Detectable Drug Levels Research Articles

Sertraline, citalopram and paroxetine in lactation: passage into breastmilk and infant exposure.

This study aimed to investigate the plasma and breastmilk concentrations for sertraline, citalopram and paroxetine for assessment of the Milk/Plasma (M/P) ratio and Absolute Infant Dose (AID), and to determine actual infant drug exposure through breastfeeding. Subsequently, informed recommendations will be formulated regarding the advisability of breastfeeding in women undergoing treatment with the three most widely used antidepressants. A pharmacokinetic study in lactating women and their infants using sertraline, citalopram or paroxetine was performed. Paired breastmilk and plasma samples and single point infant plasma samples were collected to determine antidepressant concentrations. An Area Under the Curve (AUC) based approach with the trapezoidal rule was used to calculate M/P ratios and AID for all three antidepressants by combining all measured concentrations for the same dose. Thirty-seven lactating women and their infants participated in this study. 111 paired breastmilk and plasma samples and 37 single point infant plasma samples were collected. Detectable concentrations of sertraline, citalopram and paroxetine were present in all breastmilk samples. For sertraline and citalopram M/P ratio is above one, indicating higher breastmilk than plasma concentrations, however, drug exposure by breastmilk did not lead to detectable plasma drug levels in any of the 15 infants for sertraline, for nine (out of 13) infants for citalopram and for eight (out of nine) infants for paroxetine. Given the well-known benefits of breastfeeding, our findings support breastfeeding of infants by mothers who are taking sertraline, citalopram or paroxetine is safe. Sertraline and paroxetine are the preferred antidepressants during breastfeeding, reaching mostly undetectable infant drug levels.

P1021 Comparison of subcutaneous and intravenous infliximab in patients with inflammatory bowel disease showed no differences in immunogenicity or treatment persistence at one year

Abstract Background The effectiveness of infliximab (IFX) in inflammatory bowel disease (IBD) can be impaired by the formation of anti-drug antibodies (ADA). Subcutaneous (SC) IFX has a different pharmacokinetic profile compared to intravenous (IV) administration. These differences may affect the risk of immunogenicity and we sought to explore this in a retrospective study. Methods We performed a retrospective study in Leeds, United Kingdom. Adult patients starting IFX for the first time between January 2019 and June 2022 were identified. All received standard induction with three IV doses followed by either: 1) maintenance SC IFX 2-weekly (standard practice from 2021), or 2) maintenance IV IFX (standard practice until 2021). We compared ADA levels, IFX trough levels and treatment persistence between groups after 12-months of treatment. ADA levels above 10 AU/ml were considered positive and ADA levels above 50 AU/ml as clinically relevant. Results After excluding 41 patients (16 stopped IFX after IV induction, 24 moved to SC after >4 IV doses, and 1 lost to follow-up), 101 patients receiving maintenance SC IFX were compared to 108 patients continuing with maintenance IV IFX. At 12-months, prevalence of ADA positivity was similar in both groups (48.1% SC vs 50.6%; p=0.775). Clinically relevant ADA levels (>50 AU/ml) were also similar (21.1% SC vs 26.5% IV; p=0.481). Additionally, there were no statistically significant differences in terms of detectable IFX trough levels and treatment persistence after 12-months of treatment between the two groups. Patients receiving combination therapy with IFX and immunomodulators showed a significant reduction in ADA formation irrespective of the route of IFX administration. 34.8% of patients receiving combination therapy had detectable ADA compared to 65.2% receiving IFX monotherapy (OR 0.28 (95% CI 0.13-0.58; p=0.001)). Treatment persistence was also significantly higher in those receiving combination therapy compared with monotherapy at 12-months (73.3% vs. 51.9%; p=0.004). The proportion of patients with detectable drug levels at 12-months was also higher with combination therapy (91.3% vs. 72.7%; p=0.005). Conclusion There were no significant differences in ADA levels, IFX levels, and treatment persistence between the SC and IV routes of IFX administration after 12 months of treatment. Concurrent use of immunomodulators was associated with reduced immunogenicity and better treatment persistence regardless of the route of maintenance IFX. Clinicians should advise patients on the benefits of immunomodulator combination therapy when initiating IFX regardless of route of administration.

Demonstrating service delivery models for effective initiation and retention on pre-exposure prophylaxis (PrEP) among female bar workers in Dar es Salaam, Tanzania: A double randomized intervention study protocol.

