Adequate Drug Levels Research Articles

What are the benefits of therapeutic drug monitoring in the optimization of adalimumab therapy? a systematic review and meta-analysis up to 2022.

Persistent uncertainties exist surrounding the therapeutic drug monitoring (TDM) of adalimumab in clinical settings. To address these issues, we conducted a systematic review to assess the current evidence regarding the benefits of TDM for adalimumab. PubMed, EMBASE, and Cochrane Databases were searched from inception to October 2022. The trials regarding to the list three key questions were considered: 1) Could routine proactive TDM assist in improving outcomes in patients receiving adalimumab? 2) Could reactive TDM assist in guiding subsequent treatment strategies for patients with treatment failure to adalimumab? 3) Could TDM assist in informing dose reduction or discontinuation in patients with low disease activity or in remission treated with adalimumab? Two reviewers independently selected the studies and extracted the data. Meta-analysis was performed to calculate the relative risk (RR) and 95% confidence interval (CI). A total of 9 studies was included in this review. For proactive TDM, meta-analysis indicated that proactive TDM (n = 163/257, 63.42%) showed no significant superiority over reactive TDM and/or conventional management (n = 336/606, 55.44%) in achieving and/or maintaining clinical remission by random effects model (RR: 1.24, 95% CI 0.98-1.58, I 2 = 73%). There were three studies that supporting the reactive TDM, low drug levels in the absence of anti-drug antibodies (ADA) strongly indicate the need for dose intensification, and infliximab is a feasible choice for patients with low drug levels and ADA positivity. While swapping to another class should be considered in patients with adequate drug levels. In addition, TDM can help clinicians optimize dosing schedules and prevent overtreatment in patients who have achieved low disease activity and sufficient drug concentrations, with no predictive value for successful adalimumab discontinuation. Current evidence suggests that proactive TDM is numerically but not statistically significant superiority over reactive TDM and/or conventional management. Reactive TDM can aid in understanding treatment failure and developing subsequent therapy. For patients reaching low disease activity and remission, TDM can help successful dose reduction, while it cannot inform the successful drug discontinuation. However, existing trials are limited, and more well-designed trials are necessary to clarify the role of TDM in adalimumab treatment.

Intraperitoneal pharmacokinetics of systemic oxaliplatin, 5-fluorouracil and bevacizumab in patients with colorectal peritoneal metastases

BackgroundPeritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that traditional systemic chemotherapy is not very effective for this patient population. This study investigates to what extent systemic anti-cancer therapy crosses the peritoneal barrier. MethodsIn a Phase I study, eighteen patients received systemic oxaliplatin, 5-FU, and bevacizumab. Plasma and peritoneal fluid samples were collected to measure drug concentrations. A non-compartmental analysis determined the Area Under the Curve (AUC) for oxaliplatin and 5-FU in both matrices. Intraperitoneal (IP) and intravenous (IV) exposure ratios were calculated, along with the bevacizumab concentration IP/IV ratio. The relationship between tumour load and IP/IV ratios and the correlation between the IP/IV ratios of different treatments were assessed statistically. ResultsA total of 438 5-FU samples and 578 oxaliplatin samples were analysed in plasma and peritoneal fluid. Bevacizumab was quantified with 17 measurements in plasma and 15 measurements IP. Median IP/IV ratios were 0.143, 0.352 and 0.085 for 5-FU, oxaliplatin and bevacizumab, respectively. Oxaliplatin exhibited a longer IP half-life than 5-FU. A correlation was found between oxaliplatin and bevacizumab IP/IV ratios (R=0.69, p=0.01). No statistical correlations were found between the other investigated drugs. ConclusionsOur findings indicate that only a small percentage of systemically administered anti-cancer treatment reaches the IP cavity, questioning their efficacy against PM. This strengthens the hypothesis for repeated intraperitoneal chemotherapy to reach adequate anti-cancer drug levels.

