Trough Serum Concentrations Research Articles

Suspicious of Acute Kidney Graft Rejection: Tacrolimus Pharmacokinetics Under Methylprednisolone Therapy.

Acute rejection remains one of the main complications in the first months after transplantation and may influence long-term outcomes. Tacrolimus has proven its usefulness in solid organ transplants and its monitoring through the application of pharmacokinetic concepts to optimize individual drug therapy. This research proposes to evaluate the tacrolimus pharmacokinetic parameters in patients suspected of acute kidney graft rejection under methylprednisolone pulse therapy. Eleven adult tacrolimus-treated renal recipients were selected from a prospective, single-arm, single-center cohort study, with suspicion of acute rejection although in use of methylprednisolone pulses therapy. They were followed up for three months posttransplantation, being tacrolimus trough serum concentrations determined using a chemiluminescent magnetic immunoassay, and pharmacokinetic parameters were estimated by using a nonlinear mixed-effects model implemented by Monolix 2020R1. A tacrolimus trough serum concentration range of 8 to 12 ng.mL-1 was considered therapeutic. Six patients showed acute cellular rejection, and two of them in addition had an antibody- mediated rejection. Tacrolimus trough serum concentration was below the reference range in eight patients. Most patients showed a high tacrolimus concentration intrapatient and pharmacokinetic parameters variability. The obtained pharmacokinetics parameters helped in understanding the kidney recipient patients' tacrolimus behavior, assisting in the improvement of individual drug therapy and reducing the risk of acute rejection episodes.

Association of procalcitonin with voriconazole concentrations: a retrospective cohort study

Inflammation is a potential risk factor of voriconazole (VCZ) overdose, procalcitonin (PCT) is reported to act as a diagnostic marker for bacterial infections. However, the association of PCT with VCZ trough serum concentrations (VCZ-Cmin) is not fully clear. Our study aims to investigate the associations between PCT and VCZ-Cmin. In this retrospective cohort study, we collected the clinical data of 147 patients who received VCZ and monitored the VCZ concentration of them in our hospital from August 2017 to August 2021. All patients underwent routine clinical examinations on the day or the day before VCZ administration. General information and clinical symptoms of these patients were recorded. Multivariate liner analysis showed that PCT was significantly associated with VCZ-Cmin (p < 0.001). Overall, it was shown that VCZ-Cmin was significantly increased by 0.32 µg/mL for each fold increment in PCT in crude model. In the minor adjusted model (Model 1, adjustment for sex, age, albumin, direct bi1irubin, WBC) and fully adjusted model (Model 2, adjustment for sex, age, albumin, direct bilirubin, WBC, AST and ALT), VCZ-Cmin was significantly increased by 0.23 µg/mL and 0.21 µg/mL, respectively, for each fold increment in PCT. In conclusion, this research reveals the correlation between PCT and VCZ-Cmin, indicating that PCT has the potential to serve as a valuable biomarker for drug monitoring in the treatment of VCZ.

No Correlation between Anti-drug Antibodies and Therapeutic Response in Tunisian Patients with Chronic Inflammatory Diseases Treated by TNF Blockers.

Tumor necrosis factor alpha (TNF alpha) blockers such as infliximab (IFX) and adalimumab (ADA) had significantly changed the course of inflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Crohn's disease (CD). However, about 30% of patients do not respond to these treatments. This lack of response may be due to the formation of antibodies against these drugs (anti-drug antibodies: ADAbs). The aim of this study was to determine the prevalence of ADAbs against IFX and ADA, and the trough serum concentration of IFX and ADA in RA, SpA or CD patients and to assess their impact on the therapeutic response. A cross sectional, multi-centric study was conducted, including patients with RA, SpA or CD treated with IFX or ADA as a first biotherapy for at least 6 months. ADAbs and trough levels were measured by an Enzyme Linked Immunosorbent assay (ELISA). 197 patients were included (57 RA, 73 SpA and 67 CD). ADAbs were positive in 40% of cases for IFX and 25% for ADA. They were positive in 40% of SpA, 35% of RA, and 21% of CD. The presence of ADAbs was inversely correlated to the trough levels of IFX and ADA during RA (p = 0.01 and p < 0.0001), SpA (p < 0.01 and p < 0.0001) and CD (p = 0.001 and p = 0.04). For all pathologies, the presence of ADAbs was not correlated with disease activity. Concomitant methotrexate significantly reduced immunogenicity. In our study, the presence of ADAb and low trough levels seem to not affect the therapeutic response in patients on TNF alpha antagonists. Other tracks more than immunogenicity should be investigated to explain the loss of response to these biotherapies.

Evaluation of Serum Acetaminophen Concentration Utility for Closure of Patent Ductus Arteriosus.