Pre-Exposure Prophylaxis (PrEP) has demonstrated efficacy in preventing HIV infection. Female Bar Workers (FBWs) often act as informal sex workers, placing them at risk of HIV infection. Despite expressing interest in PrEP, FBWs face barriers to accessing public-sector clinics where PrEP is delivered. We developed a study to compare the effectiveness of workplace-based PrEP provision to standard-of-care facility-based provision for PrEP initiation, retention and adherence among FBWs. In this double-randomized intervention study, FBWs aged 15 years and above will be screened, consented and initiated on PrEP (emtricitabine/tenofovir disoproxil), and followed for six months. Participants will be randomized at the bar level and offered PrEP at their workplace or at a health facility. Those who are initiated will be independently individually randomized to either receive or not receive an omni-channel PrEP champion intervention (support from an experienced PrEP user) to improve PrEP adherence. We expect to screen 1,205 FBWs to enroll at least 160 HIV negative women in the study. Follow-up visits will be scheduled monthly. HIV testing will be performed at baseline, month 1, 4 and 6; and TDF testing at months 2 and 6. Primary outcomes for this trial are: (1) initiation on PrEP (proportion of those offered PrEP directly observed to initiate PrEP); and (2) adherence to PrEP (detectable urine TDF drug level at 6-months post-enrollment). The primary outcomes will be analyzed using Intention-to-Treat (ITT) analyses. Using a randomized trial design, we will evaluate two interventions aiming to reduce barriers to uptake and retention on PrEP among FBWs, a vulnerable population at risk of HIV acquisition and onward transmission. If these interventions prove effective in promoting PrEP among FBWs, they could assist in abating the HIV epidemic in Africa. Registered with German Clinical Trials Register (www.drks.de) on 29 April 2020; Registration number DRKS00018101.

80-LB: Evaluation of the Pharmacokinetics of Glucagon-Like-Peptide-1 (GLP-1) Receptor Agonist Delivered through the BIOJET Oral Biotherapeutic Delivery Platform in Porcine Model

Glucagon-like-peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and suppress glucagon release. Semaglutide is a GLP-1 agonist currently injected subcutaneously or taken orally to treat type 2 diabetes and for weight management. However, oral administration of protein/peptide therapeutics has proven difficult due to the harsh conditions of the upper gastrointestinal tract (GIT) and poor absorption rates in the small intestine. The BIOJET™ oral biotherapeutic delivery platform is an ingestible drug-device combination developed to increase drug bioavailability via needleless jet injection in the proximal small intestine following oral administration. Previous testing of an earlier, autonomously triggered version of the device in animal models was presented at ACG 2022. In this study we evaluated the pharmacokinetics (PK) of semaglutide delivered through the BIOJET device in a porcine model. Due to prolonged and variable gastric residence times in the porcine model, devices filled with semaglutide (~1mg) were administered by intraduodenal (ID) endoscopic placement and activated in the proximal small intestine of Yucatan swine. PK blood sampling was performed from 0 to 240 hours post-dose to evaluate systemic exposure of semaglutide. Seven of eight (7/8) devices were successfully placed and activated in the duodenum. All seven animals showed detectable drug levels up to ten days post-dosing and had an oral bioavailability average of 37% ± 15% (CV: 40%), ranging from 19%-60% compared to IV control. No significant clinical signs were observed in the animals. This study demonstrated that administration of the BIOJET device has the potential to achieve a magnitude greater bioavailability than the currently marketed oral semaglutide (< 1%). The BIOJET device could provide an alternative for the oral administration of large molecules and may improve patient compliance. Disclosure S. N. Lee: Employee; Biora Therapeutics. C. A. Stork: Employee; Biora Therapeutics. R. O. Valenzuela-rivas: Employee; Biora Therapeutics. M. Walker: Employee; Biora Therapeutics. B. J. Smith: Employee; Biora Therapeutics. J. A. Smith: None. N. Quintana: None. C. Wahl: Employee; Biora Therapeutics. S. Singh: None.

Impact and cost-effectiveness of the national scale-up of HIV pre-exposure prophylaxis among female sex workers in South Africa: a modelling analysis.

In 2016, South Africa (SA) initiated a national programme to scale-up pre-exposure prophylaxis (PrEP) among female sex workers (FSWs), with ∼20,000 PrEP initiations among FSWs (∼14% of FSW) by 2020. We evaluated the impact and cost-effectiveness of this programme, including future scale-up scenarios and the potential detrimental impact of the COVID-19 pandemic. A compartmental HIV transmission model for SA was adapted to include PrEP. Using estimates on self-reported PrEP adherence from a national study of FSW (67.7%) and the Treatment and Prevention for FSWs (TAPS) PrEP demonstration study in SA (80.8%), we down-adjusted TAPS estimates for the proportion of FSWs with detectable drug levels (adjusted range: 38.0-70.4%). The model stratified FSW by low (undetectable drug; 0% efficacy) and high adherence (detectable drug; 79.9%; 95% CI: 67.2-87.6% efficacy). FSWs can transition between adherence levels, with lower loss-to-follow-up among highly adherent FSWs (aHR: 0.58; 95% CI: 0.40-0.85; TAPS data). The model was calibrated to monthly data on the national scale-up of PrEP among FSWs over 2016-2020, including reductions in PrEP initiations during 2020. The model projected the impact of the current programme (2016-2020) and the future impact (2021-2040) at current coverage or if initiation and/or retention are doubled. Using published cost data, we assessed the cost-effectiveness (healthcare provider perspective; 3% discount rate; time horizon 2016-2040) of the current PrEP provision. Calibrated to national data, model projections suggest that 2.1% of HIV-negative FSWs were currently on PrEP in 2020, with PrEP preventing 0.45% (95% credibility interval, 0.35-0.57%) of HIV infections among FSWs over 2016-2020 or 605 (444-840) infections overall. Reductions in PrEP initiations in 2020 possibly reduced infections averted by 18.57% (13.99-23.29). PrEP is cost-saving, with $1.42 (1.03-1.99) of ART costs saved per dollar spent on PrEP. Going forward, existing coverage of PrEP will avert 5,635 (3,572-9,036) infections by 2040. However, if PrEP initiation and retention doubles, then PrEP coverage increases to 9.9% (8.7-11.6%) and impact increases 4.3 times with 24,114 (15,308-38,107) infections averted by 2040. Our findings advocate for the expansion of PrEP to FSWs throughout SA to maximize its impact. This should include strategies to optimize retention and should target women in contact with FSW services.

