Subtherapeutic Drug Concentrations Research Articles

P468 Relevance of anti-drug antibodies in context of supra-therapeutic anti-TNF concentrations

Abstract Background The low serum concentration of anti-tumor necrosis factor-alpha (anti-TNFα) agents and the presence of anti-drug antibodies are related to poor therapeutic outcomes in inflammatory bowel disease (IBD). We aimed to evaluate the prognosis of patients having both antidrug antibodies and supratherapeutic drug concentrations. Methods IBD patients on maintenance infliximab (IFX) or adalimumab (ADA) therapy were prospectively recruited. Serum drug concentrations and antidrug antibodies were measured (Anser, Prometheus). The drug concentrations were classified as subtherapeutic (IFX: <3 µg/mL; ADA: <5 µg/mL), therapeutic (IFX: 3-8 µg/mL; ADA 5-10 µg/mL), and supratherapeutic (IFX > 8 µg/mL; ADA > 10 µg/mL) concentrations regardless of the timing of blood sample collection. We analysed the relationship between i) drug concentrations and ii) the presence and absence of anti-drug antibodies with use of systemic corticosteroids and anti-TNF discontinuation. Results Of 172 patients (122 CD [70.9%], 44 UC [25.6%], 3 IBD-U [1.7%], and 3 IBD-pouch [1.7%]), the median age was 32.3 years (range, 24.8-42.5), and the median duration of IBD was 9.7 years (range 5.3-15.6). IFX and ADA were used in 81 (47.1%) and 91 (52.9%) patients, respectively, and concurrent usage of immunomodulators and systemic corticosteroids was observed in 39 (22.7%) and 23 (13.4%) patients, respectively. Supratherapeutic, therapeutic, and subtherapeutic concentrations were observed in 74 (43.0%), 32 (18.6%), and 66 (38.4%), respectively. The patients with antidrug antibodies (n = 79, 45.9%) showed a higher frequency of having subtherapeutic drug concentrations (68.4% vs 12.9%, P < 0.001) compared to those without antibodies, and the presence of antibodies was an independent predictor of discontinuation of anti-TNFα agents (hazard ratio 3.50, 95% confidence interval 1.88-6.51, P < 0.001, Fig. 1A). In subgroup analysis, patients with antidrug antibodies and supratherapeutic drug concentration exhibited a tendency to have improved drug persistence compared to those with subtherapeutic drug concentration, albeit insignificantly (P = 0.099, Fig. 1B). However, the persistence in this group was still poorer than that observed in patients without antibodies (P = 0.003). Finally, neither anti-TNFα concentrations nor the presence of antidrug antibodies were associated with the need for additional systemic corticosteroid use within 6 months. Conclusion The presence of antidrug antibodies can predict the discontinuation of anti-TNFα agents despite supratherapeutic drug levels. While supratherapeutic drug concentration may improve the treatment persistence of anti-TNFα agents in patients with anti-drug antibodies, it does not last as long as in those without antibodies.

Utilization of cefepime therapeutic drug monitoring in febrile neutropenia patients with hematologic malignancies.

Cefepime is a fourth-generation cephalosporin and is a workhorse for the empiric treatment of febrile neutropenia (FN). Beta-lactam therapeutic drug monitoring (TDM) has emerged as a dose optimization strategy in patient populations with altered kinetics. Prior literature has demonstrated that patients with FN exhibit augmented renal clearance which may lead to subtherapeutic drug concentrations with standard dosing regimens. The aim of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) target attainment and clinical outcomes in patients with hematologic malignancies and FN who were treated empirically with cefepime. This was a prospective, single-center study of adults with hematologic malignancies and FN admitted to the inpatient unit. The primary outcome was PK/PD target attainment (defined as 100% free time greater than minimum inhibitory concentration (100% fT > MIC)). Secondary clinical outcomes were time to defervescence, time to ANC recovery, in-hospital mortality, and cefepime failure. There were 55 patients in our study. Forty-three (78%) patients achieved the primary outcome of PK/PD target attainment. The mean time to defervescence was similar between those that achieved PK/PD target attainment and those that did not (95% CI -0.75 to 1.25, p = 0.62). This study showed that standard cefepime dosing in patients with hematologic malignancies and FN does not result in achievement of 100% fT > MIC in all patients. Patients in the group that did not achieve PK/PD target attainment were younger with increased creatinine clearance, indicating that cefepime TDM may be especially beneficial in these patients.

Therapeutic drug monitoring and virological response at week 48 in a cohort of HIV-1-infected patients switching to dolutegravir/rilpivirine dual maintenance therapy (ANRS-MIE-BIRIDER study).