Acetaminophen for patent ductus arteriosus (PDA) closure has gained popularity over the last decade; however, therapeutic drug monitoring for this indication remains uncertain. The exact timing and goal trough serum acetaminophen concentration ranges are not well defined. The purpose of our study is to evaluate the impact of therapeutic drug monitoring on both PDA closure rates and identify real-world risk of hepatotoxicity. Retrospective single-center chart review of neonates admitted to the neonatal intensive care unit (NICU) between April 2016 and August 2022 with at least 1 serum acetaminophen concentration to monitor for PDA closure. Acetaminophen was initiated at 15 mg/kg administered intravenously every 6 hours and a trough serum concentration was obtained prior to the sixth or seventh dose. PDA closure was confirmed radiographically with corresponding provider documentation. Associations of efficacy to closure were -analyzed using descriptive statistics. Thirty-eight neonates were included in the analysis, of which 18 (47%) achieved PDA closure. First serum acetaminophen trough concentration was obtained before the seventh dose [IQR, 6-8] and ranged from undetectable (< 5 mg/L) to 30.8 mg/L. Subgroup analysis of first concentrations revealed therapeutic trough, defined as 10 to 20 mg/L, did not correlate to PDA closure (no closure median concentration = 14.7 [IQR, 13-15.6] vs closure median concentration = 15.4 [IQR, 11.4-18.5], p = 0.42), or duration of treatment. No neonate experienced acetaminophen-associated toxicity. PDA closure did not correlate to serum acetaminophen trough concentration. The regimen of 15 mg/kg every 6 hours appears safe as no neonate experienced acetaminophen toxicity or discontinued treatment early.

Evaluation of Empiric Voriconazole Dosing and Therapeutic Drug Monitoring in Hospitalized Pediatric Patients.

Invasive fungal infections are a significant cause of morbidity and mortality in children with immunodeficiencies. Current dosing recommendations for voriconazole often result in subtherapeutic exposure in pediatric patients. In this single-center retrospective study, we reviewed hospitalized pediatric patients receiving voriconazole with at least one inpatient serum trough concentration measured. Patient characteristics and voriconazole dosing courses with associated trough concentrations were summarized for all patients as well as grouped by age (0 to 1 y, 2 to 11 y, and 12 to 18 y). Of 106 included patients, the median age was 9 years (range, 29 d to 18 y). Five hundred ninety courses of voriconazole were administered with 365 associated troughs. Most troughs were subtherapeutic (49%) and 30% of patients never attained a therapeutic trough. The median oral daily dose associated with a therapeutic trough was higher in younger age groups: 21.6 mg/kg 0 to 1 year, 17.9 mg/kg 2 to 11, and 9.5 mg/kg 12 to 18 years ( P <0.001). Patients younger than 2 years had the largest proportion of subtherapeutic troughs and variability in dosing. Attainment of therapeutic voriconazole concentrations was challenging across all pediatric age groups. Higher starting doses for patients younger than 2 years are likely needed.

Factors influencing serum concentrations of levetiracetam in dogs with epilepsy.

Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy. Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs. Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam. Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction. The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R2 = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R2 = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 μg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified. Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital.

Serum Concentration-Dose Relationship and Modulation Factors in Children and Adolescents Treated with Fluvoxamine.

Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response. Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the 'TDM Vigil study' (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions-Severity (CGI-S) and -Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations. The study included 70 youths (age = 6.7-19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25-300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (rs = 0.34, p = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55-371 ng/mL, exceeding the TRR for adults with depression of 60-230 ng/mL. These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.

Association between prolonged vancomycin infusion and trough concentrations in children. Retrospective study.

Introduction: This study investigated the serum concentration of vancomycin during prolonged infusion in children. Population and methods: This retrospective cohort study included pediatric patients who received vancomycin from June 2017 to June 2020 at a tertiary referral hospital. The patients were divided into two groups according to infusion strategy, the SII (standard intermittent infusion) group and the PI (prolonged infusion) group. Demographic details, infusion period, serum creatinine, duration of vancomycin therapy, trough concentration of vancomycin, and pediatric intensive care unit stay were reviewed. Differences of the concentrations were measured. Results: Sixty-eight patients were included: 31 in the SII group and 37 in the PI group. The trough concentration of vancomycin was significantly higher in the PI group than in SII group (11.2 mg/L [5.9-13.7] vs. 7 mg/L [3.5- 9.3]; p = 0.02). The target attainment rate was higher in the PI group than in the SII group (59.4% and 19.3%, respectively; p = 0.001). There were no significant differences between the SII and PI groups regarding the peak concentrations of vancomycin, final creatinine and peak creatinine. There were no differences between the SII and PI groups regarding the failure events, PICU stay and duration of vancomycin therapy. The multivariable analysis showed that PI was significantly associated with higher trough serum concentrations of vancomycin (OR = 2.27; p = 0.005). Conclusion: Compared to the SII strategy, the PI strategy may be an optimized option to children with severe infection, as it can achieve higher trough concentrations and target concentration attainment.

