging technologies for lithium TDM and to describe the lithium quantification parameters (precision, accuracy, detection limit) attributed to each technology. PubMed, Scopus, Web of Science, and Google Scholar were searched. Studies that described lithium quantification and complied with PRISMA-ScR guidelines were included. Articles selection was conducted by 2 researchers. Good precision was defined if its relative standard deviation <3%; acceptable, from 3% to 5%; and low, >5%. Accuracy was considered good if the error <5%; acceptable, 5%1 to 0%; and low if it was >10%. Of the 2008 articles found, 22 met the inclusion criteria. Of these, 14 studies concerned laboratory devices, in which precision was found to be low in one third of cases, and half had good precision. Accuracy of one third was good, another third was low, and the remaining third did not report accuracy. The other 8 studies concerned portable devices, in which precision was low in more than 60% of the cases and good in 25% of the studies. Accuracy was low in 50% of the cases, and good in just over a third. Limits of detection included the therapeutic range of lithium in all studies. Among emerging technologies for lithium TDM, precision and accuracy remain a challenge, particularly for portable devices.

The Use of Herbal Medicines Among Cancer Patients.

Background and objective The use of herbal medicines has been increasing among cancer patients, as a way to control cancer and treatment-related symptoms; however, many patients are reluctant to disclose this use to their medical practitioners. The fact that oncological treatments have a narrow therapeutic margin, associated with the lack of control and clinical evidence concerning these supplements, makes medication-herbal interactions a reality.These interactions could lead to increased toxicity or a decreased effectiveness of oncological treatment. In light of this, we aimed to assess the prevalence of herbal medicine use in a patient population at a Portuguese central hospital: Centro Hospitalar Lisboa Ocidental. Materials and methods Patients with breast, prostate, or colorectal cancer diagnosesbetween August 2022 and July 2023 and undergoing oncological treatmentwere included. Data were collected through a surveyduring their first appointment, as well as by consulting the patients' clinical files. An interaction evaluation was carried out to assess potential medication-herbal interactions. Finally, a statistical analysis was performed to identify predictive factors for the use of herbal medicines. Results Among the 65 patients included in the study, 52% were females, and the median age of the cohort was 65 years. Breast cancer was the most prevalent diagnosis and the majority of the patients were undergoing palliative treatment. We found that 46% of patients used herbal medicines regularly: to strengthen the immune system, detoxification of the body, and treat insomnia and constipation. A medication-herbal interaction was found in 37% of the cases, the most frequent being doxorubicin-vitamin C, through an antioxidant mechanism. The univariable analysisfailed to show any predictive factors associated with the use of herbal medicines. Conclusions This study sheds light on herbal medicine use among cancer patients and the reality of medication-herbal interactions. There is an urgent need for further research and evidence-based medical protocols regarding herbal medicine use, especially incomplex cases such as cancer patients, to provide better and safer care.

Administración de citostáticos vía oral: interacciones fármacoalimento

Introductionoral chemotherapy is increasingly used in Oncology. It has important advantages. such as patient comfort. but it also brings new challenges which did not exist with the intravenous therapy. Some of these drugs have interactions with food. leading to changes in their bioavailability. As they are drugs of narrow therapeutic margin. this can lead to alterations in their efficacy and/or toxicity. ObjectivesA. Assessing the level of knowledge on the administration of oral cytostatics that present restrictions with meals (drugs that have to be taken with/without food) among the outpatients. B. Minimizing the incorrect administration and the risk of food-drug interactions. providing patients with information as to how and when drugs have to be administrated. Methodsonce the oral cytostatics with food restrictions were identified. we asked the patients in treatment about the information they had received from the doctor and the way they were taking the medication. We provided those who were taking the drug incorrectly with the right information. In the following visit. it was confirmed if the patients that had been previously taking the cytostatic incorrectly. were taking them in a correct way (intervention accepted/not accepted). Results and conclusions40% of the patients interviewed used to take the drug incorrectly. We detected a great diversity depending on the dispensed drug. 95% of the 39 interventions made were accepted. The data obtained suggest the need to reinforce the information that the patient receives. It is important to make sure that the patient understands how and when the oral cytostatic should be administered.