Abstract 2790: Preclinical studies of ZG19018, a novel irreversible covalent inhibitor of KRAS G12C, for the treatment of advanced non-small cell lung cancer and other solid tumors

Abstract Growing evidences of covalent irreversible inhibitors in clinical treatments of solid tumors with KRAS G12C mutation have recently emerged after FDA-approved AMG510 (Sotorasib) for NSCLC chemotherapies. ZG19018 is an irreversible KRAS G12C inhibitor with novel structure that shows promising preclinical results for in vitro molecular and biological studies and in vivo G12C-mutated cancer models and safety studies in animals. For instance, ZG19018 rapidly and selectively forms covalent bonds with G12C-GDP, which accounts for lock-in KRAS protein as the inactive GDP-bound state but inhibits the activation of numerous downstream signaling pathways like RAF/MEK on ERK phosphorylation. ZG19018 showed highly inhibition of a 3D growth panel for human cancer cell lines harboring the KRAS G12C mutation, e.g. H358 (NSCLCs), MIA PaCa-2 (pancreatic) and SW837 (colorectal), etc. For pharmacodynamics, a battery of in vitro and in vivo ADME/DMPK studies indicated a high plasma protein binding (>99.6%) of ZG19018 with over 40% bioavailability in rat and dog via oral administration for the adequate drug levels in various tissues including lung, crossing BBB to reach brain, and accumulation in tumors. For in vivo anti-tumor efficacy, ZG19018 exhibited significant dose-dependent inhibition of tumor growth of G12C-driven subcutaneous models in nude mouse like H358 NSCLC cells but induced further tumor regression in pancreatic cancer MIA PaCa-2 xenograft. ZG19018 also showed an enhanced anti-tumor activities as combined with chemo-reagent Donafinib, a broad tyrosine kinase inhibitor blocking RAF/MEK/ERK signaling pathways of tumor cells, in the same H358 xenograft model. The general toxicology studies in rat under 28 days repeated oral administration (q.d.) showed NOAEL and STD10 values at 75 and 150 mg/kg/day, respectively. The safety pharmacological studies showed no notable effects of ZG19018 on the cardiovascular, respiratory and CNS systems. The genotoxic potential studies indicated ZG19018 without mutagenesis. Collectively, ZG19018 is now in phase I/II clinical trials for the treatments of solid tumors with KRAS G12C mutation in China. Citation Format: Bing Zhu, Dawei Cui, Ruifeng Liu, Weidong Feng, Zelin Sheng, Binhua Lv. Preclinical studies of ZG19018, a novel irreversible covalent inhibitor of KRAS G12C, for the treatment of advanced non-small cell lung cancer and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2790.

Development of denture-fitting, palate-mucoadhesive miconazole nitrate films for denture stomatitis

Denture stomatitis commonly affects denture users. Most available antifungal buccal formulations cannot maintain adequate drug levels in the mouth cavity for a sufficient time unless applied frequently. In the present study, denture-fitting, palate-mucoadhesive buccal miconazole nitrate films were developed and assessed for the management of upper denture stomatitis, caused by Candida albicans, in comparison to a commercial oral gel. Three films were prepared by solvent casting; the common film ingredients apart from miconazole nitrate, included propylene glycol as plasticizer, and hydroxypropyl methylcellulose polymer as mucoadhesive film-forming agent (F1–F3). The second and third film (F2 & F3) also contained sodium carboxy methyl cellulose as an additional mucoadhesive polymer. In films F1 and F2, miconazole nitrate was dissolved in the plasticizer propylene glycol. The third film (F3) contained miconazole nitrate-loaded chitosan nanoparticles dispersed in the film matrix. Films were characterized. Performance-related tests assessed in vitro drug release, in vitro mucoadhesion, in-vitro antifungal efficiency and in vivo clinical efficacy in denture stomatitis patients (colony counts following palate swabs and pain scoring during treatment). Attachment of film to denture was also investigated in vitro. Film F3 proved statistically more effective compared to films F1 & F2 and to the commercial oral gel, based on patients’ pain scoring at three days (P ≤ 0.05) and colony count at ten days (P ≤ 0.05) post treatment initiation, in spite of reduced amount of miconazole applied per day in case of films compared to gel. Differences in fungi inhibition zones, tested under equivalent amount of miconazole per agar well, were also statistically significant (P ≤ 0.05). Film (F3) can be promoted for effective local treatment of denture-related candidiasis with reduced application frequency, and less daily amount of applied miconazole compared to a commercial oral gel application.

Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease.