Mycophenolate Metabolite Trough Concentrations Are Not Well Correlated With Dosing or Adverse Outcomes in Pediatric Heart Transplant Recipients.

Although mycophenolate metabolite trough concentrations in serum are routinely obtained for pediatric orthotopic heart transplant (OHT) recipients, limited data support this practice. We sought to investigate the relationship of mycophenolic acid (MPA) and MPA glucuronide (MPAG) serum concentrations to dosing and adverse outcomes among pediatric OHT patients. This retrospective study included OHT recipients ages 0 to 21 years who received mycophenolate mofetil (MMF) with MPA and MPAG serum trough concentration monitoring. The primary outcome was the relationship between MPA and MPAG serum concentrations and dosing. Secondary outcomes included the relationship of adverse outcomes to either MPA and MPAG concentrations or dosing. A total of 98 patients with 1287 MPA and MPAG trough serum concentrations (each) were included. The median initial MMF dose was 40.3 mg/kg/day (IQR, 35.12-51.83) and 1164.4 mg/m2/day (IQR, 1080.77-1206.86). There was no correlation between either MPA or MPAG serum concentrations and mg/kg dosing, or mg/m2 dosing. When comparing the adverse effect of bone marrow suppression with no adverse effect, the median MPA serum trough concentration was 2 (IQR, 1.1-3.2) versus 1.6 (IQR, 0.8-2.5), p = 0.003. When comparing the adverse effect of infection with no adverse effect, median MPA serum trough concentration was 0.9 (IQR, 0.49-1.7) versus 1.6 (IQR, 0.8-2.5), p < 0.001. The clinical utility of this finding is of uncertain benefit. There was no association between MPAG serum concentrations and any adverse outcome (p = 0.053). We did not identify a correlation between mycophenolate serum trough concentrations and either adverse outcomes or dosing. Based on these results, we discourage routine monitoring of mycophenolate trough concentrations.

Subcutaneous (SC) nivolumab (NIVO) vs intravenous (IV) NIVO in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Safety and patient-reported outcomes (PROs) of the randomized phase 3 CheckMate 67T trial.

4532 Background: CheckMate 67T (NCT04810078), a multicenter, randomized, open-label, phase 3 study, evaluated pharmacokinetics and objective response rate (ORR) noninferiority of NIVO SC vs IV in previously treated patients with advanced/metastatic ccRCC. Noninferiority endpoints of exposure (time-averaged serum concentration over the first 28 days and trough serum concentration at steady state) and efficacy (ORR by BICR) were met. Safety was comparable in the SC vs IV arms. NIVO-related immunogenicity was as expected for SC administration and further assessments did not identify apparent clinically meaningful impact. This report focuses on additional safety analyses and PROs. Methods: Patients were randomized 1:1 to NIVO SC 1200 mg + recombinant human hyaluronidase PH20 Q4W (n = 248) or NIVO IV 3 mg/kg Q2W (n = 247). Eligibility criteria were previously reported. Safety analyses were performed for all-causality adverse events (AEs) across weight categories (&lt; 50 kg, ≥ 50 kg–&lt; 70 kg, ≥ 70–&lt; 90 kg, ≥ 90 kg–&lt; 110 kg, and ≥ 110 kg). The onset, management, and resolution of treatment-related select AEs were studied; duration and grade of local site reactions and the effect of immunogenicity on local site reactions were reported. PROs were assessed using the Functional Assessment of Chronic Illness Therapy (FACIT) GP5 item. Results: The overall AE incidence rates in the SC arm were generally comparable to or lower than in the IV arm across weight categories, but limited by small sample sizes in the &lt; 50 kg and ≥110 kg subgroups. Across the treatment-related select AE categories, most events were manageable with established algorithms and resolved with immune-modulating medications. Local site reactions were mild to moderate with a median duration of 2.0 and 0.01 days in the SC and the IV arms, respectively; most resolved without treatment. The proportion of patients with a local site reaction of any grade was 8.1% in the SC arm and 2.0% in the IV arm. In patients testing NIVO-specific anti-drug antibody (ADA)-positive, 15.2% of patients in the SC arm reported a local site reaction, but all were grade 1–2 and most resolved without treatment. No hypersensitivity/infusion reaction select AEs were reported in ADA-positive patients in either arm. A majority of patients in SC and IV arms reported minimal bother by treatment side effects in their FACIT GP5 scores. Conclusions: The safety profile of SC was consistent with IV, supporting the use of NIVO SC as an option improving patient experience. This aligns with patient preference for SC administration over IV. Analyses based on weight and ADA subgroups were consistent with the known NIVO safety profile. Toxicity was manageable with immune-modulating medications. FACIT GP5 scores indicated no bother by treatment side effects. Clinical trial information: NCT04810078 .

A phase 2, open-label, 2-cohort study to evaluate patient preference for nivolumab (NIVO) + relatlimab (RELA) fixed-dose combination (FDC) subcutaneous (SC) vs NIVO + RELA FDC intravenous (IV) and NIVO SC vs NIVO IV in participants with melanoma.