39: INCIDENCE OF DETECTABLE DRUG LEVELS WITH INHALED AMINOGLYCOSIDE THERAPY IN CRITICALLY ILL ADULTS

Introduction: Advantages of aminoglycosides administered via inhalation include achievement of high concentrations in the lung parenchyma, optimization of concentration-dependent bactericidal killing, and minimization of dose-dependent systemic toxicity. Systemic accumulation of inhaled antibiotic therapy has been reported, though is poorly understood. The objective of this study is to characterize the incidence of a detectable drug level (DDL) in critically ill patients that received inhaled aminoglycoside therapy. Methods: This retrospective, single-center study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during intensive care unit (ICU) hospitalization between January 1, 2009, and July 1, 2020. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn as a trough. Drug levels were considered detectable for tobramycin ≥ 0.5 mcg/mL or amikacin ≥ 1.5 mcg/mL. Results: A total of 93 drug levels in 54 critically ill patients were included in the study. Median age was 44.5 years; median BMI was 20; 43 (79.6%) patients were lung transplant recipients and 20 (37%) patients had cystic fibrosis. A DDL was observed for 39 (41.9%) levels: 29 (31.2%) tobramycin and 10 (10.7%) amikacin. The median DDL was 3.7 mcg/mL (IQR 1.98-4.53) for amikacin and 0.9 mcg/mL for tobramycin (IQR 0.7 -1.6). Therapy was modified in 30 (76.9%) DDLs: frequency reduction in 18 (60%), therapy discontinuation in 6 (20%), dose and frequency reduction in 4 (13.3%), and dose reduction in 2 (6.7%). Conclusions: For critically ill adults receiving inhaled aminoglycoside therapy, approximately 40% of drug levels evaluated were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy. Future trials with protocolized therapeutic drug monitoring and clinical outcomes and safety endpoints associated with dose adjustments are needed for patients receiving inhaled aminoglycoside therapy.

Incidence and associated risk factors for systemic drug levels with inhaled aminoglycoside therapy.

To characterize the incidence of and risk factors for a detectable drug level (DDL) in patients that received inhaled aminoglycoside therapy. This retrospective, single-centre study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during inpatient hospitalization. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn within 4 h of the next dose. A repeated measures logistic regression model evaluated the association between potential risk factors and a DDL. Among 286 drug levels, 88 (30.8%) drug levels were detectable. In multivariable analysis, cystic fibrosis (CF) (OR: 3.03; 95% CI: 1.10-8.35), chronic kidney disease (CKD) (OR: 4.25; 95% CI: 1.84-9.83), lung transplant recipient (OR: 3.08; 95% CI: 1.09-8.73), mechanical ventilation (OR: 2.99; 95% CI: 1.25-7.15) and tobramycin (OR: 5.26; 95% CI: 2.35-11.78) were associated with higher odds of a DDL. Among those with a DDL, inhaled aminoglycoside type and drug level concentration were not associated with acute kidney injury (P = 0.161). Among 286 drug levels identified among inpatients receiving inhaled aminoglycoside therapy, 88 (30.8%) unique drug levels were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy with CF, CKD, lung transplantation, mechanical ventilation or tobramycin.