Anti-tumor necrosis factor (anti-TNF) therapy has been successfully used as first-line biologic treatment for moderate-to-severe inflammatory bowel disease (IBD), in both “step-up” and “top-down” approaches, and has become a cornerstone of IBD management. However, in a proportion of patients the effectiveness of anti-TNF therapy is sub-optimal. Either patients do not achieve adequate initial response (primary non-response) or they lose response after initial success (loss of response). Therapeutic drug monitoring determines drug serum concentrations and the presence of anti-drug antibodies (ADAbs) and can help guide treatment optimization to improve patient outcomes. For patients with low drug concentrations who are ADAb-negative or display low levels of ADAbs, dose escalation is recommended. Should response remain unchanged following dose optimization the question whether to switch within class (anti-TNF) or out of class (different mechanism of action) arises. If ADAb levels are high and the patient has previously benefited from anti-TNF therapy, then switching within class is a viable option as ADAbs are molecule specific. Addition of an immunomodulator may lead to a decrease in ADAbs and a regaining of response in a proportion of patients. If a patient does not achieve a robust therapeutic response with an initial anti-TNF despite adequate drug levels, then switching out of class is appropriate. In conjunction with the guidance above, other factors including patient preference, age, comorbidities, disease phenotype, extra-intestinal manifestations, and treatment costs need to be factored into the treatment decision. In this review we discuss current evidence in this field and provide guidance on therapeutic decision-making in clinical situations.

Drug concentration at the site of disease in children with pulmonary tuberculosis.

BackgroundCurrent TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB.ObjectivesTo determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB.MethodsWe quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions.ResultsIsoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions.ConclusionsDespite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.

525. Atovaquone for Treatment of COVID-19 (Ataq COVID-19) Trial

BackgroundOur group performed an in-silico screen to identify FDA approved drugs that inhibit SARS-C0V-2 main protease (Mpro), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication.MethodsEnrolled patients were randomized in a 2:1 fashion to atovaquone 1500 mg twice daily versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Patients agreed to allow collection of saliva at baseline and twice a day while hospitalized or up to 10 days. Saliva was collected and RNA extracted for viral load (VL) measurement by Real-time PCR. Our primary outcome was to examine the between group differences in log transformed VL(copies/mL) using generalized linear mixed-effect models of repeated measures from all samples. Additional analysis of Atovquone plasma concentrations were examined and correlated with viral load and body mass index (BMI).ResultsOf the 61 patients enrolled; 41 were received atovaquone and 19 placebo. Overall the population was predominately male Hispanic with a mean age of 51 years. The two groups were balanced (Table 1) with regard to age, gender, race, co-morbidities, days from onset of symptoms, baseline oxygen requirements, and receipt of COVID-19 specific standard of care treatment. A higher proportion with diabetes was noted in the Atovaquone arm. The log10 VL was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Although there was a decrease in VL over time, there was no differences between the atovaquone plus standard of care arm versus the standard of care arm (Figure 1). Additional analysis of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, inverse association between atovaquone levels and BMI (rho -0.44, p=0.03), and Day 5 concentrations and VL (rho -0.54, p=0.005). Figure 1. Mean viral load of COVID-19 over time of atovaquone (blue) vs. placebo (red).Table 1. Baseline characteristics ConclusionAlthough atovaquone showed promising in vitro antiviral properties for COVID-19, in this pilot study we did not detect a change in VL in patients who received atovaquone compared to placebo, possibly due to failure of patients achieve adequate drug levels. Disclosures Mamta K. Jain, MD, MPH, Gilead Sciences Inc. (Individual(s) Involved: Self): Research Grant or Support, Scientific Research Study Investigator; GlaxoSmithKline (Individual(s) Involved: Self): Scientific Research Study Investigator; Merck (Individual(s) Involved: Self): Scientific Research Study Investigator; Vasgene (Individual(s) Involved: Self): Scientific Research Study Investigator

Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels

In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma-either ADA dose optimization or switching to vedolizumab or ustekinumab. Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Adalimumab was optimized (n = 61 patients, 42 Crohn's disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn's disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.53; 95% CI, 1.16-10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13-0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

DOP62 Immunogenicity to second anti-TNF therapy (IMSAT): Implications for sequencing of biologic therapy