TPS9619 Background: The oncology burden on healthcare resources and patients increases as the number of individuals with cancer grows, necessitating treatment options offering improved convenience to patients. SC delivery of monoclonal antibodies in various cancer indications has previously been shown to be effective, well tolerated, and preferred by patients over IV infusion. In CheckMate 67T (NCT04810078), noninferiority of exposure (time-averaged serum concentration at Day 28 and trough serum concentration at steady state) and efficacy (objective response rate by BICR) were previously reported for NIVO SC 1200 mg + recombinant human hyaluronidase PH20 (rHuPH20) vs IV in patients with locally advanced/metastatic clear cell renal cell carcinoma. RELATIVITY-127 (NCT05625399) is ongoing to establish exposure noninferiority of NIVO + RELA + rHuPH20 FDC SC to IV in patients with previously untreated metastatic/unresectable melanoma. This phase 2, open-label study CA224-1044 (NCT06101134) assesses patient preference for NIVO SC or NIVO + RELA FDC SC vs IV formulations after transitioning from IV to SC in patients with melanoma and aims to further characterize the safety profile of immuno-oncology therapy during IV-to-SC switch. Methods: Cohort 1 includes adult patients with previously untreated stage III (unresectable) or stage IV (metastatic) melanoma who will receive NIVO + RELA FDC IV every 4 weeks (Q4W) for 2 cycles (28-day cycle) followed by NIVO + RELA + rHuPH20 FDC SC Q4W until disease progression, unacceptable toxicity, or a maximum total treatment duration of 2 years, whichever comes first. Cohort 2 includes adult patients with completely resected stage IIB/C, stage III or stage IV melanoma who will receive NIVO IV Q4W for 2 cycles (28-day cycle) followed by NIVO SC + rHuPH20 Q4W until disease recurrence, unacceptable toxicity, or a maximum total treatment duration of 1 year, whichever comes first. The primary endpoint is the proportion of participants preferring the SC route of administration based on question 7 of the Patient Experience and Preference Questionnaire after the Cycle 4 Day 1 dose. This question evaluates patient preference for IV or SC or no preference in treatment administration and was previously used in CheckMate 8KX. Secondary endpoints include safety outcomes such as adverse events (AEs), serious AEs, treatment-related AEs, AEs leading to discontinuation, immune-mediated AEs, other events of special interest, injection/infusion-related AEs, deaths, and laboratory abnormalities. Safety is assessed for IV period, SC period (8 weeks each) and overall study period. Exploratory endpoints include additional measures of patient experience and preference for IV vs SC. The study is recruiting to enroll 50 patients per cohort. Clinical trial information: NCT06101134 .

Ethosuximide lowers lamotrigine serum concentrations: Evidence for a clinically relevant interaction.

We investigated the effect of comedication with ethosuximide (ESM) on lamotrigine (LTG) blood levels. Based on observations from clinical practice, we hypothesized that ESM reduces the LTG serum concentration. We additionally evaluated this effect in the presence of concomitant valproic acid (VPA). We retrospectively analyzed samples of inpatients from our department who had been treated with a combination of ESM and LTG between 2017 and 2021. We additionally used data on LTG serum concentrations from a previously published cohort from our center. Generalized estimation equations (GEEs) were used for statistical analyses. We included 523 samples from 209 patients. GEE analyses showed that LTG trough serum concentrations were significantly lower in samples with ESM comedication and significantly higher in samples with concomitant VPA. The effect of ESM was moderated by patients' age; in children and adolescents, LTG serum concentrations were 37% lower than in samples without ESM, whereas in adults, LTG serum concentrations were 14% lower. The effect we found in our data is relevant to daily clinical practice, if patients are not seizure-free despite typical daily LTG dosage, or if they develop side effects during ESM withdrawal. It should be considered especially in children and adolescents.

Serum trough concentration threshold and risk factors of cefoperazone-induced coagulopathy in critically ill patients: A retrospective case-control study.

To analyze the risk factors influencing the development of cefoperazone-induced coagulopathy in critically ill patients and determine the threshold of serum trough concentration. A retrospective case-control study was conducted in the intensive care unit patients treated with cefoperazone, and it was approved by the Ethical Committee of Drum Tower Hospital affiliated with the Medical School of Nanjing University (NO.2023-158-01). Patients were divided into the normal group and coagulopathy group based on prothrombin time. The clinical characteristics of the two groups were compared using univariate analysis. The serum concentration threshold and influencing factors of cefoperazone-induced coagulopathy in critically ill patients were analyzed using the receiver operating characteristic curve and multivariate logistic regression analysis. A total of 113 patients were included, and cefoperazone-induced coagulopathy occurred in 39 patients, with an incidence of 34.5%. These patients experienced significant prothrombin time prolongation around day 6 (median) after cefoperazone application. The serum trough concentration threshold of cefoperazone-induced coagulopathy in critically ill patients was 87.765mg/l. Multivariate logistic regression analysis revealed that the APACHE II score (p = 0.034), prophylactic use of vitamin K1 (p < 0.001), hepatic impairment (p = 0.014), and Cmin ≥ 87.765mg/l (p = 0.005) were associated with cefoperazone-induced coagulopathy. Cefoperazone-induced coagulopathy usually occurs on the 6th day of cefoperazone use in critically ill patients. The risk will increase in patients with an APACHE II score > 25, hepatic impairment, and cefoperazone Cmin ≥ 87.765mg/l. Vitamin K1 is effective in preventing this adverse reaction.