EXTH-67. PRECLINICAL ASSESSMENT OF THE EFFICACY OF MPT0B640, AN ORALLY BIOAVAILABLE SMALL MOLECULE HSP90 INHIBITOR, AGAINST GLIOMAS

Abstract BACKGROUND Heat-shock protein 90 (HSP90), an evolutionary conserved protein, is a key member of the epichaperome complex involved in maintenance of protein homeostasis during non-stress and stress conditions. It is overexpressed in gliomas and supports tumor cell survival and resistance. Hsp90 inhibition can impact several pathways essential for glioma cell survival and overcome tumor heterogeneity. Here, we examined the activity and toxicity profile of MPT0B640, an orally bioavailable Hsp90 inhibitor, against gliomas and its ability to cross the blood-brain barrier (BBB). METHODS Using genetically heterogeneous glioma stem-like cell (GSC) lines, we determined the effects of MPT0B640 on cell proliferation (Cell Titre Glo assay), apoptosis induction and cell cycle changes (flowcytometry; AnnexinV/PI staining), and alterations in protein expressions (western blot and reverse-phase protein array, RPPA assays). Pharmacokinetic and pharmacodynamic (PK/PD) studies were performed in non-tumor bearing mice to assess BBB permeability and antitumor effects of MPT0B640. RESULTS MPT0B640 inhibited proliferation of both adherent (LN229, A172, U251-HF) and patient-derived GSCs (GSC262, GSC811, GSC11, GSC23, GSC20 and GSC272) in a dose- and time-dependent fashion with an IC50 range of 50-1000 nM. MPT0B640-treated cells underwent apoptosis and/or cell cycle arrest with downregulation of pro-survival signal kinases, phospho-Akt, p-ERK1/2 and p-S6. PK/PD studies showed increased HSP70 expression (a marker of Hsp90 inhibition) and detectable levels of drug in brain specimens from non-tumor bearing mice after a single dose of MPT0B640, indicating BBB permeability and target inhibition of the agent. Results of ongoing animal studies assessing drug toxicity and animal survival with MPT0B640 will be presented. CONCLUSIONS MPT0B640 is a potent HSP90 inhibitor that has potent antitumor activity against genetically heterogeneous gliomas in vitro, effectively crosses the intact BBB and demonstrates target inhibition warranting further investigation for treatment of gliomas.

Biological Monitoring via Urine Samples to Assess Healthcare Workers’ Exposure to Hazardous Drugs: A Scoping Review

Although biological monitoring is beneficial as it assesses all possible routes of exposure, urine sampling of healthcare workers exposed to hazardous drugs is currently not routine. Therefore, a scoping review was performed on this subject matter to understand what is known about exposure and identify knowledge gaps. A literature search was performed on three databases: ProQuest, Web of Science, and PubMed. Articles published between 2005 and 2020 and written in English were included. Overall, this review consisted of 39 full-text articles. The studies varied with respect to design, sample sizes, sample collection times, and drugs examined. Many articles found at least one sample had detectable levels of a hazardous drug. Studies reported urinary drug contamination despite controls being employed. Knowledge gaps included a lack of an exposure limit, lack of a standardized sampling method, and lack of correlation between health effects and urinary contamination levels. Due to differences in sample collection and analysis, a comparison between studies was not possible. Nevertheless, it appears that biological monitoring via urine sampling is meaningful to aid in understanding healthcare workers’ exposure to hazardous drugs. This is supported by the fact that most studies reported positive urine samples and that case-control studies had statistically significant findings.

S1566 Evaluation of the Pharmacokinetics of PGN-OB1 Following Oral Administration of an Oral Biotherapeutics Delivery System (OBDS) in Yucatan Swine

Introduction: Biologics/peptides/nucleic acids are highly effective drugs; however, oral delivery of these therapeutics has proved to be difficult due to the harsh conditions of the upper gastrointestinal tract (GIT) and the poor absorption rate in the small intestinal mucosa. We aimed to develop an oral biotherapeutic delivery system (OBDS) that protects these biomolecules from degradation in the upper GIT and increases oral bioavailability via needless injection in the submucosal space of the small intestine. We describe the development of models to assess the functional capability of the OBDS capsule. A Yucatan minipig model was chosen to better represent the pharmacokinetic properties of submucosal injection in humans and evaluate the injection efficiency of OBDS in vivo. Methods: Due to prolonged and variable gastric residence times in the swine model, the semi-autonomous OBDS capsules containing a variant of adalimumab (PGN-001), PGN-OB1, were administrated by intraduodenal endoscopic placement (ID) and released into the proximal small intestines of the female Yucatan swine. Blood samples post-ID dosing were collected to evaluate the injection efficiency of the OBDS compared with the IV control group. Results: All OBDS capsules were successfully advanced through the pyloric sphincter via endoscopic placement, without early deployment, and released in the proximal duodenum to naturally transit and deploy in vivo. Out of 13 animals dosed, 8 animals showed detectable drug levels (Figure), and an oral bioavailability average of 22% or 25% (range from 7-55%) excluding an animal showing a late deployment at 72hr post-dose. The variability in the swine model is believed to be due to physiologic variability that may not directly translate to humans including variability in small intestinal transit time, and more frequent and larger, gas and fluid pockets in the swine. Conclusion: Here we have provided proof-of-concept of a semi-autonomous OBDS device that can achieve as high as 55% bioavailability of a variant of adalimumab that is a magnitude higher than current oral protein or peptide delivery technology in the market and at levels much closer to the subcutaneous route of administration estimated in human trials. The OBDS capsules could potentially provide a better alternative for the non-invasive route of administration with better patient compliance.Figure 1.: Plasma concentration of PGN-001 treated with ID and IV over time

