Serum Drug Levels Research Articles

S845 Evaluation of the Relationship Between COVID-19 Severity and Serum Biologic Level in Inflammatory Bowel Disease Patients

Introduction: Studies suggest a protective effect of biologic therapy (BT) from severe Coronavirus 19 (COVID-19) in inflammatory bowel disease (IBD) patients (pts). However, studies are lacking on the impact of BT intake timing on COVID-19 disease course. This study aims to evaluate the relationship between COVID-19 severity and serum biologic level in IBD pts. Methods: Crohn’s Disease (CD) and Ulcerative Colitis (UC) pts on BT, from an academic medical center that tested COVID-19 positive from 3/1/2020 to 3/14/2021, were included. Comorbidities including obesity, type II diabetes, COPD, smoking history, and chronic kidney disease were documented. The interval between last BT intake and COVID-19 diagnosis (dx) was recorded. The biologic half-life (HL), used as a surrogate marker for serum drug level, for infliximab/biosimilar, adalimumab, natalizumab, ustekinumab, and vedolizumab was 9.5, 14, 16, 19, and 25 days, respectively. COVID-19 severity was defined as mild if managed outpatient or in the emergency room, and moderate (mod)/severe if requiring hospitalization, intensive care unit admission or resulting in death. Mann Whitney U test was used for continuous variables. Results: 37 (28 CD, 9 UC) pts, 20 females and 17 males were identified. Median age, BMI, and number of comorbidities were 43, 30.5, and 1, respectively. Of the patients on biologics, 1 was on natalizumab, 3 on vedolizumab, 5 on ustekinumab, 11 on adalimumab, and 17 on infliximab/biosimilar. No pt was on concomitant steroid therapy. Mild and mod/severe outcomes were seen in 32 and 5 pts, respectively. No deaths were reported. The mean interval between drug intake and COVID 19 dx was 1.5 HL in mild and 2 HL in mod/severe COVID-19 pts. There was no significant association between timing of BT and COVID-19 severity in patients on BT (p=0.98), those on anti-TNFs alone (p=0.75), and those on ustekinumab alone (p=0.54). Conclusion: There is no association between severity of COVID-19 and timing of BT in IBD pts suggesting no detrimental effect of biologics on the COVID-19 disease course. The small number of pts with mod/severe outcomes suggests a protective effect. Future studies are needed to further evaluate the relationship between serum biologic levels and COVID-19 severity.Table 1.: a: number of white patients b: number of black and hispanic patients c: number of patients with Ulcerative Colitis d: number of patients with Crohn's Disease e: Average age in years f: number of patients on 5mg/kg dosing g: number of patients on 10mg/kg dosing h: median dosing frequency i: Average number of biologic half lives between the patient's last biologic intake and COVID-19 diagnosis j: Not available.Table 2

CML-268: Study to Evaluate the Effect of Fatty Meals on Nilotinib Drug Levels in Patients with CML-CP

Context: Nilotinib is an oral tyrosine kinase inhibitor used in chronic myeloid leukemia (CML) and is known to have food interactions. It is recommended for administration in a fasting state (meals taken either 2 hours after dose or 1 hour before a dose). Food, especially fat-rich food, has been shown to increase the bioavailability of drugs. If the drug is allowed to be taken with food, it will be convenient for patients and also lower the dose needed to produce clinical benefit. This will decrease the cost of therapy and will improve the quality of life of patients. Objective: To assess the effect of fatty meals on nilotinib drug levels in patients with CML. Design/Setting/Patients/Intervention: It is a single-center, open-label, pharmacokinetic study. There were 5 cohorts with 6 patients enrolled in each. A total of 30 patients were included in the study. The patient population included patients of newly diagnosed CML (chronic phase). The dose of nilotinib in each cohort was 150 mg OD, 200 mg OD, 150 mg BD, 200 mg BD, and 300 mg BD, respectively. The drug was given an empty stomach for an initial 8 days, followed by fatty meals for the next 8 days. Fatty meals were defined as 2 slices of bread with 10 grams of butter. Two ml blood was withdrawn at specified time points at 0 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, and 24 hours and on day 8 (0 hour and 3 hours). Nilotinib drug levels were estimated by liquid chromatography mass spectrometry. Main Outcome Measures: To assess serum drug levels of nilotinib in both fasting and post-meals statuses to determine an increase in drug levels with fatty meals. Results: Initial results of the study have shown the significant benefit of food on nilotinib drug levels. We will discuss the complete results at the SOHO conference. Acknowledgements: The study is funded by a research grant from the Indian Council of Medical Research, New Delhi (ICMR).