P1081 Pharmacokinetics and immunogenicity of the ustekinumab biosimilar candidate ABP 654 in patients with moderate-to-severe plaque psoriasis

Abstract Background ABP 654 is being developed as a biosimilar candidate to ustekinumab reference product (RP), a biologic agent used in the treatment of certain chronic, immune-mediated, inflammatory diseases. Previously, we reported no clinically meaningful differences in efficacy or safety between ABP 654 and ustekinumab RP in a 52-week randomised, double-blinded, active-controlled study in patients with moderate-to-severe plaque psoriasis. Here, we describe the pharmacokinetics (PK) and anti-drug antibody (ADA) results from the same study. Methods A total of 563 patients were randomised in a 1:1 ratio to receive ABP 654 or ustekinumab RP at a subcutaneous dose of 45 mg (baseline body weight [BW] ≤ 100 kg) or 90 mg (baseline BW &amp;gt; 100 kg) (Fig. 1). Serum samples for PK and ADA evaluations were collected at various timepoints. Concentrations of ABP 654 and ustekinumab RP were measured using an electrochemiluminescent (ECL) assay based on the Meso Scale Discovery platform. All ADA samples were tested in a validated binding, acid-dissociation ECL assay. Samples testing positive for binding antibodies were evaluated for neutralising ADA in a validated ECL-based affinity capture elution assay. Results From baseline to Week 52, the geometric least-squares (LS) means of trough serum concentrations were similar between the ABP 654 and ustekinumab RP groups. In addition, the geometric LS means of serum concentrations were similar post Week 28 for patients (ABP 654, n=25 and ustekinumab RP, n=34) who received dose intensification. Of patients with a post-baseline ADA result through Week 28, 52 (18.6%) patients in the ABP 654 group and 104 (37.1%) patients in the ustekinumab RP group tested positive for binding ADAs. Of these, 24 (8.6%) patients in the ABP 654 group and 50 (17.9%) patients in the ustekinumab RP group tested positive for neutralising ADAs. For dose intensification patients with a post-baseline result post Week 28, no patients in the ABP 654 group tested positive for binding or neutralising ADAs, and 2 (5.9%) patients in the ustekinumab RP group tested positive for binding and neutralising ADAs. Conclusion Throughout the study, serum trough concentrations remained comparable between ABP 654 and ustekinumab RP. While the percentages of binding and neutralising ADAs were numerically lower for the ABP 654 group compared with the ustekinumab RP group through Week 28 (and in patients who received dose intensification), the available clinical efficacy, safety, and PK data suggest that these differences were not clinically impactful. Overall, the results support a conclusion of no clinically meaningful differences between ABP 654 and ustekinumab RP.

P660 Serum Leucine-rich Alpha-2 Glycoprotein Can be a Biomarker for Selecting Anti-Cytokine Biologics in Patients with Inflammatory Bowel Disease: A Multicentre Prospective Cohort Study