Colchicine Intoxication Subsequent to an Autolytic Attempt with Positive Evolution

Background and objectives: Colchicine is a drug that has been used to treat gout for several centuries, it is also indicated in certain autoimmune diseases and has been tested as a chemotherapeutic. Only a few cases of intoxication by this drug have been described, but it is known that it has a narrow therapeutic margin (0.5 to 0.8 mg/kg), almost always resulting in fatal results above these limits. Regarding therapeutic management, the initiation of supportive measures is essential. Initial strategies are gastric lavage, administration of activated charcoal and fluid resuscitation aimed at preventing renal failure. Case report: A 63-year-old man with a history of spondylodiscitis and gouty arthropathy, receiving colchicine treatment. He reported abdominal symptoms with nausea, vomiting, watery stools, and diffuse pain after taking 36 tablets of 1 mg of colchicine due to exacerbation of arthralgias (the patient later recognized the autolytic ideation). He was hospitalized in the ICU due to hemodynamic instability, severe pancytopenia, respiratory failure requiring mechanical ventilation and non-oliguric acute renal failure. The patient improved and was discharged from the ICU after 14 days. Conclusions: Colchicine poisoning is rare and has high mortality despite the favorable evolution of our patient. There is no specific treatment at the moment and management should emphasize early admission to the ICU, close monitoring and organ support measures.

The role of oxygen in the development and treatment of bronchopulmonary dysplasia

Oxygen (O2) is crucial for both the development and treatment of one of the most important consequences of prematurity: bronchopulmonary dysplasia (BPD). In fetal life, the hypoxic environment is important for alveolar development and maturation. After birth, O2 becomes a double-edged sword. While O2 is needed to prevent hypoxia, it also causes oxidative stress leading to a plethora of morbidities, including retinopathy and BPD. The advent of continuous O2 monitoring with pulse oximeters has allowed clinicians to recognize the narrow therapeutic margins of oxygenation for the preterm infant, but more knowledge is needed to understand what these ranges are at different stages of the preterm infant's life, including at birth, in the neonatal intensive care unit and after hospital discharge. Future research, especially in innovative technologies such as automated O2 control and remote oximetry, will improve the understanding and treatment of the O2 needs of infants with BPD.

P30 Evaluating vancomycin continuous infusion protocol compliance and gauging therapeutic target attainment in neonates

Abstract Background Vancomycin is commonly indicated to treat neonatal late-onset sepsis. At St. George’s Hospital, neonates with central-line access are administered vancomycin by continuous infusion. A protocol instructs a 1-hour 15 mg/kg-loading dose, followed by a creatinine clearance- (CLCR)/weight–based maintenance dose. Due to vancomycin’s narrow therapeutic margin, daily therapeutic drug monitoring (TDM) of serum concentrations is necessary to obtain safe/effective therapy. Concentrations between 15 and 25 μg/mL act as a surrogate therapeutic target extrapolated from adult data.1 Methods A locally approved service evaluation retrospectively analysed 78 courses of vancomycin from 46 patient’s electronic prescribing and medicine administration (ePMA) records (July 2021–March 2022). Data on vancomycin administration/TDM were analysed using descriptive statistics. Results Individual loading and maintenance doses were calculated correctly in 83% (65/78) and 97% (75/77) of records. 72% (33/46) of patients received both correctly calculated loading/maintenance doses. A gap greater than 1 hour between loading and maintenance doses was recorded in 32% (24/75) of courses. 61% (41/67) of courses had appropriately taken serum concentrations within 22–26 hours of treatment initiation. In correctly dosed patients, therapeutic vancomycin courses increased from 43% (23/54) to 53% (19/36) and 55% (17/31) between 24–48–72-hour timepoints. In pre-term neonates &amp;lt; 28 weeks gestational age (GA), subtherapeutic courses were consistent between 38% (15/40)–42% (11/26)–36% (8/22) at 24–48–72-hour timepoints. Supra-therapeutic courses decreased from 20% (8/40)–0% (0/26)–5% (1/22), respectively. In term neonates &amp;gt; 37 weeks GA, subtherapeutic courses increased from 33% (3/9)–43% (3/7)–50% (3/6) between 24–48–72-hour timepoints. As did respective supra-therapeutic courses from 11% (1/9)–14% (1/7)–17% (1/6). Insufficient course data (5) were available for neonates between 28–32/32–37 weeks GA. Conclusions Non-therapeutic treatment worsened over 72 hours for neonates &amp;gt; 37 weeks GA, whereas toxic concentrations decreased over time despite consistent subtherapeutic concentrations in neonates &amp;lt; 28 weeks. Neonatal pharmacokinetic (PK) variability due to evolving renal function/distribution volume/non-blood protein-bound vancomycin concentrations, likely contributed to non-therapeutic concentrations. As did limitations of sample size/non-capture of dosing amendment impact. Population PK–derived dosing based on covariates explaining vancomycin PK variability could be used to improve neonatal target attainment. Whereas, neonatal area under the vancomycin concentration time curve targets supported by clinical data are needed to benchmark the therapeutic target. This will provide insight into if lower concentrations adequately treat common infections with coagulase-negative organisms.1 A quality improvement project addressing protocol ePMA interface issues and implementing a dose-amendment nomogram may improve dose calculation/monitoring. Delays between manually input loading/maintenance dose administration times onto the ePMA system require investigation before dosing revisions. Aspects of protocol compliance require improvement. Therapeutic target attainment was erratic, but reflective of the literature.1 Optimized dosing is required for specific neonatal subgroups.