Drug and Neurofilament Levels in Serum and Breastmilk of Women With Multiple Sclerosis Exposed to Natalizumab During Pregnancy and Lactation.

ObjectiveTo determine the transfer of the monoclonal antibody natalizumab into breastmilk and to evaluate drug and serum neurofilament light chain ((s)NfL) levels in natalizumab exposed pregnancies and lactation periods.MethodsEleven women with relapsing remitting multiple sclerosis treated with natalizumab during pregnancy and lactation were included in this study. Breastmilk samples were collected up to 302 days after delivery and analyzed for natalizumab concentration and NfL. Additionally, maternal drug levels and sNfL were determined preconceptually, in each trimester, at delivery and postpartum. Clinical and radiological disease activity was systemically assessed across pregnancy and postpartum period.ResultsThe mean average natalizumab concentration in breast milk was low at 0.06 µg/ml [standard deviation (SD) 0.05] in the eight patients who provided serial breastmilk samples with an estimated mean absolute infant dose of 0.007 mg/kg/d (SD 0.005). The relative infant dose (RID), a metric comparing the infant with maternal drug exposure was low as well with a mean of 0.04% (SD=0.03). Most patients had a maximum concentration in breast milk at one to eight days after infusion. Pregnancy was associated with a non-significant decline of the median natalizumab serum concentration. All patients exposed to natalizumab prior (n=10) and during pregnancy (n=11) kept free of disease activity during gestation. While pregnancy was associated with low sNfL levels in patients treated with natalizumab prior and during pregnancy, the postpartum period was linked to a transient sNfL increase in some patients without any evidence of clinical or radiological disease activity. NfL was detectable in the majority of breastmilk samples with a median concentration of 1.7 pg/ml (range 0.004-18.1).ConclusionWe determined transfer of natalizumab into breastmilk with an RID far below the threshold of concern of 10%. Studies including childhood development assessment are needed in order to gain safety data about natalizumab-exposed breastfeeding. SNfL assessment might be a useful adjunct to monitor silent disease activity and therapeutic response during pregnancy and postpartum period. However, further investigations regarding transient postpartum sNfL increases are required to determine its association to parturition per se or to a silent disease activity in people with multiple sclerosis.

MoS2-Assisted LDI Mass Spectrometry for the Detection of Small Molecules and Quantitative Analysis of Sulfonamides in Serum.

A two-dimensional MoS2 nanosheet was prepared by a chemical exfoliation method and served as an excellent matrix for the detection of small molecules by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). In comparison with organic matrices (CHCA, 3-AQ) and a graphene matrix, we found that a MoS2 matrix showed better performance in analysis of amino acids, peptides, fatty acids, and sulfonamides. A systematic comparison of the MoS2 matrix with both ion modes showed that mass spectra produced in negative ion mode featured a corresponding single deprotonated ion, which was rather different from the complex multiple alkali metal addition peaks present in positive ion mode. In addition, better sensitivity and reproducibility were obtained in negative ion mode. The ionization mechanism of MoS2 as a matrix in negative ion mode was further discussed. The deproton peak intensity of the analyte fatty acid decreased after the addition of the hole-scavenger KSCN, indicating that the ionization of the fatty acid was caused by the Auger complex effect of MoS2 and electron injection. Experiments have shown that the MoS2 matrix detects small molecules with good repeatability and can perform semiquantitative analysis of sulfonamides. Finally, the MoS2 matrix was employed for quantitative determination of sulfamethoxine in serum samples by an internal standard method. This MoS2-assisted laser desorption/ionization mass spectrometry (MoS2-assisted LDI MS) method provides a simple, rapid, high-throughput approach to evaluate the drug levels in the patient serum and can achieve convenient drug therapy monitoring.