Abstract Background Serum leucine-rich alpha-2 glycoprotein (LRG) is a biomarker reflecting endoscopic activity in patients with inflammatory bowel disease (IBD). However, it remains unclear whether serum LRG can predict the effectiveness of anti-cytokine biologics (biologics) in patients with IBD. This study aimed to evaluate whether serum LRG could predict the effectiveness and serum trough concentrations of biologics in patients with IBD. Methods This was a multicentre prospective cohort study including patients with IBD (including ulcerative colitis [UC] or Crohn’s disease [CD]) who received the biologics [ustekinumab (UST), anti-tumor necrosis factor (anti-TNF)] from January 2019 to March 2023 at 15 hospitals participating in the Osaka Gut Forum. The effectiveness of biologics was evaluated by clinical remission (CR) at week 8. We defined CR as a partial Mayo score of 2 or lower, with each subscore of 0 or 1 for UC and a CD activity index of &amp;lt; 150 for CD. Factors associated with CR at week 8 such as backgrounds, disease activities and concomitant medications at week 0 were analyzed by Cox proportional hazards model. For each biologic, we compared the effectiveness of biologics in the high LRG group with that in the low LRG group divided by the median serum LRG levels at week 0 (cut-off = 18.2 μg/mL). Results A total of 184 patients with IBD (UC, 80; CD, 104) were enrolled (UST/ anti-TNF, 119/ 65; biologic exposure, 31.5%; median disease duration, 6 years [Interquartile range (IQR) 1-14]). Median serum LRG levels at week 0 and serum C-reactive protein levels at week 0 were 18.2 μg/mL [IQR 12.5-28.1] and 0.19 mg/dL [IQR 0.03-0.77], respectively. At week 0, 63 (34.2%) and 64 (34.8%) patients concomitantly received corticosteroids and immunomodulators, respectively. In 184 patients with IBD, multivariate analysis revealed that serum LRG level at week 0 &amp;lt; 18.2 μg/mL was extracted as a significant factor for CR at week 8 (Odds ratio: OR 2.70, 95% confidence interval: CI 1.22-5.96). In patients who received UST, the proportion of CR at week 8 in the low-LRG group (76.9%) was significantly higher than that in the high-LRG group (59.3%, P = 0.038). In patients who received anti-TNF, however, the proportion of CR in the low-LRG group (84.6%) was not differ from that in the high-LRG group (82.1%, P = 0.781). Median serum trough concentrations of UST at week 8 in the low-LRG group (10.9 μg/mL, IQR 6.7-13.4) was significantly higher than that in the high-LRG group (5.3 μg/mL, IQR 2.4-8.3, P &amp;lt; 0.001). Conclusion Serum LRG could predict the effectiveness and serum trough concentrations of UST and be a biomarker for selecting biologics in patients with IBD.

P964 Vedolizumab trough concentrations during subcutaneous treatment in patients with inflammatory bowel diseases

Abstract Background An exposure-response relationship has been described for intravenous (IV) vedolizumab (VDZ), but little is known about through levels and real life outcomes of subcutaneous (SC) VDZ treatment. We aimed to study the effect of SC VDZ in a prospective real life cohort and assessed what clinical variables are associated with vedolizumab trough concentrations. Methods IBD patients initiating VDZ SC treatment were included in our nationwide, prospective Initiative on Crohn and Colitis (ICC) registry. Adult IBD patients were included if a known trough level during IV and SC therapy was available. Two different assays were used for trough levels measurements : i.e. an enzyme linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The primary outcome measure was the mean VDZ trough concentration during maintenance treatment (after at least four SC injections). In addition, associations between VDZ serum trough concentrations and corticosteroid-free clinical remission were assessed. A Receiver Operating Characteristic (ROC) analysis was performed to determine the concentration threshold that was associated with corticosteroid free clinical remission after 4 SC VDZ injections (i.e. defined as a Harvey Bradshaw Index (HBI) score ≤ 4 for CD and a Short Clinical Colitis Activity Index (SCCAI) score ≤ 2 for UC). Results In total, 24 with Crohn’s disease (CD) and 32 with ulcerative colitis (UC) patients were included. Twelve patients started SC VDZ after a maximum of three VDZ infusions and 44 patients switched to VDZ SC after at least four VDZ infusions. The mean VDZ trough concentration was 34.4 µg/mL (SD 12.9) after 13 (IQR 11-20) weeks of SC treatment. The mean VDZ trough concentration increased from 20.5 µg/mL to 35.2 µg/mL (P &amp;lt; 0.001) in patients who switched from IV to SC VDZ. Biochemical remission (defined as a C-reactive protein (CRP) ≤ 5 µg/mL with a faecal calprotectin (FC) ≤ 250 µg/g) prior to the switch, VDZ measurements using LC-MS/MS and higher VDZ levels during IV therapy were associated with higher VDZ serum levels during SC therapy. Active smoking and prior use of &amp;gt;1 biologic and/or tofacitinib were associated with lower VDZ levels during SC therapy (table 1). A VDZ trough concentration of ≥ 34.5 µg/mL during SC maintenance therapy predicted corticosteroid free clinical remission with a sensitivity, specificity, positive predictive value and negative predictive value of 60%, 75%, 86% and 43%, respectively. Conclusion VDZ serum concentrations were significantly higher during SC therapy versus IV treatment. A VDZ trough concentrations ≥ 34.5 µg/mL was associated with corticosteroid free remission.

Efficacy and safety of mTOR inhibition in cutaneous sarcoidosis: a single-centre trial