Physiological Basis for Using Vitamin D to Improve Health.

Vitamin D is essential for life-its sufficiency improves metabolism, hormonal release, immune functions, and maintaining health. Vitamin D deficiency increases the vulnerability and severity of type 2 diabetes, metabolic syndrome, cancer, obesity, and infections. The active enzyme that generates vitamin D [calcitriol: 1,25(OH)2D], CYP27B1 (1α-hydoxylase), and its receptors (VDRs) are distributed ubiquitously in cells. Once calcitriol binds with VDRs, the complexes are translocated to the nucleus and interact with responsive elements, up- or down-regulating the expression of over 1200 genes and modulating metabolic and physiological functions. Administration of vitamin D3 or correct metabolites at proper doses and frequency for longer periods would achieve the intended benefits. While various tissues have different thresholds for 25(OH)D concentrations, levels above 50 ng/mL are necessary to mitigate conditions such as infections/sepsis, cancer, and reduce premature deaths. Cholecalciferol (D3) (not its metabolites) should be used to correct vitamin D deficiency and raise serum 25(OH)D to the target concentration. In contrast, calcifediol [25(OH)D] raises serum 25(OH)D concentrations rapidly and is the agent of choice in emergencies such as infections, for those who are in ICUs, and for insufficient hepatic 25-hydroxylase (CYP2R1) activity. In contrast, calcitriol is necessary to maintain serum-ionized calcium concentration in persons with advanced renal failure and hypoparathyroidism. Calcitriol is, however, ineffective in most other conditions, including infections, and as vitamin D replacement therapy. Considering the high costs and higher incidence of adverse effects due to narrow therapeutic margins (ED50), 1α-vitamin D analogs, such as 1α-(OH)D and 1,25(OH)2D, should not be used for other conditions. Calcifediol analogs cost 20 times more than D3-thus, they are not indicated as a routine vitamin D supplement for hypovitaminosis D, osteoporosis, or renal failure. Healthcare workers should resist accepting inappropriate promotions, such as calcifediol for chronic renal failure and calcitriol for osteoporosis or infections-there is no physiological rationale for doing so. Maintaining the population's vitamin D sufficiency (above 40 ng/mL) with vitamin D3 supplements and/or daily sun exposure is the most cost-effective way to reduce chronic diseases and sepsis, overcome viral epidemics and pandemics, and reduce healthcare costs. Furthermore, vitamin D sufficiency improves overall health (hence reducing absenteeism), reduces the severity of chronic diseases such as metabolic and cardiovascular diseases and cancer, decreases all-cause mortality, and minimizes infection-related complications such as sepsis and COVID-19-related hospitalizations and deaths. Properly using vitamin D is the most cost-effective way to reduce chronic illnesses and healthcare costs: thus, it should be a part of routine clinical care.

Evaluation of Renal Impairment Influence on Metabolic Drug Clearance using a Modelling Approach.