Pharmaco-Electroencephalography-Based Assessment of Antidepressant Drug Efficacy-The Use of Magnesium Ions in the Treatment of Depression.

Pharmaco-electroencephalography (pharmaco-EEG) is a technique used to assess the effects of psychotropic medications on the bioelectrical activity of the brain. The purpose of this study was to assess the treatment response with the use of the Hamilton Depression Rating Scale (HDRS) and via EEG. Over an 8-week period, we analyzed electroencephalographic tracings of 91 patients hospitalized for major depression at the Medical University of Warsaw. Thirty-nine of those patients received tricyclic antidepressants (TCAs), 35 received fluoxetine, and 17 received fluoxetine augmented with magnesium (Mg) ions. All patients had their serum drug levels monitored. The highest proportion of patients (88.2%) who showed adequate responses to treatment was observed in the fluoxetine+Mg group, whereas the lowest rates of treatment response were observed in the TCA group (58.3%). This difference was statistically significant (p = 0.029, Phi = 0.30). Our study demonstrated a relationship between achieving remission (HDRS ≤ 6 at week 8 of treatment) and obtaining a positive pharmaco-EEG profile 6 h after administration of the first dose in the group receiving fluoxetine augmented with Mg ions (p = 0.035, Phi = 0.63).

Case Report of A Rare Idiosyncratic Hepatotoxicity Induced by Valproic Acid

Valproate induced hepatotoxicity is a well-known side effect, which frequently required periodic monitoring of serum drug level. Hepatotoxicity caused by valproate typically occurs at supratherapeutic drug levels. Once in a while, an idiosyncratic reaction is elicited, liver injury might occur despite normal serum valproate level mainly in chronic users. We hereby identify an unusual case of acute idiosyncratic valproate induced hepatotoxicity. We report a case of a 65 years old male with dyslipidemia and history of seizure, on valproic acid therapy, presented with altered mental status and drowsiness. The patient’s home medications include only zenil 10 mg daily and valproate which was started one month ago. At presentation, He was awake, oriented, but lethargic. Laboratory testing reveals hepatocellular injury with elevated transaminase levels, direct hyperbilirubinemia and coagulopathy. The ammonia level was normal and valproate level was within the therapeutic range. Abdomen computed tomography with IV contrast and MRCP results were irrelevant. Idiosyncratic valproate toxicity was diagnosed after exclusion of all other possible etiologies and after a rapid clinical and laboratory improvement once the drug was discontinued. Based on the patient’s clinical context the diagnosis of valproate induced hepatotoxicity was confirmed. This case emphasizes the importance of identifying, diagnosing, and managing valproate toxicity when no alternative clarification for their symptoms. We need further attempts and more researches to improve the detection of adverse hepatic reactions and to obtain reliable information about the discovery of new biomarkers or tools for early prediction of DILI, as well as to obtain accurate information on epidemiology, drug safety, and pathogenesis in order to improve management for better survival.