Sarcoidosis is an inflammatory condition that can affect various organs and tissues, causing the formation of granulomas and subsequent functional impairment. The origin of sarcoidosis remains unknown and there are few treatment options. Mechanistic target of rapamycin (mTOR) activation is commonly seen in granulomas of patients across different tissues and has been shown to induce sarcoidosis-like granulomas in a mouse model. This study aimed to examine the efficacy and safety of the mTOR inhibitor sirolimus as a treatment for cutaneous sarcoidosis. We did a single-centre, randomised study treating patients with persistent and glucocorticoid-refractory cutaneous sarcoidosis with sirolimus at the Vienna General Hospital, Medical University of Vienna (Vienna, Austria). We recruited participants who had persistent, active, and histologically proven cutaneous sarcoidosis. We used an n-of-1 crossover design in a placebo-controlled, double-blind topical treatment period and a subsequent single-arm systemic treatment phase for 4 months in the same participants. Participants initially received either 0·1% topical sirolimus in Vaseline or placebo (Vaseline alone), twice daily. After a washout period, all participants were subsequently administered a 6 mg loading dose followed by 2 mg sirolimus solution orally once daily, aiming to achieve serum concentrations of 6 ng/mL. The primary endpoint was change in the Cutaneous Sarcoidosis Activity and Morphology Index (CSAMI) after topical or systemic treatment. All participants were included in the safety analyses, and patients having completed the respective treatment period (topical treatment or systemic treatment) were included in the primary analyses. Adverse events were assessed at each study visit by clinicians and were categorised according to their correlation with the study drug, severity, seriousness, and expectedness. This study is registered with EudraCT (2017-004930-27) and is now closed. 16 participants with persistent cutaneous sarcoidosis were enrolled in the study between Sept 3, 2019, and June 15, 2021. Six (37%) of 16 participants were men, ten (63%) were women, and 15 (94%) were White. The median age of participants was 54 years (IQR 48-58). 14 participants were randomly assigned in the topical phase and 2 entered the systemic treatment phase directly. Daily topical treatment did not improve cutaneous lesions (effect estimate -1·213 [95% CI -2·505 to 0·079], p=0·066). Systemic treatment targeting trough serum concentrations of 6 ng/mL resulted in clinical and histological improvement of skin lesions in seven (70%) of ten participants (median -7·0 [95% CI -16·5 to -3·0], p=0·018). Various morphologies of cutaneous sarcoidosis, including papular, nodular, plaque, scar, and tattoo-associated sarcoidosis, responded to systemic sirolimus therapy with a long-lasting effect for more than 1 year after treatment had been stopped. There were no serious adverse events and no deaths. Short-term treatment with systemic sirolimus might be an effective and safe treatment option for patients with persistent glucocorticoid-refractory sarcoidosis with a long-lasting disease-modulating effect. The effect of sirolimus in granulomatous inflammation should be investigated further in large, multi-centre, randomised clinical trials. Vienna Science and Technology Fund, Austrian Science Fund.

Effects of Vancomycin Subtherapeutic Concentration on Staphylococcus aureus Isolated from Hemodialysis Patients with Low Serum Trough Concentrations.

Blood bactericidal activity and antimicrobial therapy are crucial against catheter-related infection in patients undergoing hemodialysis (HD). It is well-known that catheters colonized by biofilm-producing bacteria are a risk factor for bacteremia in HD-patients. Methicillin-resistant S. aureus bacteremia in HD-patients justify the use of vancomycin as empiric therapy. The recommended vancomycin target for therapeutic efficacy is a minimum serum concentration of 10µgmL-1 to avoid resistance. However, subtherapeutic concentrations of vancomycin have frequently occurred in HD-patients. Thus, we aim to investigate the effect of subtherapeutic vancomycin concentration on S. aureus growth, susceptibility to antimicrobials, resistance to whole blood activity, and biofilm formation. Seventeen S. aureus strains isolated from bacteremia in HD-patients and two reference strains were exposed to a vancomycin-gradient (0-10µgmL-1) for five consecutive days to mimic the dosing interval of vancomycin in HD-patients. After that, we observed the following: no effect on growth curve; decreased susceptibility to vancomycin and daptomycin; increased S. aureus survival to whole blood bactericidal action; and a strain-dependent biofilm production after drug exposure. In conclusion, our findings suggest that the subtherapeutic concentration of vancomycin decrease S. aureus susceptibility to vancomycin and daptomycin and increases its survival to whole blood bactericidal action.

Phase 2 Study of Daratumumab (DARA) Plus Bortezomib, Cyclophosphamide, and Dexamethasone (D-VCd) in a Diverse Patient Population with Newly Diagnosed Amyloid Light Chain (AL) Amyloidosis: Aquarius