Chronic kidney disease (CKD) may alter drug renal elimination but is also known for interacting with hepatic metabolism via multiple uremic components. However, few global models, considering the five major cytochromes, have been published, and none specifically address the decrease in cytochrome P450 (CYP450) activity. The aim of our study was to estimate the possibility of quantifying residual cytochrome activity as a function of filtration rate, according to the data available in the literature. For each drug in the DDI-predictor database, we collected available pharmacokinetic data comparing drug exposition in the healthy patient and in various stages of CKD, before building a model capable of predicting the variation of exposure according to the degree of renal damage. We followed an In vivo Mechanistic Static Model (IMSM) approach, previously validated for predicting change in liver clearance. We estimated the remaining fraction parameters at glomerular filtration rate (GFR) = 0 and the alpha value of GFR to 50% impairment for the 5 major cytochromes using a non-linear constrained regression using Matlab software. Thirty-one compounds had usable pharmacokinetic data, with 51 AUC ratios between healthy and renal impaired patients. The remaining CYP3A4 activity was estimated to be 0.4 when CYP2D6, 2C9, 2C19 and 1A2 activity was estimated to be 0.43; 1; 0.73 and 0.7, respectively. The alpha value was estimated to be at 6.62; 25; 9.8; 1.38 and 11.04 for each cytochrome. In comparison with published data, all estimates but one were correctly predicted in the range of 0.5-2. Our approach was able to describe the impact of CKD on metabolic elimination. Modelling this process makes it possible to anticipate changes in clearance and drug exposure in CKD patients, with the advantage of greater simplicity than approaches based on physiologically-based pharmacokinetic modelling. However, a precise estimation of the impact of renal failure is not possible with an IMSM approach due to the large variability of the published data, and thus should rely on specific pharmacokinetic modelling for narrow therapeutic margin drugs.

La toxicidad cardiovascular de los fármacos anticancerosos: el lado oscuro del éxito

Cancer represents the second cause of death in the European Union after cardiovascular diseases, accounting for 27% of all deaths. Anticancer drugs (ACDs) have poor cell selectivity and a narrow therapeutic margin, in such a way that small increases in their plasma levels lead to the appearance of adverse reactions in multiple tissues. The FACs can produce a wide range of adverse cardiovascular reactions (named cardiotoxicity) that increase morbidity and can even lead to death in some patients whose cancer has been cured by the ACD. The risk of cardiotoxicity increases with age, and since up to two-thirds of cancer patients are older than 65 years of age, cancer, cardiovascular diseases whose incidence increases with age and CAD-induced cardiotoxicity will coexist in this population. The diagnosis, prognosis, follow-up, and treatment of cardiotoxicity induced by CAFs represent a challenge in daily clinical practice that makes teamwork among cardiologists, oncologists, and hematologists essential. The recent guidelines on cardio-oncology of the European Society of Cardiology represents the first experience of this joint work to comprehensively address the cardiotoxicity due to anticancer drugs.

Adherence With Oral Anticancer Therapies: Clinical Trial versus Real-World Experiences with a Focus on Prostate Cancer.

In this review, we address adherence rates in clinical settings, barriers to compliance with dosing schedules, and potential strategies to overcome challenges in maintaining high levels of adherence. Four studies reporting real-world adherence to prostate cancer medications, 52 studies describing barriers to adherence, and 16 studies on methods to minimize poor adherence were reviewed. Mean nonadherence rates of 25 to 51% have been identified in prostate cancer patients prescribed oral therapies, with higher rates in older patients. An extensive review of prostate cancer patients receiving gonadotropin hormone-releasing hormone agonist injections found an overall nonadherence rate of over 27%. Patients may encounter barriers to complying with dosing instructions related to the medication (eg, complex dosing schedules, the total burden of medication management, fasting or dietary requirements, high medication costs, adverse effects, and drug-drug interactions). Barriers may also be related to patient-specific factors (eg, suboptimal education regarding the importance of adherence, physical limitations and cognitive decline associated with advancing age, living alone without a care partner, high symptom burden, needle phobia, and comorbid mental disorders). Interventions to improve dosing adherence may include automated reminders, treatment diaries, educational materials, and the involvement of patients, family members, care partners, and healthcare teams. Many oral anticancer medications improve survival in men with prostate cancer and therefore it is vital to establish good adherence by understanding the pitfalls that patients may encounter. In situations where both oral and injectable drugs are interchangeable, injections of long-acting drugs lead to fewer opportunities for dosing nonadherence than oral therapies. In contrast, oral medicines do not require scheduling for injections and travel for injection appointments. Therefore, maximizing adherence to all treatment regimens will reduce the chance of efficacy failures and likely lead to improved clinical outcomes.