Case Report of A Rare Idiosyncratic Hepatotoxicity Induced by Valproic Acid

Valproate induced hepatotoxicity is a well-known side effect, which frequently required periodic monitoring of serum drug level. Hepatotoxicity caused by valproate typically occurs at supratherapeutic drug levels. Once in a while, an idiosyncratic reaction is elicited, liver injury might occur despite normal serum valproate level mainly in chronic users. We hereby identify an unusual case of acute idiosyncratic valproate induced hepatotoxicity. We report a case of a 65 years old male with dyslipidemia and history of seizure, on valproic acid therapy, presented with altered mental status and drowsiness. The patient’s home medications include only zenil 10 mg daily and valproate which was started one month ago. At presentation, He was awake, oriented, but lethargic. Laboratory testing reveals hepatocellular injury with elevated transaminase levels, direct hyperbilirubinemia and coagulopathy. The ammonia level was normal and valproate level was within the therapeutic range. Abdomen computed tomography with IV contrast and MRCP results were irrelevant. Idiosyncratic valproate toxicity was diagnosed after exclusion of all other possible etiologies and after a rapid clinical and laboratory improvement once the drug was discontinued. Based on the patient’s clinical context the diagnosis of valproate induced hepatotoxicity was confirmed. This case emphasizes the importance of identifying, diagnosing, and managing valproate toxicity when no alternative clarification for their symptoms. We need further attempts and more researches to improve the detection of adverse hepatic reactions and to obtain reliable information about the discovery of new biomarkers or tools for early prediction of DILI, as well as to obtain accurate information on epidemiology, drug safety, and pathogenesis in order to improve management for better survival.

Pattern of adverse drug reactions and serum level of maintenance lithium treatment in patients with bipolar affective disorder: a cross-sectional study in Eastern Nepal

<p class="abstract"><strong>Background:</strong> Benefits of lithium maintenance therapy in bipolar affective disorder (BPAD) are restricted by adverse drug reactions (ADRs) and low therapeutic index. The same dose of lithium has sub-therapeutic, therapeutic and supra-therapeutic serum level in different patients. The objective of this study was to describe the pattern of ADR and serum concentration of maintenance dose of lithium in patients with BPAD.</p><p class="abstract"><strong>Methods:</strong> A cross-sectional study was conducted in patients diagnosed with BPAD and taking lithium monotherapy 900 mg daily at least for 6 months at outpatient department of psychiatry, B. P. Koirala institute of health sciences. Sociodemographic profile and relevant laboratory investigations were recorded on a self-designed proforma. Chi square test, ANOVA test and student’s t test were used for analysing the data at p value <0.05.</p><p class="abstract"><strong>Results:</strong> Out of 123, 64 (52.0%) were female. Serum concentration ranged from 0.31 to 1.51 mmol/l with mean of 0.803 mmol/l and was in therapeutic range in 104 (84.6%) patients. At least one ADR was seen in 81 (65.9%) patients and hand tremor (43.6%) was the commonest ADR. Hypothyroidism and hyperthyroidism were seen in 9 (6.8%) and 6 (4.5%) patients, respectively. Occurrence of ADRs were more in female and was significantly significant (P value <0.05).</p><p class="abstract"><strong>Conclusions:</strong> The serum level of lithium 900 mg/day varied widely and was in therapeutic range in majority of the patients. Prevalence of ADRs was 65.9%. Occurrence of ADRs were significantly more common in female patients and supra-therapeutic serum concentration of lithium. A prospective long-term study should be conducted to validate the study findings.</p>

Systematic review: efficacy of escalated maintenance anti-tumour necrosis factor therapy in Crohn's disease.

Loss of response to anti-TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD). To perform a systematic review assessing the efficacy of escalated maintenance anti-TNF therapy in CD. EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full-text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included. A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%-100%) and remission (15%-83%) after empiric dose escalation for loss of response to standard anti-TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose-escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure-response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end-points. Strategies including Bayesian dashboard-dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long-term outcomes. Empiric escalation of maintenance anti-TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.