Randomized Controlled Trial of Automated Directly Observed Therapy for Measurement and Support of PrEP Adherence Among Young Men Who have Sex with Men

Measurement of adherence to oral pre-exposure prophylaxis (PrEP) in real-time has been challenging. We developed DOT Diary, a smartphone application that combines automated directly observed therapy with a PrEP adherence visualization toolkit, and tested its ability to measure PrEP adherence and to increase adherence among a diverse cohort of young men who have sex with men (MSM). We enrolled 100 MSM in San Francisco and Atlanta and randomly assigned them 2:1 to DOT Diary versus standard of care. Concordance between DOT Diary measurement and drug levels in dried blood spots was substantial, with 91.0% and 85.3% concordance between DOT Diary and emtricitabine-triphosphate and tenofovir-diphosphate, respectively. There was no significant difference in the proportion of participants with detectable PrEP drug levels at 24 weeks between study arms. These results suggest DOT Diary is substantially better than self-reported measures of adherence, but additional interventions are needed to improve PrEP adherence over time.

Risk Factors Associated with Suboptimal Tobramycin Levels in the Medical Intensive Care Unit.

Optimal aminoglycoside dosing in critically ill patients represents a challenge for practitioners, especially in the medical intensive care unit (MICU). MICU patients exhibit altered pharmacokinetics due to pathophysiological changes the body undergoes in critical illness, leading to possible treatment failure. The literature surrounding optimal dosing and therapeutic drug monitoring strategies of aminoglycosides in MICU patients is scarce and conflicting. Additionally, only a few studies have investigated risk factors for suboptimal pharmacokinetic target obtainment. Currently, no definitive risk factors have been identified to predict suboptimal aminoglycoside target obtainment in MICU patients. The objective of this study was to determine risk factors for suboptimal pharmacokinetic target obtainment in patients receiving tobramycin in the MICU. This single-center, retrospective cohort study included patients 18-89 years old who received at least one 7 mg/kg tobramycin dose in the MICU from January, 1 2015 to September, 30 2020. Patients also had to have at least two detectable drug levels obtained at least one half-life apart following the first tobramycin dose. The primary outcome was to determine the incidence of optimal pharmacokinetic target obtainment, defined as a tobramycinmaximum concentration (Cmax)≥10 mcg/ml, and to identify the risk factors for suboptimal (Cmax < 10 mcg/mL) pharmacokinetic target obtainment, in MICU patients. Secondary outcomes were compared between suboptimal and optimal target obtainment in patients with culture confirmed gram-negative infection susceptible to tobramycin. These secondary outcomes included all-cause in-hospital mortality, ICU length of stay (LOS), hospital LOS, and vasopressor duration in those with shock. A total of 230 patients were included in this retrospective study. For the primary outcome, 187 (81.3%) patients achieved optimal target obtainment. Through multivariate logistic regression, female sex and serum albumin <2.5 g/dL were identified as independent risk factors for suboptimal target obtainment; [OR = 2.14; 95% CI (1.05-4.37), p = 0.037], [OR = 2.50; 95% CI (1.21-5.19), p = 0.014], respectively. Fifty-four (23%) patients had culture-confirmed gram-negative infections susceptible to tobramycin and were included in the subgroup analysis. Of these 54 patients, 11 (20.4%) did not achieve optimal target concentrations. In patients with culture-confirmed gram-negative infection, there was no difference between patients with optimal target obtainment and suboptimal target obtainment in ICU LOS, hospital LOS, all-cause mortality, or vasopressor duration in those with shock. Among patients receiving their first dose of tobramycin in the MICU, 81.3% obtained an optimal serum concentration. Female sex and serum albumin <2.5 g/dL were identified as risk factors for suboptimal target obtainment; however, further research is warranted to assess the utility of using these two covariates as risk factors for more aggressive dosing in critically ill MICU patients.