Lower Time in Therapeutic Range Relates to a Worse Kidney Graft Outcome

Tacrolimus has a narrow therapeutic margin. Maintaining tacrolimus blood levels in the appropriate range is difficult because of its intrapatient variability. In fact, greater blood level variability has been related to worse kidney graft outcome, but only measuring variability does not consider the therapeutic range goal. Determining the time in therapeutic range (TTR) using the Rosendaal method allows dose optimization by considering the adverse events associated with both supratherapeutic and subtherapeutic doses. Some previous studies in kidney and lung transplantation have shown that the measurement of TTR has been related to the subsequent graft outcome. We performed a single-center, observational study including 215 consecutive kidney transplants performed in our center. The percentage of time that the patient remained with levels above 6 ng/mL between months 3 and 12 (%TTR3-12) was calculated using the Rosendaal method. A lower %TTR3-12 was associated with a higher risk of acute rejection (area under the receiver operating characteristic curve, 0.614; 95% confidence interval [CI], 0.513-0.714; P=.018) and with a higher risk of having a 1-year glomerular filtration rate < 30 mL/min/1.73 m2 (area under the receiver operating characteristic curve, 0.676; 95% CI, 0.542-0.811; P=.014). The lowest tertile of %TTR3-12 was independently associated with a higher risk of death-censored graft loss (hazard ratio, 10.773; 95% CI, 1.315-88.264; P=.027) after adjusting by 1-year glomerular filtration rate, expanded criteria donation, and acute rejection throughout the first year. To conclude, measuring TTR after kidney transplant is an easy way to estimate the time of exposure to adequate levels of tacrolimus and relates to kidney graft outcome.

Implementation and Cross-Validation of a Pharmacokinetic Model for Precision Dosing of Busulfan in Hematopoietic Stem Cell Transplanted Children.

Busulfan, a drug used in conditioning prior to hematopoietic stem cell transplantation (HSCT) in children, has a narrow therapeutic margin. The model-informed precision dosing (MIPD) of busulfan is desirable, but there is a lack of validated tools. The objective of this study was to implement and cross-validate a population pharmacokinetic (PK) model in the Tucuxi software for busulfan MIPD in HSCT children. A search of the literature was performed to identify candidate population PK models. The goodness of fit of three selected models was assessed in a dataset of 178 children by computing the mean error (ME) and root-mean-squared error of prediction (RMSE). The best model was implemented in Tucuxi. The individual predicted concentrations, the area under the concentration-time curve (AUC), and dosage requirements were compared between the Tucuxi model and a reference model available in the BestDose software in a subset of 61 children. The model from Paci et al. best fitted the data in the full dataset. In a subset of 61 patients, the predictive performance of Tucuxi and BestDose models was comparable with ME values of 6.4% and −2.5% and RMSE values of 11.4% and 13.6%, respectively. The agreement between the estimated AUC and the predicted dose was good, with 6.6% and 4.9% of the values being out of the 95% limits of agreement, respectively. To conclude, a PK model for busulfan MIPD was cross-validated and is now available in the Tucuxi software.

Colchicine et inflammation oculaire non sévère hors maladie de Behcet : 16 cas et revue de la littérature