Serum Inhaled Corticosteroid Detection for Monitoring Adherence in Severe Asthma

Daily inhaled corticosteroids (ICSs) are fundamental to asthma management, but adherence is low. To investigate (1) whether LC-MS/MS could be used to detect ICSs in serum and (2) whether serum levels related to markers of disease severity. We collected blood samples over an 8-hour period from patients with severe asthma prescribed at least 1000 μg daily of beclomethasone dipropionate equivalent. Following baseline sampling, patients were observed taking their usual morning dose. Subsequent blood samples were obtained 1, 2, 4, and 8 hours postinhalation and analyzed by LC-MS/MS. Correlations between serum ICS levels and severity markers were investigated. A total of 60 patients were recruited (41 females; 39 prescribed maintenance prednisolone; mean age, 49 ± 12 years; FEV1, 63 ± 20 %predicted). Eight hours postinhalation, all patients using budesonide (n= 10) and beclomethasone dipropionate (15), and all but 1 using fluticasone propionate (28), had detectable serum drug levels. Fluticasone furorate was detected in 2 patients (of 4), ciclesonide in none (of 7). Low adherence by repeat prescription records (<80%) was identified in 43%. Blood ICS levels correlated negatively with exacerbation rate, and (for fluticasone propionate only) positively with FEV1 %predicted. Commonly used ICSs can be reliably detected in the blood at least 8 hours after dosing, and could therefore be used as a measure of adherence in severe asthma. Higher exacerbation rates and poorer lung function (for fluticasone propionate) were associated with lower blood levels.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases

Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). The primary end point was clinical remission at week 30. Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. ClinicalTrials.gov Identifier: NCT03074656.

Sinonasal and gastrointestinal bacterial composition and abundance are stable after 1 week of once-daily oral antibiotic treatment for chronic rhinosinusitis.

Despite the widespread prescription of antibiotics for the treatment of chronic rhinosinusitis (CRS), their efficacy remains uncertain. Limited penetration of systemic antibiotics into the sinonasal mucosa has been reported previously by this group. This study aimed to investigate the short-term effects of antibiotics on the sinus and gut microbiota as well as any relationships these had with drug distribution. Thirty subjects undergoing functional endoscopic sinus surgery for CRS were randomized to one of three groups: (1) doxycycline (100mg daily for 7 days); (2) roxithromycin (300mg daily for 7 days); and (3) control (no antibiotics given). Sinonasal and stool samples collected before and after treatment were analyzed using 16S ribosomal RNA (rRNA) gene-targeted amplicon sequencing and Droplet Digital polymerase chain reaction (PCR) for bacterial community composition and the quantification of bacterial DNA, respectively. There were no significant major bacterial community shifts or changes to bacterial diversity and load following the treatment period in all patient groups. Non-significant trend reductions were observed in gut microbial diversity with antibiotics. For the roxithromycin group, sinonasal bacterial diversity was negatively correlated with serum drug levels and reduced overall compared to controls (p<0.05). The relative abundance of Staphylococcus ASV129 in sinonasal samples reduced with increasing mucus doxycycline levels (p=0.01). Antibiotic prescription for CRS should be further investigated because of preliminary evidence of poor sinonasal drug penetration, unproven efficacy, and the potential impact of dysbiosis in the sinuses and off-target sites. Further studies should consider distinguishing the presence of DNA from viable and nonviable bacteria.

Systemic conbercept pharmacokinetics and VEGF pharmacodynamics following intravitreal injections of conbercept in patients with retinopathy of prematurity

BackgroundData on serum vascular endothelial growth factor (VEGF) and drug levels in patients with retinopathy of prematurity (ROP) following intravitreal injections of conbercept (IVC) are lacking.MethodsMulticentre, prospective, non-randomised study of...

Markers of Quality Care for Newly Diagnosed People With Epilepsy on Medicaid.

For newly diagnosed people with epilepsy (PWE), proper treatment is important to improve outcomes, yet limited data exist on markers of quality care. Examine markers of quality care for newly diagnosed PWE. Using Medicaid claims data (2010-2014) for 15 states we identified adults 18-64 years of age diagnosed with incident epilepsy in 2012 or 2013. We built 5 sequential logistic regression models to evaluate: (1) seeing a neurologist; (2) diagnostic evaluation; (3) antiepileptic medication adherence; (4) serum drug levels checked; and (5) being in the top quartile of number of negative health events (NHEs). We adjusted for demographics, comorbidities, county-level factors, and the outcomes from all prior models. Of 25,663 PWE, 37.3% saw a neurologist, with decreased odds for those of older age, those residing in counties with low-density of neurologists, and certain race/ethnicities; about 57% of PWE received at least 1 diagnostic test; and nearly 62% of PWE were adherent to their medication. The most common comorbidities were hypertension (37.1%) and psychoses (26.9%). PWE with comorbidities had higher odds of seeing a neurologist and to have NHEs. Substance use disorders were negatively associated with medication adherence and positively associated with high NHEs. There are notable differences in demographics among people with incident epilepsy who do or do not see a neurologist. Differences in NHEs persist, even after controlling for neurologist care and diagnostic evaluation. Continued attention to these disparities and comorbidities is needed in the evaluation of newly diagnosed PWE.