Abstract Background Anti-TNF (aTNF) treatment failure in patients with IBD is common. International guidelines recommend switching out of class when aTNF drug levels are therapeutic and within class with an immunomodulator when aTNF drug levels are suboptimal and associated with antibody development. We sought to define the: 1) risk of immunogenicity to a second aTNF stratified by immunogenicity to the first aTNF and 2) rates of drug persistence to a second aTNF in patients with pharmacodynamic or immunogenic failure of their first aTNF drug. Methods We performed a retrospective cohort study across 32 UK hospitals. 870 patients (444 male, 630 (72%) Crohn’s disease) who had both infliximab and adalimumab therapeutic drug monitoring performed by our service from May 2013 to November 2020 were identified. Drug and antibody levels were measured using the IDKmonitor® drug tolerant ELISA assays. Treatment failure included primary nonresponse, secondary loss of response, adverse drug reactions and IBD-related surgeries, and was identified by case note review. Immunogenic failure was defined as treatment failure with suboptimal drug levels (infliximab level &amp;lt;2 mg/L, adalimumab level &amp;lt;6 mg/L) with an antibody concentration ≥10 AU/ml. Pharmacodynamic failure was defined as treatment failure despite adequate drug levels. Results Patients who developed immunogenicity to adalimumab (first) were more likely to develop immunogenicity to infliximab (second) (63% vs 40%, p = 0.004), and patients who developed immunogenicity to infliximab (first) were more likely to develop immunogenicity to adalimumab (second) (33% vs 19%, p = 0.002) (Fig 1). Patients who developed: antibodies and undetectable drug, low drug levels, or low drug levels with immunogenicity to infliximab (first), were more likely to develop these outcomes to adalimumab (second) (all p&amp;lt;0.001). There was no difference in drug persistence to second aTNF in patients with pharmacodynamic and immunogenic treatment failure (Fig 2). In patients with immunogenic (but not pharmacodynamic) failure, commencing an immunomodulator at the time of switching to second aTNF drug was associated with longer drug persistence than in patients treated with an immunomodulator throughout or not all (Fig 3). Conclusion Immunogenicity to the first aTNF was associated with immunogenicity to the second aTNF, irrespective of drug sequence. Commencing an immunomodulator at the time of switching to second aTNF was associated with improved drug persistence in immunogenic, but not pharmacodynamic, failure. However, 50% of patients remained on second aTNF at 5 years in both groups, suggesting switching in-class may be appropriate irrespective of the cause of treatment failure to first aTNF.

P408 Anti-Drug Antibodies Detected in the Presence of Adequate Infliximab Drug Levels In IBD Patients in Clinical Remission have Limited Clinical Significance

Abstract Background Immunogenicity, with the development of antibodies-to-infliximab (ATI) increases drug clearance and can lead to loss of infliximab (IFX) response in inflammatory bowel disease(IBD). Reporting of ATI is variable between commercial assays with some assays having high sensitivity for low-titre antibodies. Uniform thresholds for clinically relevant antibody titres are lacking. It is unclear how ATI affect treatment outcome when adequate trough IFX concentrations are present and ATI are detected. Methods We aimed to assess the impact of ATI detected in the presence of adequate IFX levels on the outcome of IFX therapy in IBD patients in clinical remission. A proactive therapeutic drug monitoring(TDM) strategy was utilized in our unit with IFX and ATI levels, assessed at trough, in all IBD patients receiving IFX. Baseline demographics were collected. Patients were grouped based on disease activity. An adequate trough IFX level was a concentration &amp;gt; 3 µg/mL, with low levels defined as &amp;lt; 3 µg/mL. ATI positivity was defined as a concentration &amp;gt; 10 AU/mL. Receiver operating characteristic analysis was performed to evaluate the classifying performance of ATI concentration for low IFX levels. Survival analysis was performed to determine IFX persistence in patients with adequate IFX levels and positive ATI. Follow up TDM assessments, where available, were documented to determine changes in ATI concentration over time in patients with adequate IFX levels. Results 108 patients were included. Median age 36years. 46% were female. 36% had ulcerative colitis, 60% Crohn’s disease. 35% were receiving concomitant immunomodulators. 56% of patients were in remission at the time of TDM assessment. 44%, 30% and 26% of patients had IFX levels &amp;lt; 3 µg/mL, 3 – 7 µg/mL and &amp;gt; 7 µg/mL. Median [range] ATI concentration was 11 AU/mL [0 – 800]. ATI positivity occurred in 25%, 19% and 8% of IFX groups with levels &amp;lt; 3 µg/mL, 3 – 7 µg/mL and &amp;gt; 7 µg/mL. There was a weak inverse correlation between trough ATI and IFX concentration (p=0.01)(Figure 1). ATI concentration performed poorly as a classifier of low IFX levels (AUC 0.568)(p=0.39). 83%(15/18) of IBD patients in remission with adequate IFX levels and positive ATI remained on IFX for the duration of follow up with a mean cumulative time on IFX of 111.2 weeks (95% CI 105.1 – 117.3)(Figure 2). In this group, there was no significant change in ATI titre comparing index with follow up TDM assessments (p=0.14)(Figure 3). Conclusion ATI positivity in the presence of adequate IFX levels is common with proactive TDM. For patients in clinical remission ATI positivity in the presence of adequate IFX levels has limited clinical significance. Care should be taken to avoid unnecessary therapy alterations in this patient subgroup.

Extracorporeal Membrane Oxygenation to Support Life-Threatening Drug-Refractory Electrical Storm.