PD11-09 CELLULAR MECHANISMS OF 5-ALPHA REDUCTASE INHIBITOR TREATMENT RESISTANCE IN BENIGN PROSTATIC HYPERPLASIA

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD11)1 Sep 2021PD11-09 CELLULAR MECHANISMS OF 5-ALPHA REDUCTASE INHIBITOR TREATMENT RESISTANCE IN BENIGN PROSTATIC HYPERPLASIA Diya Binoy Joseph, Gervaise Henry, Alicia Malewska, Jeffrey Reese, Ryan Mauck, Jeffrey Gahan, Ryan Hutchinson, James Mohler, Claus Roehrborn, and Douglas Strand Diya Binoy JosephDiya Binoy Joseph More articles by this author , Gervaise HenryGervaise Henry More articles by this author , Alicia MalewskaAlicia Malewska More articles by this author , Jeffrey ReeseJeffrey Reese More articles by this author , Ryan MauckRyan Mauck More articles by this author , Jeffrey GahanJeffrey Gahan More articles by this author , Ryan HutchinsonRyan Hutchinson More articles by this author , James MohlerJames Mohler More articles by this author , Claus RoehrbornClaus Roehrborn More articles by this author , and Douglas StrandDouglas Strand More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001986.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 5-alpha reductase inhibitors (5ARIs) are prescribed to reduce prostate volume and alleviate lower urinary tract symptoms due to Benign Prostatic Hyperplasia (BPH). In some patients, prostate shrinkage is focal and does not result in improved urinary symptoms. We examined the phenotypic changes in glandular acini accompanying 5ARI treatment to determine the cellular mechanisms of treatment resistance. METHODS: Mass spectrometry was performed to measure 5ARI drug and hormone levels in prostate tissue from BPH patients. Patients with confirmed presence of 5ARI drug, low DHT and histological response were selected for spatial transcriptomics. Visium spatial transcriptomics was performed on histologically-responsive and non-responsive regions. Primary prostate epithelial cells were treated with TNF-α to activate NF-κB and qPCR was used to measure lineage-specific gene expression. RESULTS: We observed that patients with detectable levels of 5ARI drug display reduced DHT and increased testosterone regardless of phenotypic response. In 5ARI treated patients, regions of normal prostate glandular architecture can often be seen adjacent to regions of smaller acini with multiple cell layers, defined as histologically-resistant and -responsive, respectively. Spatial transcriptomics performed on histologically-resistant vs. -responsive regions revealed a urethral club-like molecular signature in small acini. These regions displayed increased TNF-α expression and nuclear localization and phosphorylation of p65. Treatment of primary prostate epithelial cells with TNF-α activated NF-κB and upregulated club cell genes, recapitulating the in vivo expression of these genes in responsive regions. CONCLUSIONS: We conclude that 5ARI treatment results in small ducts of androgen-independent club cells. It is unclear whether 5ARI treatment is inducing direct lineage switching of prostate luminal cells to club-like cells for survival or whether 5ARI-induced apoptosis of prostate luminal cells is indirectly driving altered differentiation of basal epithelia to club epithelia. Alternatively, androgen-independent club cells may be expanded during BPH and survive 5ARI treatment and repopulate prostate glands after 5ARI withdrawal. Further studies are required to determine how adjacent, histologically normal prostate glands maintain AR-dependent signaling despite low levels of tissue DHT and whether club cells can act as progenitors during androgen replenishment and prostate regrowth. Source of Funding: AUA Research Scholar Award 659333 to DBJ, R01 DK115477 to DWS and NCI P30CA016056 to Roswell Park Comprehensive Cancer Center for support of the Bioanalytical, Metabolomics, and Pharmacokinetics Shared Resource © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e201-e201 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Diya Binoy Joseph More articles by this author Gervaise Henry More articles by this author Alicia Malewska More articles by this author Jeffrey Reese More articles by this author Ryan Mauck More articles by this author Jeffrey Gahan More articles by this author Ryan Hutchinson More articles by this author James Mohler More articles by this author Claus Roehrborn More articles by this author Douglas Strand More articles by this author Expand All Advertisement Loading ...

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.

Prior Immunogenicity to Anti-TNF Biologics Is Not Associated with Increased Anti-drug Antibodies to Vedolizumab or Ustekinumab

Patients with inflammatory bowel disease (IBD) on biologic therapy may lose response to anti-tumor necrosis factor agents (anti-TNFs) due to the development of anti-drug antibodies (ADAs). A history of anti-TNF ADA increases the risk of developing ADA to subsequent anti-TNFs; however, it is not known whether ADA to anti-TNFs increases the risk of ADA development to vedolizumab (VDZ) or ustekinumab (UST). We aimed to investigate whether prior history of ADA to anti-TNF increases the risk of ADA to VDZ and UST. We conducted a retrospective cohort study of patients at a tertiary care IBD center over the course of four years who had previous anti-TNF drug and ADA level data during maintenance treatment and subsequent VDZ or UST drug and antibody levels, all collected as standard of care. The primary outcome was the rate of ADA development to VDZ and UST in patients with and without prior anti-TNF immunogenicity. Descriptive statistics summarized the data and univariate tested associations. Of the 152 IBD patients analyzed, 41 (27%) had a history of previous anti-TNF ADA with 22 (53.7%) having simultaneously undetectable anti-TNF drug levels. There was no significant difference in the rates of ustekinumab and vedolizumab ADA development between patients with prior ADA and patients without prior ADA (1/41 [2.7%] vs 1/111 [0.9%]; p = 0.54). There was also no difference in concomitant immunomodulator use with ustekinumab or vedolizumab initiation in patients with or without prior ADA (13/41 [31.7%] vs 31/111 [27.9%], p = 0.84). Neither patient who developed ADA to VDZ or UST was on concomitant immunomodulator at drug initiation, and both patients had detectable drug levels at the time of antibody detection. We observed that prior immunogenicity to anti-TNF agents does not confer an increased risk of immunogenicity to ustekinumab or vedolizumab. Our data support the use of vedolizumab or ustekinumab as monotherapy for the treatment of IBD.

Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.

P202 Administering live vaccines to infants exposed to biologic and targeted synthetic DMARDs in-utero for maternal treatment of rheumatic disease: a systematic review of the literature

Abstract Background/Aims Increasing utilisation of biologic disease modifying anti-rheumatic drugs (DMARDs) and targeted synthetic (ts)DMARDs in women of reproductive age has potential for informed or accidental use in pregnancy and impact on fetal immunity. Transplacental passage of certain biologic DMARDs result in detectable drug levels in the neonate. Current British Society for Rheumatology (BSR) guidelines recommend all live vaccines be delayed in infants until 7 months of age after in-utero exposure in later pregnancy to the tumour necrosis factor inhibitors (TNFi) etanercept, adalimumab or infliximab. This advice affects administration of rotavirus, BCG and potentially MMR vaccination. Therefore, we performed a systematic review to evaluate vaccine safety in infants exposed to bDMARDs or tsDMARDs in pregnancy. Methods A systematic review of Embase, Medline and Cochrane identified live vaccine outcomes in the infants of mothers who took bDMARDs or tsDMARDs during pregnancy, focussing on drugs used in standard rheumatology practice. Studies were reviewed in accordance with the PRISMA guidelines. Results A total of 226 titles and abstracts were screened and 8 papers selected for final analysis. Studies included in-utero exposures to adalimumab (n = 326), certolizumab pegol (n = 18), etanercept (n = 1), infliximab (n = 408), golimumab (n = 1), rituximab (n = 1), tocilizumab (n = 3) and ustekinumab (n = 1). No relevant articles on tsDMARDs were identified. Maternal disease included inflammatory bowel disease (n = 849), rheumatoid arthritis (n = 3) and Burkitt’s lymphoma (n = 1). For infants exposed to biologic medications in utero, we identified infant vaccination to: BCG (n = 111) and/or rotavirus (n = 48) in the first year of life, many &amp;lt; 6 months; and MMR (n = 605) at 12 months (n = 590), 6-9 months (n = 12) and at 1, 2 or 4 months (n = 3). Adverse events with BCG vaccination included 1 death, 2 large local skin reactions, and 1 infant with axillary lymphadenopathy. A freedom of information request to the MHRA revealed 4 further suspected fatal BCG infections in infants exposed to TNFi in-utero (2 infliximab, 1 adalimumab, 1 unspecified TNFi). Side-effects noted in infants given rotavirus vaccination were mild and at similar frequency to those in non-biologic exposed infants. No complications were reported with MMR vaccination. Conclusion Overall, we found most evidence of clinically harmful effects after administration of BCG to infants &amp;lt; 3 months of age and after in-utero exposure to infliximab. In contrast, outcomes following rotavirus (mostly &amp;lt; 6 months) and MMR (mostly at a year) vaccinations were reassuring. These findings are limited to live vaccine usage at standard time points in Europe/USA following maternal use of TNFis with significant placental transfer. Therefore, further understanding of live vaccine safety after exposure to any bDMARD or tsDMARD is required, including confirmation of the presumed safety of live vaccine use following maternal usage of bDMARDs with negligible rates of placental transfer. Disclosure B. Goulden: None. N. Chua: None. E. Parker: None. I. Giles: Consultancies; Educational grant from UCB; speakers fees from UCB; travel fees from UCB. Other; Chair of guideline group on prescribing anti-rheumatic drugs in pregnancy for British Society of rheumatology.

Systemic detectability of dexamethasone and prednisolone after eye drop application in horses.

Equine sport agencies list steroids as prohibited substances for competing horses. The objective of this study was to investigate if the controlled substances dexamethasone and prednisolone are detectable in equine serum and urine samples during and after treatment with eye drops and if this can generate a positive doping test. Prospective cohort study. The study cohort included 11 horses. One eye of the horses was treated with either dexamethasone (Maxitrol® 0.1%, n=5 eyes) or prednisolone (Pred forte® 1%, n=6 eyes) eye drops 3 times daily for 14days. Dexamethasone and prednisolone concentrations were determined in serum and urine at day 0 (negative control), 1, 7, 14, 15, 17 and 21 using liquid chromatography-tandem mass spectrometry. Blood samples were collected within 2hours post application. Urine samples were collected during spontaneous urination. All serum samples (range: 0.7-43ng/mL, mean 2.1ng/mL) and urine samples (range 1.2-5ng/mL, mean 0.8ng/mL) showed measurable amounts of dexamethasone during the course of treatment. Concentrations in both serum and urine samples were below limit of detection (LOD) 24hours after the last dexamethasone treatment (day 15). All serum samples (range 1.1-32.5ng/mL, mean 6.4ng/mL) and urine samples (range 3.7-19ng/mL, mean 4.6ng/mL) were positive for prednisolone during treatment. Urine samples were below LOD on day 15; serum samples on day 21. Dexamethasone and prednisolone eye drops can induce detectable drug levels in serum and urine samples of horses after a 14-day treatment plan. This can lead to a positive doping result. All samples tested negative (below LOD of the analytical method) for dexamethasone one day and for prednisolone one week after treatment cessation.