Polypharmacy Results in Functional Impairment in Mice: Novel Insights Into Age and Sex Interactions.

Males and females may respond differently to medications, yet knowledge about sexual dimorphisms in the effects of polypharmacy remains limited, particularly in aging. This study aimed to assess the effect of high Drug Burden Index (DBI) polypharmacy treatment compared to control on physical function and behavior in young and old, male and female mice. We studied whether age and sex play a role in physical function and behavior following polypharmacy treatment and whether they are paralleled by differences in serum drug levels. Young (2.5 months) and old (21.5 months), C57BL/6 mice were randomized to control or high DBI polypharmacy treatment (simvastatin, metoprolol, oxybutynin, oxycodone, and citalopram; n = 6-8/group) for 4-6 weeks. Compared to control, polypharmacy reduced physical function (grip strength, rotarod latency, gait speed, and total distance), middle zone distance (increased anxiety), and nesting score (reduced activities of daily living) in mice of both ages and sexes (p < .001). Old animals had a greater decline in nesting score (p < .05) and midzone distance (p < .001) than young animals. Grip strength declined more in males than females (p < .05). Drug levels at steady state were not significantly different between polypharmacy-treated animals of both ages and sexes. We observed polypharmacy-induced functional impairment in both age and sex groups, with age and sex interactions in the degree of impairment, which were not explained by serum drug levels. Studies of the pathogenesis of functional impairment from polypharmacy may improve management strategies in both sexes.

Een patiënte gered door alcohol

A patient saved by alcohol The medical history of a 43-year-old female patient with auto-intoxication of ethylene glycol is reported. Ethylene glycol is a toxic alcohol leading to severe complications if not treated early. Ethylene glycol itself is relatively nontoxic, however life-threatening toxicity appears after metabolization in the liver. These toxic metabolites lead to metabolic acidosis, renal failure, multiple organ failure and death. A quick diagnosis and therapeutic management are important to avoid formation of the metabolites. Serum drug levels give certainty regarding diagnosis, but are rarely available in time to guide management. There is often a strong suspicion or clear history of auto-intoxication. Shortly after large ingestions, patients may present with sedation or inebriation and have a large osmolar gap, but minimal acidosis. After several hours a profound metabolic acidosis with high anion gap will be present. Management involves supportive care, administration of sodium bicarbonate to correct systemic acidosis, inhibition of the enzyme alcohol dehydrogenase with either fomepizole or ethanol, haemodialysis and treatment with cofactors to optimize nontoxic metabolic pathways. Methanol poisoning is also discussed in this article, as methanol is another toxic alcohol with a similar therapeutic management.

Real world use of biologic drug levels and anti-drug antibodies in patients with psoriasis – does therapeutic drug monitoring have a place in routine clinical practice?

Background: Psoriasis is a chronic disorder with increasing new treatments targeting the T-helper cell (Th)-1/Th17 axis. There remains a subset of patients who experience a primary or secondary failure to biologic treatments. Methods: We present ten patients with psoriasis who failed biologic therapy with measurement of serum drug levels and anti-drug antibody levels (ADAs) with review of the current literature. Our objective was to identify demographic factors, disease status, drug level and ADAs which might correlate with primary and secondary failure. Results: There are a number of factors affecting drug levels in patients with psoriasis on biologics including the presence of ADAs, patient adherence to treatment regimes, pharmacogenetics and the pharmacokinetic properties of the drug following subcutaneous injection. Our results demonstrate that biologic failure is related to low serum drug levels subtherapeutic in 80% of our cohort. Primary failure may correlate with the presence of ADAs but not with serum drug levels. All patients were ANA negative and there remains considerable debate on the utility of routine ANA testing. Conclusions: The role of therapeutic drug monitoring in dermatology remains uncertain and requires further study. We aim to promote debate in the dermatology community as to the utility of therapeutic drug monitoring in routine practice.