Despite rapid implementation of anti-arrhythmic treatment and sedation and controlling the triggering event, rare patients develop treatment-refractory electrical storm and their hemodynamic instability prevents emergency catheter ablation. In that context, venoarterial extracorporeal membrane oxygenation could rapidly restore hemodynamics and tissue perfusion and reduce myocardial oxygen consumption, until adequate anti-arrhythmic drug levels are reached to safely perform catheter ablation. Retrospective, multicenter study over an 8-year period. Two French tertiary care centers. Eighty-three consecutive adults with venoarterial extracorporeal membrane oxygenation-supported treatment-refractory electrical storm (median [interquartile range] age, 55 yr [48-63 yr]). Fifty-nine percent of these patients had acute ischemic cardiomyopathy and 66% underwent cardiopulmonary resuscitation prior to venoarterial extracorporeal membrane oxygenation initiation, with 18% cannulated during it. Fifty patients (60%) had ventricular tachycardia and/or ventricular fibrillation alternating with short periods of sinus rhythm and 33 (40%) had refractory ventricular tachycardia and/or ventricular fibrillation. Twelve patients (15%) underwent safe catheter ablation under venoarterial extracorporeal membrane oxygenation. After a median of 3 days (1-13 d) on extracorporeal membrane oxygenation support, 37 patients (45%) were successfully weaned off and 42% were alive 6 months post-ICU admission. Multivariable analysis retained ventricular tachycardia and/or ventricular fibrillation episodes alternating with short periods of sinus rhythm (odds ratio, 0.18; 95% CI, 0.06-0.52; p = 0.002) and age less than 50 years (odds ratio, 0.32; 95% CI, 0.18-0.89; p = 0.002) as being independent protective factors with 6-month survival, regardless of the underlying electrical storm cause. Among venoarterial extracorporeal membrane oxygenation-supported drug-refractory electrical storm patients, 42% survived 6 months post-ICU admission. Ventricular tachycardia and/or ventricular fibrillation episodes alternating with short periods of sinus rhythm and age less than 50 years were independently associated with better survival.

P590 Outcomes of patients treated with sequential anti-TNF therapy in a tertiary referral centre

Abstract Background Anti-TNF agents are administered intravenously(iv) or subcutaneously(SC).Factors such as speed of onset and patient preference influence that decision. The aim of this study was to assess the characteristics and outcomes of patients transitioned between iv and sc anti-TNF therapy. Methods Patients attending a single tertiary referral centre, treated with two different anti-TNF drugs were included. Patient and disease characteristics, biochemical, endoscopic and radiological data were collated. Results 69 patients were included. Table 1 describes the patient cohort. 28 (40.6%) patients transitioned from SC anti-TNF to infliximab (IFX). N=35 (50.7%) switched from IFX to Adalimumab and 6 to Golimumab. 31 patients demonstrated some degree of endoscopic activity prior to anti-TNF switch;14/16 (87.5%) demonstrated radiological activity. 48 patients had endoscopic assessment post-switch; 28 (58.3%) had endoscopic remission.Of the 19 patients with post-transition imaging, 42.1% (8/19) had no active disease. 43 (79.6%) patients had therapeutic trough concentrations of the current anti-TNF. 13 (26%) were previously on combination therapy, while 22 (32.8%) currently are. 24 (39.3%) patients had detectable anti-drug antibodies to their prior anti-TNF, 10 (16.4%) had primary non-response and 12 (19.7%) had loss of response with adequate drug levels. There were significantly more patients with antibody formation in the group switching from IFX to SC anti-TNF (n = 20; p = 0.001). A significantly higher proportion of patients who were transitioned from IFX to SC anti-TNF currently have therapeutic/supratherapeutic drug levels when compared with patients transitioning SC to IFX (p = 0.01). There is no significant difference in the proportion currently on combination therapy (p = 0.668). There is a significant improvement in c-reactive protein, albumin and haemoglobin in the cohort as a whole. However, there is no significant difference in rates of clinical remission (p = 0.556) or endoscopic remission (p = 0.89) after switching from one mode of delivery to another. Conclusion Patients converted from IFX to SC anti-TNF have similar rates of endoscopic and clinical remission to those transitioned to IFX. However, many patients had previous antibody formation. Subsequently, this group has significantly higher rates of therapeutic or supra-therapeutic drug concentrations, suggesting the conscientious use of therapeutic drug monitoring to optimise response.

Improving Post-induction Antitumor Necrosis Factor Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease.