Background: AL amyloidosis is a rare disorder in which deposition of insoluble amyloid fibrils composed of misfolded light chains in vital organs, such as the heart or kidney, leads to serious and life-threatening organ dysfunction. Cardiac involvement is the primary determinant of clinical outcomes for patients with AL amyloidosis, and survival expectations decrease with increasing cardiac stage. Subcutaneous DARA (DARA SC) in combination with VCd recently became the first and only approved treatment for newly diagnosed AL amyloidosis based on results of the phase 3 ANDROMEDA study. In the ANDROMEDA study, a higher hematologic complete response rate was consistently achieved with D-VCd versus VCd in patients with newly diagnosed AL amyloidosis, regardless of baseline cardiac stage (Kastritis E, et al. N Engl J Med. 2021;385[1]:46-58). However, cardiac involvement leads to challenges in the attribution of cardiac events to underlying disease and/or treatments. Additionally, among patients randomized to receive D-VCd in the ANDROMEDA study, 15.4% were Asian, 4.6% were Hispanic or Latino, and 3.1% were Black or African American, limiting the interpretation of safety, efficacy, and pharmacokinetic results among patients of different racial and ethnic backgrounds. Therefore, the ongoing phase 2 AQUARIUS (AMY2009) study will characterize the cardiac safety of different D-VCd treatment regimens in patients with newly diagnosed AL amyloidosis with cardiac involvement to identify potential mitigation strategies for cardiac toxicity, as well as better characterize the safety, efficacy, and pharmacokinetics of D-VCd among racial and ethnic minorities. Study Design and Methods: This ongoing multicenter, multicohort, open-label phase 2 study will enroll ~150 patients aged ≥18 years with newly diagnosed systemic AL amyloidosis and measurable disease from ~45 sites across 10 countries. Patients in Cohort 1 (n = ~120) will have cardiac involvement (AL amyloidosis Mayo Cardiac Stage II and Stage IIIa) with or without other organ involvement. Patients in Cohort 2 (n = ~30) will be of racial or ethnic minority (including ≥15 Black or African American patients) and have ≥1 organ affected by systemic AL amyloidosis. Patients in Cohort 1 will be stratified by baseline cardiac stage (Stages II and IIIa) and randomly assigned (2:1) to receive DARA SC plus immediate VCd (Arm A) or DARA SC plus deferred VCd (Arm B; Figure 1). In both arms, DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE ® drug delivery technology, Halozyme, Inc., San Diego, CA, USA]) will be administered QW during Cycles 1-2, Q2W during Cycles 3-6, and Q4W thereafter until a maximum of 24 cycles or the start of subsequent therapy. In Arm A, starting at Cycle 1 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. In Arm B, starting at Cycle 4 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. Patients in Cohort 2 will receive DARA SC plus immediate VCd. Several unique initiatives were incorporated into the study to enhance enrollment of patients of racial or ethnic minority in Cohort 2, including selecting sites from the ANDROMEDA study that enrolled racially/ethnically diverse patients, targeting new sites in diverse communities, raising awareness of AL amyloidosis and the AQUARIUS study among minority patients at the local and national levels, and educating sites on engagement of patients from diverse backgrounds. The first primary endpoint is incidence of any toxicity grade cardiac events for the different D-VCd treatment regimens (DARA SC + immediate VCd and DARA SC + deferred VCd). The second primary endpoint is trough serum concentration (C trough) of DARA at the end of QW dosing (Cycle 3 Day 1 predose). Efficacy evaluations include assessment of hematologic response and organ response. Data will be summarized using descriptive statistics. The first patient was enrolled on March 17, 2022. As of July 10, 2023, the study has enrolled 75 patients; 71 in Cohort 1 and 4 in Cohort 2. In the US, 2 of the 8 patients enrolled were of racial minority ( Figure 2). Efforts to increase enrollment of minorities continue to be optimized and new collaborative initiatives explored to ensure representative and diverse enrollment in clinical trials. The ClinicalTrials.gov Identifier is NCT05250973.

A descriptive study of vancomycin use at Red Cross War Memorial Children's Hospital, Cape Town.

Antimicrobial stewardship principles guide the clinical use of antimicrobials, including vancomycin, but paediatric vancomycin prescribing practices have not been evaluated in South Africa. To document the use, prescribing practices and monitoring of intravenous vancomycin and the spectrum of bacteria isolated on microbiological culture in children treated with intravenous vancomycin during a 12-month period at Red Cross War Memorial Children's Hospital (RCWMCH). A retrospective audit of intravenous vancomycin use in children admitted to RCWMCH during 2019 was performed. All 158 vancomycin prescription episodes for 143 children were included. Overall usage of intravenous vancomycin was 63 days of therapy per 1000 patient days (interquartile range [IQR]: 38-72). The median starting dose was 15 mg/kg per dose (IQR: 14-15) and median daily dose was 45 mg/kg per day (IQR: 43-60). Vancomycin was prescribed as empiric (127/158, 80%) and directed (31/158, 20%) treatment. The median duration of treatment for the directed group (7 days) was longer than the empiric group (4 days) (p = 0.001). Vancomycin serum trough concentrations were performed in 65/98 (66%) episodes where vancomycin treatment exceeded 3 days, with only 16/65 (25%) of these samples obtained before the fourth dose. Prolonged antibiotic treatment of 14 days or more was not associated with Gram-positive bacteria on culture (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 0.17-4.2). Dosing errors, prolonged empiric treatment and inappropriate vancomycin monitoring were problems associated with vancomycin prescriptions. The study identified multiple opportunities for improved vancomycin prescribing and monitoring. Further research and implementation of improved prescribing practices could contribute to the preservation of vancomycin as an effective antibiotic.