Advances in the optimization of therapeutic drug monitoring using serum, tissue and faecal anti-tumour necrosis factor concentration in patients with inflammatory bowel disease treated with TNF-α antagonists

ABSTRACT Introduction The relationship between clinical outcomes and serum anti-TNF levels is controversial. The aim of this study was to perform simultaneous analyses of serum, mucosal, and fecal anti-TNF-α levels. Methods Consecutive IBD patients who received maintenance anti-TNF-α therapy were enrolled. The number of TNF-α positive cells in the mucosa was detected using immunofluorescent labeling on biopsy samples. Serum, mucosal and fecal anti-TNF-α, serum anti-drug antibody, and fecal calprotectin levels were determined using ELISA. Each patient underwent body composition analysis as well. Results Data of 50 patients were analyzed. The number TNF-α positive cells was significantly higher in the inflamed part of the colon than in the un-inflamed part of the colon. Tissue and fecal drug levels did not show any association with serum drug levels; moreover, serum anti-TNF concentration did not correlate with endoscopic activity. Mucosal anti-TNF levels were higher only in IFX-treated patients in remission and IFX-treated patients with detectable fecal anti-TNF had lower tissue drug levels. Presence of the drug in the feces was significantly different according to disease activity. Conclusion Fecal drug concentration is suggested to be a better predictor of endoscopic activity and loss of response, and fecal drug monitoring may improve the estimation accuracy of tissue drug levels.

A151 COMPARABLE NEONATAL AND PREGNANCY-RELATED OUTCOMES BETWEEN EARLY AND LATE DISCONTINUATION OF BIOLOGICS IN PREGNANT WOMEN WITH INFLAMMATORY BOWEL DISEASE

Abstract Background Inflammatory bowel disease (IBD) disease activity during pregnancy is related to adverse neonatal and pregnancy-related outcomes. Biologics are used to suppress disease activity, however, since there is known transplacental passage, the American Gastroenterology Association (AGA) recommends timing the final dose with drug-specific half-lives although there is little evidence demonstrating adverse outcomes. Aims We aim to assess the safety of early versus late discontinuation of biologics according to drug-specific half-lives by comparing various neonatal and pregnancy-related outcomes. Methods This is a REB approved single-center retrospective cohort study on all patients with IBD ≥18 years of age on a biologic agent prior to conception, have a documented final dose during pregnancy, and were seen at Mount Sinai Hospital from 2016–2019. Neonate and pregnancy-related outcomes were compared amongst the two groups (Table 1) using the student’s t-test (birthweight, gestational age, Apgar scores) and Fischer’s exact test (NICU admission, congenital anomalies, GBS, chorioamnionitis) analyzed in SPSS Version 27. The level of significance was set at p&amp;lt;0.05. Results We identified 53 patients on biologics pre-conception. 26 patients had a documented final dose (19 early cohort, 7 late cohort) and were included in the analysis. Aside from mean birthweight (3014 vs 3561 g, p=0.036), there were no statistically significant differences between the early and late cohorts for gestational age (37.4 vs 39.0 weeks, p=0.20), 1- and 5-min Apgar scores (7.8 vs 8.8, p=0.37 and 8.5 vs 9.0, p=0.49), NICU admissions (p=0.54), congenital anomalies (p=1.00), GBS (p=0.55), and chorioamnionitis (p=1.00). Conclusions Overall, our study suggests that early and late discontinuation of biologics have comparable safety profiles based on various neonatal and pregnancy-related outcomes. In fact, we see significantly higher birthweights in the late cohort along with a consistent (non-statistically significant) trend of later gestational ages, and higher Apgar scores. Further, no cases involving NICU admissions, congenital abnormalities, GBS, or chorioamnionitis were seen in the late cohort. Next, we hope to verify our findings by conducting a prospective cohort study with a larger study population and more comprehensive data collection. This will provide higher statistical power and allow for additional subgroup analyses based on objective disease activity (FCP levels) and therapeutic drug monitoring (serum drug levels). Funding Agencies None