Adequate serum drug levels of tumor necrosis factor-alpha inhibitors (anti-TNF) have been shown to improve outcomes in patients with inflammatory bowel disease. We aim to describe the quality improvement (QI) methods used at our institution to improve post-induction therapeutic drug monitoring (TDM) in children initiating anti-TNF therapy (infliximab and adalimumab) and describe the frequency of subtherapeutic anti-TNF levels. Beginning in February 2016, all patients initiating anti-TNF therapy were identified and tracked. Interventions to improve TDM, including the initiation of therapy plans for infliximab, real-time reminders for practitioners, and scheduling modifications for those initiating anti-TNF therapies were implemented using the Institute for Healthcare Improvement Plan-Do-Study-Act cycle approach. Statistical process control charts were used to demonstrate improvement over time. Anti-TNF levels and presence of antidrug antibodies were also recorded. Using QI methodology, we improved post-induction anti-TNF TDM from a baseline of 43% in 2015 to >80% by the end of 2017, with sustained improvement. Infliximab post-induction TDM improved from a baseline of 59% to 82%, whereas adalimumab post-induction TDM improved from baseline of 14% to 79%. In total, 36% of all anti-TNF post-induction levels were <5 μg/mL, with nearly 60% of post-induction infliximab levels being <5 μg/mL. Through incremental QI approaches, we improved the utilization of anti-TNF post-induction TDM with sustained improvement, approaching our goal of 90%. Subtherapeutic post-induction infliximab levels were common, indicating a strong need for anti-TNF TDM and an opportunity for dose optimization.

Egyptian consensus for the use of antimicrobial therapy in Preoperative prophylaxis, surgical site infections and diabetic foot infections

Use of antimicrobials in surgical prophylaxis These consensuses focus on primary perioperative prophylaxis for the prevention of an initial infection, the administration of the first dose of antimicrobial beginning within 60 min before surgical incision is recommended, but administration of vancomycin and fluoroquinolones should begin within 120 min before surgical incision because of the prolonged infusion times required for these drugs. Dosing In general, it is advisable to administer prophylactic agents in a manner that will ensure adequate levels of drug in serum and tissue for the interval during which the surgical site is open, If the duration of the procedure exceeds two half-lives of the antimicrobial or there is excessive blood loss (>1500 ml), the re-dosing interval should be measured from the time of administration of the preoperative dose, not from the beginning of the procedure. The selection of certain antimicrobial in most of the surgeries is shown in Table 2, and the special dosing of antimicrobials in patients with renal impairment is shown in Table 3. Surgical site infections “SSI” SSIs or wound infections are the most common adverse events affecting hospitalized surgical patients. The most important therapy for an SSI is to open the incision, evacuate the infected material, and continue dressing changes until the wound heals by secondary intention. Before starting an empiric antibiotics course, culture should be done. The antibiotic choice is usually empiric but can be supported by Gram stain, culture of the wound contents, the site of surgery, and the hospital antimicrobial susceptibility test system ‘Hospital Biogram’. The selection of Antibiotics for treatment of incisional surgical site infections is summarized in table 4. Diabetic foot infections Diabetic Foot infections typically begin in a wound, most often a neuropathic ulceration, while all wounds are colonized with microorganisms, and the presence of infection is defined by greater than or equal to 2 classic findings of inflammation or purulence. Most DFIs are polymicrobial, with aerobic gram-positive cocci, and especially Staphylococci spp., the most common causative organisms. Clinicians should consider the possibility of infection occurring in any foot wound in a patient with diabetes. Clinicians should evaluate a diabetic patient presenting with a foot wound at three levels: the patient as a whole, the affected foot or limb, and the infected wound. The clinically noninfected wounds should not be treated with antibiotic therapy. Prescription of antibiotic therapy for all infected wounds should be done, but with caution, as it is often insufficient unless combined with appropriate wound debridement. The clinicians need to select an empiric antibiotic regimen on the basis of the severity of the infection and the likely etiologic agent(s) (shown in Table 6).