IntroductionColchicine is a narrow therapeutic margin drug that does not have the adverse effects of corticosteroids and immunosuppressants. Its use in non-severe ocular inflammatory disease excluding Behcet's disease has not been studied. MethodsWe included patients seen in the internal medicine department of Dijon University Hospital consecutively between September 2020 and September 2021 if they had received colchicine during their pathology. Patients with suspected Behçet's disease were excluded. Treatment efficacy was studied in patients with at least one year of disease progression who had received more than one year of colchicine. Successful treatment was defined as a 50 % reduction in the number of annual relapses on colchicine. ResultsSixteen patients were included (9 women and 7 men). They had recurrent anterior uveitis (n=10), recurrent scleritis (n=5) and intermediate uveitis. Opthalmological involvement was neither severe nor complicated. All patients combined, the annual relapse ratio (ARR) decreased from 1.8 (0.8–3.5) to 0.3 (0–1.6), (P=0.06). Colchicine was considered effective in three of 10 analyzable patients. In only one patient, treatment was stopped for adverse effects after six weeks. ConclusionIn view of the interesting benefit-risk ratio of colchicine, it seems appropriate to focus on this molecule in non-granulomatous anterior uveitis and non-severe recurrent scleritis.

Impact of Inflammation on Midazolam Metabolism in Severe COVID-19 Patients.

Midazolam is a benzodiazepine frequently used for sedation in patients hospitalized in the intensive care unit (ICU) for coronavirus disease 2019 (COVID‐19). This drug is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes. Several studies have suggested that inflammation, frequently observed in these patients, could modulate CYP3A activity. The objective of this work was to study the impact of inflammation on midazolam pharmacokinetics in patients with COVID‐19. Forty‐eight patients hospitalized in the ICU for COVID‐19 and treated with midazolam administered by continuous infusion were included in this study. Midazolam and α‐hydroxymidazolam concentrations were measured and patient data, including the use of CYP3A inhibitors, were collected. Total and unbound concentrations of midazolam and α‐hydroxymidazolam were measured in plasma using a validated liquid‐chromatography coupled with mass spectrometry method. Inflammatory condition was evaluated by C‐reactive protein (CRP) level measurement. Both drug concentrations and CRP measurements were performed on 354 plasma samples. CRP elevation was significantly associated with the α‐hydroxymidazolam/midazolam plasma ratio decrease, whether for the unbound fraction or for the total fraction. Conversely, inflammation was not associated with protein binding modifications. Logically, α‐hydroxymidazolam/midazolam plasma ratio was significantly reduced when patients were treated with CYP3A inhibitors. In this study, we showed that inflammation probably reduces the metabolism of midazolam by CYP3A. These results suggest that molecules with narrow therapeutic margins and metabolized by CYP3A should be administrated with care in case of massive inflammatory situations.

Chronic Misuse of Paracetamol in OCD Without Hepatic Injury: A Case Report and Literature Review

AimsParacetamol is a commonly used antipyretic and analgesic over the counter medication. In acute or chronic overuse it is associated with dose-dependent hepatic injury. There is a narrow therapeutic margin and that consistent use of as little as 7.5 g/day may be hazardous. Unintentional overdose with paracetamol is the most common cause of acute liver failure in the United Kingdom Here we present an unusual case of a 60-year-old lady with a reported chronic history of self-medicating with an above daily recommended dose of paracetamol without evidence of hepatic injury.MethodsA 60-year-old Caucasian lady known to psychiatric services for 20 years with Recurrent Depressive disorder, Obsessive Compulsive Disorder (OCD), Dependent Personality Disorder with Borderline personality traits. She reported consuming 32 tablets of paracetamol (16gm per day) every day for the past 11 years. She experienced obsessions of fear that if she did not take a particular number of paracetamols in a day then her friends will come to harm and her anxiety was relieved by the compulsion of consuming supratherapeutic doses of paracetamol. There was no evidence of misuse of any other medications other than paracetamol. Her blood investigations revealed liver function tests within normal limits and ultrasound of the liver was unremarkable.ResultsA literature search of “paracetamol or acetaminophen” and “no liver or hepatic” and “damage or injury” found only one case report. The case reported that studies of paracetamol metabolism were performed in a 58-year-old female with rheumatoid arthritis who had consumed 15–20 g paracetamol daily for 5 years without developing liver damage and data were compared with results in seven normal volunteers. The report concluded that a combination of slow paracetamol absorption, enhanced detoxication of paracetamol (by sulphation) and reduced metabolism to potentially cytotoxic metabolites may have reduced the risk of liver damage in this patient.ConclusionIn OCD, misusing medications can be an uncommon presentation of compulsive acts to relieve anxiety. The diagnostic dilemma of factitious illness is probable, however supratherapeutic use of paracetamol without physical harm is rare but possible.