Abstract PS8-12: Interim analysis of a phase I dose escalation study of topical bexarotene in women at high risk for breast cancer

Abstract Background: Breast cancer prevention with anti-estrogens, including tamoxifen, raloxifene, and exemestane, has been shown to reduce the incidence of hormone receptor-positive breast cancer. However, agents that can reduce the incidence of hormone receptor negative breast cancer are currently lacking. Rexinoids such as bexarotene are vitamin A analogues that have been shown to be involved in cell differentiation, growth, and apoptosis. In preclinical mouse models that develop ER-negative breast cancers, bexarotene showed a significant reduction in mammary tumor development. Oral bexarotene has been evaluated in BRCA mutation carriers and significant decreases in cyclin D1 were noted in breast cells suggesting biological activity of bexarotene on breast tissue. Systemic side effects of hyperlipidemia and hypothyroidism were also found. Data from chemoprevention studies with topical 4-hydroxytamoxifen support the concept of topical agents penetrating into the breast tissue and exhibiting biological activity. We hypothesize that topical bexarotene can be applied to the breast as a prevention agent with penetration into the breast tissue and without subsequent systemic side effects as seen with oral bexarotene. Methods: Women at high risk for breast cancer were recruited and assigned to escalating doses of 1% topical bexarotene: 10mg (1ml) every other day, 10mg (1ml) daily and 20mg (2ml) daily for 4 weeks. Cohorts of 3-4 participants were enrolled and fully evaluated through 4 weeks prior to enrolling the next cohort. Each dose level enrolled a maximum of 10 participants. The primary endpoint of the study was to determine the recommended phase II dose of topical bexarotene 1% gel for evaluation in healthy at-risk women. Dose Limiting Toxicity (DLT) was defined as a grade 2 skin adverse event that persists for at least 6 days or any grade 3 or greater adverse event related to the study drug. A grade 2 skin adverse event that recurs and persists for at least 3 days is also a DLT. The Maximum Tolerated Dose (MTD) was defined as the highest dose level at which no more than 2 participants experience a DLT among 10 participants treated. Once the MTD was determined, interim biomarker analysis will be completed to assess bexarotene levels in serum and tissue samples. An expansion cohort of an additional 10 patients will be recruited at the MTD to further evaluate safety and toxicity. Secondary endpoints include serum bexarotene level, tissue bexarotene levels, and changes in thyroid function tests, lipid profile, and calcium. Results: Ten women were enrolled at the dose level of 10mg every other day and 9/10 participants experienced Grade 1 skin related events at the application site. Two participants reported Grade 2 skin related events at the application site but did not last long enough to be considered DLTs. Four women were enrolled at the second dose level of 10mg daily and 3/4 experience Grade 2 skin related events including 2 DLTs which stopped accrual to the study. Therefore, the MTD was determined to be 10mg every other day. No laboratory abnormalities were noted across either dose level and no grade 3 or 4 adverse events were reported. Conclusion: Maculopapular rash at treatment site was the most common adverse event related to study drug and resolved with discontinuation. Analysis is ongoing to assess bexarotene drug levels in serum and breast tissue samples. Citation Format: Parijatham S Thomas, Anisha B Patel, Diane Liu, J. Jack Lee, Seema Khan, Miguel Muzzio, Alejandro Contreras, Lana Vornik, Eileen P Dimond, Marjorie Perloff, Brandy Heckman-Stoddard, Powel H Brown. Interim analysis of a phase I dose escalation study of topical bexarotene in women at high risk for breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-12.