Application of photodynamic therapy drugs for management of glioma

Human gliomas are one of the most prevalent and challenging-to-treat adult brain tumors, and thus result in high morbidity and mortality rates worldwide. Current research and treatments of gliomas include surgery associated with conventional chemotherapy, use of biologicals, radiotherapy, and medical device applications. The selected treatment options are often guided by the category and aggressiveness of this deadly disease and the patient’s conditions. However, the effectiveness of these approaches is still limited due to poor drug efficacy (including delivery to desired sites), undesirable side effects, and high costs associated with therapies. In addition, the degree of leakiness of the blood–brain barrier (BBB) that regulates trafficking of molecules in and out of the brain also modulates accumulation of adequate drug levels to tumor sites. Active research is being pursued to overcome these limitations to obtain a superior therapeutic index and enhanced patient survival. One area of development in this direction focuses on the localized application of photodynamic therapy (PDT) drugs to cure brain cancers. PDT molecules potentially utilize multiple pathways based on their ability to generate reactive oxygen species (ROS) upon photoactivation by a suitable light source. In this communication, we have attempted to provide a brief overview of PDT and cancer, photoactivation pathways, mechanism of tumor destruction, effect of PDT on tumor cell viability, immune activation, various research attempted by applying PDT in combination with novel strategies to treat glioma, role of BBB and clinical status of PDT therapy for glioma treatment.

Single Arm, Single Centre Prospective Study to Assess the Effect of Therapeutic Drug Monitoring (TDM) Based Dosage Adjustment of Posaconazole on the Incidence of Invasive Fungal Infections (IFIs) in AML Patients on Induction Chemotherapy on Posaconazole Prophylaxis

Background: Invasive fungal infections (IFIs) continue to remain a significant cause of morbidity and mortality in AML patients affecting the final outcomes and increasing health care costs. Posaconazole is commonly used as prophylaxis against IFIs due to its broad spectrum of action. The incidence of breakthrough IFIs is particularly high in our setting - one of the several reasons being suboptimal drug levels as we use posaconazole suspension whose absorption is influenced by multiple factors. A breakthrough IFI rate of 51% was seen in a previous study from our centre by Sengar et.al (ASH 2016) and it was seen that sub-optimal drug levels (&lt; 700ng/ml) were associated with a higher rate of breakthrough IFI. This group can benefit from TDM but there are not many studies to guide TDM-based dosing of posaconazole. TDM is expensive and time consuming and the final impact on clinical outcomes has been difficult to estimate. To determine the impact of TDM-based dosing of posaconazole on breakthrough IFI rate, we have undertaken this prospective study. Methods: This prospective, single-arm interventional study included patients 16 years or older undergoing induction chemotherapy for de novo AML with no evidence of IFI at baseline (normal CT chest and normal serum galactomannan ) who have consented for participation (assent and guardian consent were used for those who were &lt; 18 years). Concomitant drugs during induction were recorded everyday. 3 dosing schedules for posaconazole were used based on the drug level : Level 1 - 200mg TDS which was the starting dose in all patients, Level 2 - 200mg QID and Level 3 - 400mg TDS which was the maximum dose. Posaconazole was given with a high fat meal or an aerated drink to improve its absorption. The cut off for day 2 drug level (i.e after atleast 3-4 doses ) was 350ng/ml and the cut-off level at subsequent time points was 700 ng/ml. At any time point, if the patient's drug level was below this cut off, the dose was escalated and a repeat level was sent 5 complete days after the changed dose to allow for re-establishment of the pharmacokinetic equilibrium. A day 2 level was sent for all the patients and the timing of subsequent levels was based on dose escalation. Patients who were continued on the same dose due to adequate drug levels were sampled once in 7 days. QTc interval and liver function tests were monitored for posaconazole toxicity. Posaconazole was continued till the absolute neutrophil count recovered to more than 500 cells/ µl or till the patient was started on an alternative anti-fungal for a proven , possible or probable IFI or empirically at the clinician's discretion for reasons like persistent fever, cough, breathlessness, diarrhoea or vomiting. Relevant imaging and microbiological tests were performed as needed for investigating a suspected IFI. To analyze the primary endpoint chi-square test was used to compare the breakthrough IFI rate with that in a historical cohort from our own centre in which TDM based dosing was not used. Results: A total of 278 samples were collected for drug levels in these 90 patients with a mean of 3.08 (range 1 to 6 samples) per patient . 2 patients were proven to have mixed phenotypic acute leukemia after enrollment and hence were excluded from the analysis. 46 out of 88 patients i.e 52.3% were changed to alternative antifungals. Out of these 46, 13 patients (i.e 28.3%) had proven, probable or possible IFI as per the Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) . The change to alternative antifungals in the remaining 33 out of 46 patients (i.e 71.7%) was empirical due to persistent fever spikes, vomiting or diarrhoea. Thus overall 13 out of 88 patients i.e 14.8% had developed a breakthrough IFI. A similar historical cohort from our own institute, without the TDM based dosing of posaconazole, had a breakthrough IFI rate of 52%. The difference between the breakthrough IFI rate of these 2 cohorts was 37.2% which was statistically significant (p &lt; 0.0001, 95% CI 27.9% to 52.4%). 1 patient had developed grade 3 transaminitis and 1 patient had grade 3 rise in total bilirubin while on posaconazole. Conclusion: TDM-based dose escalation of prophylactic posaconazole in AML patients during induction leads to a significant reduction in the breakthrough IFI rates. Disclosures No relevant conflicts of interest to declare.