Anatomic distribution of local recurrence of nasopharyngeal carcinoma in the Era of IMRT: Suggestion of modification of clinical target volume delineation.

e18060 Background: Target volume delineation in nasopharyngeal carcinoma (NPC) remains a challenge because of the narrow therapeutic margin. There are no-well established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony structure and experience from conventional two and three- dimensional radiation. The aim of our study, is to clarify different anatomic distribution of local recurrence of NPC based on various T stages and spread patterns, provide a high-risk map of local recurrence of NPC, and thus provide suggestion for modification of CTV delineation based on T stages and spread patterns. Methods: We retrospectively enrolled 869 patients with newly diagnosed nonmetastatic NPC treated with definitive IMRT in our institution. With a median follow-up of 54.4 months, 72 patients developed local failure. All the cases of local failure were reviewed and those of local residual disease were excluded. After that, 52 cases with tracaeble primary radiotherapy plans and MR imaging of local recurrence were included in this study. Gross tumor volume of local recurrence (GTVr) and normal structures were delineated in each recurrent patient on primary CT of radiotherapy. The overlap of normal structures with GTVr were analyzed, as well as the stepwise patterns of tumor spread in NPC, based on different T stages and relapsed risk (≥5%, ≥10%, ≥20%, etc). Results: The anatomic distributions of local recurrence of various primary T stages were compared between early and late stages of NPC. Of note, these structures were significantly highly involved in T3/4 cases, compared with T1/2 cases, including lateral pterygoid muscle, inferior orbital fissure，posterior ethmoid sinus，cavernous sinus as well as hypoglossal canal. As for tumor spread patterns of local relapse, most cases relapsed in the nasopharynx and retropharyngeal lymph node (38.5%), followed by anterior-lateral tumor extension (via nasal cavity-pterygoid process-pterygopalatine fossa, 17.31%), posterior tumor extension (via prevertebral muscle-clivus, 13.46%), anterior-superior extension (via nasal cavity-ethmoid sinus-sphenoidal sinus,13.46%), superior extension(via foramen lacerum-cavernous sinus, 11.54%), etc. Finally, we depicted a map of high-risk area based on different T stages and relapsed risk (≥5%, ≥10%, ≥20%). Conclusions: Comprehensive analysis of local recurrence distributions and tumor spread patterns in real-world IMRT provides important reference for modification of CTV delineation for primary NPC. Certain structures such as cavernous sinus and lateral pterygoid muscle are not routinely recommended in the delineation of high-risk CTV for T1-2 disease. Future individualized delineations should be based on relapsed risk and tumor spread patterns.

MO1013: What is the Best Measure of Time in the Therapeutic Range of Tacrolimus for Kidney Transplantation?