Plasma, urine and tissue concentrations of Flunixin and Meloxicam in Pigs.

BackgroundThe objective of this study was to determine the renal clearance of flunixin and meloxicam in pigs and compare plasma and urine concentrations and tissue residues. Urine clearance is important for livestock show animals where urine is routinely tested for these drugs. Fourteen Yorkshire/Landrace cross pigs were housed in individual metabolism cages to facilitate urine collection. This is a unique feature of this study compared to other reports. Animals received either 2.2 mg/kg flunixin or 0.4 mg/kg meloxicam via intramuscular injection and samples analyzed by mass spectrometry. Pigs were euthanized when drugs were no longer detected in urine and liver and kidneys were collected to quantify residues.ResultsDrug levels in urine reached peak concentrations between 4 and 8 h post-dose for both flunixin and meloxicam. Flunixin urine concentrations were higher than maximum levels in plasma. Urine concentrations for flunixin and meloxicam were last detected above the limit of quantification at 120 h and 48 h, respectively. The renal clearance of flunixin and meloxicam was 4.72 ± 2.98 mL/h/kg and 0.16 ± 0.04 mL/h/kg, respectively. Mean apparent elimination half-life in plasma was 5.00 ± 1.89 h and 3.22 ± 1.52 h for flunixin and meloxicam, respectively. Six of seven pigs had detectable liver concentrations of flunixin (range 0.0001–0.0012 µg/g) following negative urine samples at 96 and 168 h, however all samples at 168 h were below the FDA tolerance level (0.03 µg/g). Meloxicam was detected in a single liver sample (0.0054 µg/g) at 72 h but was below the EU MRL (0.065 µg/g).ConclusionsThese data suggest that pigs given a single intramuscular dose of meloxicam at 0.4 mg/kg or flunixin at 2.2 mg/kg are likely to have detectable levels of the parent drug in urine up to 2 days and 5 days, respectively, after the first dose, but unlikely to have tissue residues above the US FDA tolerance or EU MRL following negative urine testing. This information will assist veterinarians in the therapeutic use of these drugs prior to livestock shows and also inform livestock show authorities involved in testing for these substances.

Abstract 5709: Disruption of mitochondrial metabolism underlies the efficacy of devimistat in acute myeloid leukemia

Abstract Background: Acute myeloid leukemia (AML) remains an agressive malignancy with poor clinical outcomes, particularly in older patients. Dysregulated metabolism has long presented a promising target for cancer therapeutics; however, the development of clinical-stage therapies targeting cancer cell metabolism has been limited and faces challenges to achieve both efficacy and acceptable toxicity. As an exception, the lipoic acid analogue devimistat has shown positive clinical outcomes in numerous early-phase clinical trials including for relapsed and refractory AML patients. While inhibition of lipoic acid-dependent ketoacid dehydrogenase (KADH) enzymes has been proposed as the mechanism of these antineoplastic effects, the mechanisms underlying the efficacy devimistat and its possible relation to metabolism in patients has not been established. Methods: Samples of bone marrow and blood plasma from patients with relapsed or refractory AML before and after treatment with devimistat were collected. The samples were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) methods to profile ~400 polar metabolites. Kinetic flux profiling in cultured cancer cell lines treated with devimistat was also performed. Results: Analysis of blood plasma samples collected following devimistat treatment revealed detectable levels of drug, consistent with clinically therapeutic concentrations. Comprehensive metabolite profiling of pretreatment and posttreatment blood plasma samples revealed distinct metabolic alterations induced by devimistat administration. Devimistat is thought to inhibit ketoacid dehydrogenase (KADH) enzyme, and consistent with this proposed mechanism of action, accumulations of KADH substrates were observed in the posttreatment samples. Local metabolism in the tumor microenvironment was also altered by devimistat therapy, with robust reductions of TCA intermediates measured in bone marrow plasma samples collected after treatment. Interestingly, quantification of these metabolites revealed an association between overall clinical outcomes and changes in concentrations of bone marrow metabolites. Kinetic flux tracing demonstrated an expected reduction of mitochondrial metabolic flux in cultured tumor cells following treatment with devimistat. Conclusions: Comprehensive metabolite profiling reveals that devimistat targets KADH enzymes and reduces mitochondrial metabolism in humans. Furthermore, these metabolic changes are quantitatively associated with clinical outcomes, posing a potential opportunity for biomarker development and precision metabolic therapy. Citation Format: Michael A. Reid, Shree Bose, Zhengtao Xiao, Peter G. Mikhael, Juan Liu, Jason W. Locasale, Timothy S. Pardee. Disruption of mitochondrial metabolism underlies the efficacy of devimistat in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5709.