Effects of Pharmacogenetic Screening for CYP2D6 Among Elderly Starting Therapy With Nortriptyline or Venlafaxine: A Pragmatic Randomized Controlled Trial (CYSCE Trial).

The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression.

Inflammatory Cytokine Profile in Crohn's Disease Nonresponders to Optimal Antitumor Necrosis Factor Therapy.

A significant number of patients receiving therapy with antitumor necrosis factor (TNF) agents for Crohn's disease experience primary or secondary nonresponse. The aim of this study was to assess whether patients with nonresponse to anti-TNF agents have increased expression of alternative cytokine pathways. We designed a prospective, cross-sectional study that included patients with Crohn's disease receiving anti-TNF undergoing colonoscopy with adequate serum trough drug levels (≥8 µg/mL) and without anti-drug antibodies. Inflammatory cytokines and cell adhesions markers measured included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, interleukin (IL)-8, IL-1β, and IL-6. The primary outcome was the presence of active endoscopic inflammation defined as the presence of at least 1 ulceration ≥5 mm. In total, 47 patients were included. Patients with active inflammation had significantly higher levels of ICAM-1 and IL-1β when compared with those without intestinal inflammation (45.9 vs. 35.8 ng/mL, P<0.0001 and 3.2 vs. 1.5 pg/mL, P=0.002, respectively). There were no significant differences in the other study variables. Using receiving operating curves, ICAM and IL-1β had a good correlation (receiver operating characteristic ≥0.8) with inflammation in this cohort of patients with "anti-TNF resistance." The results were similar in the group of patients with previous anti-TNF exposure. Our study suggests that patients who have active inflammation with seemingly adequate serum anti-TNF levels have increased levels of specific inflammatory pathways that may serve as biomarkers of nonresponse as well as potential targets of therapy in anti-TNF nonresponders.

Formulation and Investigation of a Lipid Based Delivery System Containing Antimicrobials for the Treatment of Periodontal Disease.

Periodontitis is a chronic inflammatory disease, which affects the supporting tissues of the teeth, and without proper treatment it may lead to tooth loss. Antibiotics - administered orally - have been widely used in the treatment of periodontitis. With the conventional administration routes, adequate drug levels cannot be reached in the periodontal pockets and oral application of antimicrobials could lead to side effects. Drug delivery systems containing antibiotics, administered at the site of infection, could possibly help eliminate pathogen bacteria and treat periodontitis. The aim of the recent study was to create a locally swellable, biodegradable, biocompatible, mucoadhesive, lipophilic drug delivery system containing antimicrobial drugs which softens at body temperature, accommodate to the shape of the periodontal pocket and can provide extended drug release for at least one week. During the formulation, thermoanalytical, consistency, wettability, swelling, degradation and drug release studies were applied to determine the ideal ratios of lipid bases, structure-building components and surface active agent concentrations. The structure-building component cetostearyl alcohol appeared to be the most convenient, thanks to its wettability and mechanical properties, which led to controlled drug release. With the use of ideal concentrations of components (10% surfactant, 40% structure-building component, 32 % lipid base, 15% antimicrobial agent and 3% polymer), sustained drug release can be provided up to nearly 3 weeks.

Beyond the Biomedical: Preexposure Prophylaxis Failures in a Cohort of Young Black Men Who Have Sex With Men in Atlanta, Georgia

Human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) has high biomedical efficacy; however, awareness, access, uptake, and persistence on therapy remain low among black men who have sex with men (BMSM), who are at highest risk of HIV in the United States. To date, discussions of "PrEP failure" have focused on one typology: rare, documented HIV acquisitions among PrEP users with adequate serum drug levels (ie, biomedical failure). In our cohort of HIV-negative young BMSM in Atlanta, Georgia, we continue to observe a high HIV incidence (6.2% annually at interim analysis) despite access to free PrEP services. Among 14 seroconversions, all were offered PrEP before acquiring HIV. Among these participants, we identified 4 additional typologies of PrEP failure that expand beyond biomedical failure: low PrEP adherence, PrEP discontinuation, PrEP contemplation without initiation, and PrEP refusal. We describe the 5 typologies and suggest interventions to improve PrEP effectiveness among those at highest risk.