Abstract BACKGROUND AND AIMS Tacrolimus is the main immunosuppressive drug in the vast majority of kidney transplants, but it is a drug with a narrow therapeutic margin. Each centre must establish therapeutic ranges to optimize its efficacy and minimize its toxic effects. Maintaining levels in the appropriate range is difficult due to its inherent inter- and intra-patient variability. In the monitoring of transplants, in addition to assessing the drug levels at each visit, the measurement of time in therapeutic range (TTR) allows us to measure how long the patient has been exposed to the appropriate doses. Currently, it is not known which are the optimal ranges of time or of blood levels that are better related to the subsequent evolution of kidney transplantation. METHOD We performed a single centre, observational study of 215 consecutive kidney transplant recipients performed in our centre from October/2014 to January/2020 who received uninterrupted treatment with tacrolimus during the first year, excluding hypersensitized recipients. TTR was calculated using the Rosendaal method between months 3 and 12 (TTR-M3-12) or 6 and 12 (TTR-M6-12) with a target for blood levels &amp;gt;6 ng/mL (TTR-M3-12-T &amp;gt; 6, TTR-M6-12-T &amp;gt; 6) or between 6 and 10 ng/mL (TTR-M3-12-T6-10, TTR-M6-12-T6-10). RESULTS The mean follow-up time was 4.1 ± 2.0 years. The TTR that had a greater capacity to discriminate the risk of rejection {TTR-M3-12-T &amp;gt; 6: AUC-ROC 0.614, [95% confidence interval (95% CI) 0.513–0.714]; P = .018; TTR-M6-12-T &amp;gt; 6: AUC-ROC 0.607, 95% CI 0.502–0.713, P = .029; TTR-M3-12-T6-10: AUC-ROC 0.610, 95% CI 0.516–0.703, P = .023; TTR-M6-12-T6-10; AUC-ROC 0.596, 95% CI 0.495–0.696, P = .051} during the first year and of having a glomerular filtration rate of &amp;lt;30 mL/min/1.73 m2 at the first year (TTR-M3-12-T &amp;gt; 6: AUC-ROC 0.676, 95% CI 0.542–0.811; P = .014; TTR-M6-12-T &amp;gt; 6: AUC-ROC 0.623, 95% CI 0.511–0.795; P = .037; TTR-M3-12-T6-10: AUC-ROC 0.566, 95% CI 0.429–0.703; P = .358; TTR-M6-12-T6-10: AUC-ROC 0.575, 95% CI 0.446–0.703; P = .310) was TTR-M3-12-T &amp;gt; 6. By Cox regression, the TTR that was significantly related to death censored graft loss of the kidney graft censoring for death was TTR-M3-12-T &amp;gt; 6 (TTR-M3-12-T &amp;gt; 6: HR = 0.972, 95% CI 0.949–0.995; P = .079; TTR-M6-12-T &amp;gt; 6: HR = 0.980, 95% CI 0.961–0.998; P = .033; TTR-M3-12-T6-10: HR = 0.985, 95% CI 0.962–1.009; P = .230; TTR-M6-12-T6-10: HR = 0.987, 95% CI 0.968–1.007; P = .199). By multivariate Cox regression analysis, patients in the lower tertile of TTR (HR = 10.027, 95% CI 1.244–81.447; P = .031) had worse survival than those in the upper tertiles, regardless of kidney function in the first year (Fig. 1). CONCLUSION The measurement of TTR after kidney transplantation makes possible to easily estimate the time of exposure to adequate levels of tacrolimus, relating it to the risk of acute rejection, kidney function in the first year, and death-censored graft survival. Among the possible TTR measures, the one that is best related to post-transplant outcome is taking into account tacrolimus blood levels between month 3 and 12 and those &amp;gt;6 ng/mL (TTR-M3-12-T &amp;gt; 6).

Therapeutic Drug Monitoring of Antibiotic Drugs in Patients Receiving Continuous Renal Replacement Therapy or Intermittent Hemodialysis: A Critical Review.

Antibiotics are frequently used in patients receiving intermittent or continuous renal replacement therapy (RRT). Continuous renal replacement may alter the pharmacokinetics (PK) and the ability to achieve PK/pharmacodynamic (PD) targets. Therapeutic drug monitoring (TDM) could help evaluate drug exposure and guide antibiotic dosage adjustment. The present review describes recent TDM data on antibiotic exposure and PK/PD target attainment (TA) in patients receiving intermittent or continuous RRT, proposing practical guidelines for performing TDM. Studies on antibiotic TDM performed in patients receiving intermittent or continuous RRT published between 2000 and 2020 were searched and assessed. The authors focused on studies that reported data on PK/PD TA. TDM recommendations were based on clinically relevant PK/PD relationships and previously published guidelines. In total, 2383 reports were retrieved. After excluding nonrelevant publications, 139 articles were selected. Overall, 107 studies reported PK/PD TA for 24 agents. Data were available for various intermittent and continuous RRT techniques. The study design, TDM practice, and definition of PK/PD targets were inconsistent across studies. Drug exposure and TA rates were highly variable. TDM seems to be necessary to control drug exposure in patients receiving intermittent and continuous RRT techniques, especially for antibiotics with narrow therapeutic margins and in critically ill patients. Practical recommendations can provide insights on relevant PK/PD targets, sampling, and timing of TDM for various antibiotic classes. Highly variable antibiotic exposure and TA have been reported in patients receiving intermittent or continuous RRT. TDM for aminoglycosides, beta-lactams, glycopeptides, linezolid, and colistin is recommended in patients receiving RRT and suggested for daptomycin, fluoroquinolones, and tigecycline in critically ill patients on RRT.