Dolutegravir (DTG) and rilpivirine (RPV) dual therapy is now recommended as a switch option in virologically suppressed HIV patients. Literature suggests that virological failure with dual therapy could possibly relate to subtherapeutic drug concentrations. In this study, we aimed at describing the DTG and RPV trough plasma concentrations (Cmin) and plasma HIV-1 RNA viral load (VL) during maintenance dual therapy. We performed a retrospective analysis of DTG and RPV therapeutic drug monitoring in people living with HIV/AIDS (PLWHA) with dual therapy in 9 French centres. DTG and RPV trough plasma concentrations were estimated using a Bayesian approach to predict Cmin. The relationship between the pharmacokinetics of DTG and RPV and VL > 50 copies (cp)/mL was explored using joint nonlinear mixed models. The frequency of subtherapeutic threshold (DTG Cmin below 640 ng/mL and RPV Cmin below 50 ng/mL) were compared between PLWHA presenting VL > 50 cp/mL or not during the study. At baseline, 209 PLWHA were enrolled in the study. At week 48, 19 people living with HIV/AIDS (9.1%) discontinued their treatment and 15 PLWHA (7.1%) exhibited VL > 50 cp/mL. Six PLWHA out of 15 (40.0%) with VL > 50 cp/mL during the follow-up had at least 1 Cmin below the respective thresholds while only 26/194 patients (13.4%) without virological replication had at least 1 concentration below the threshold (P= .015). A majority of PLWHA receiving DTG/RPV maintenance dual therapy demonstrated VL < 50 cp/mL but virological replication was more frequent in people living with HIV/AIDS with subtherapeutic Cmin.

Medication Management in the Critically Ill Patient with Acute Kidney Injury.

AKI occurs frequently in critically ill patients. Patients with AKI, including those who require KRT, experience multiple pharmacokinetic and pharmacodynamic perturbations that dynamically influence medication effectiveness and safety. Patients with AKI may experience both subtherapeutic drug concentrations, which lead to ineffective therapy, and supratherapeutic drug concentrations, which increase the risk for toxicity. In critically ill patients with AKI not requiring KRT, conventional GFR estimation equations, especially those based on serum creatinine, have several limitations that can limit the accuracy when used for medication dosing. Alternative methods to estimate kidney function may be informative, including use of measured urinary creatinine clearance, kinetic eGFR, and equations that integrate novel kidney biomarkers. For critically ill patients with AKI requiring KRT, physicochemical properties of the drug, the KRT prescription and circuit configuration, and patient-specific factors each contribute to medication clearance. Evidence-based guidance for medication dosing during AKI requiring KRT is often limited. A working knowledge of the basic tenets of drug elimination during KRT can provide a framework for how to approach decision making when the literature is lacking. Iterative re-evaluation of a patient's progress toward therapeutic goals with a medication must occur over the arc of critical illness, including and especially in the setting of dynamic kidney function.

Dapagliflozin efficacy as an add-on therapy in double and triple-drug regimens: A meta-analysis of randomized control trial

Background: Diabetes is one of the most common diseases compared to others. There are many drugs available in the market to treat diabetes. Still, most of them have adverse drug reactions like hypoglycemia, weight gain, and subtherapeutic drug concentrations. SGLT-2 inhibitors are a new class of drugs used as add-on therapy to treat type-2 Diabetes Mellitus. They act by inhibiting glucose reabsorption and increasing glucose excretion via the kidneys. In an average adult, two kidneys filter about 180g of glucose per day. About 98% of the glucose filtered in the kidneys get reabsorbed in the proximal convoluted tubule back into the bloodstream, which can be inhibited by SGLT-2 inhibitors.&#x0D; Method: A systematic review and meta-analysis were performed on randomized clinical trial data, extracted from PubMed, Cochrane and Embase. All data, including baseline and shift of baseline, standard deviation, and number of participants, were recorded for HbA1c, Fasting blood glucose (FBG), Bodyweight and SBP/DBP.&#x0D; Results: Twelve randomized clinical trials, including 8000 participants, were compared and divided into three groups of drugs: SAXA+DAPA+MET, SAXA+MET and DAPA+MET. The comparison is done for HbA1c (WMD:-6.78; 95% CI:-8.28; P &lt;0.00001) (WMD:-4.88; 95% CI:-6.93; P &lt;0.00001), FBG (SMD: -6.50; 95% CI: -8.55, -4.45; P &lt;0.00001) (SMD: -7.75; 95% CI: -8.84, -6.66; P&lt;0.00005,), body weight (SMD: 0.30; 95% CI: 0.27, 0.33; P =1.00) (SMD: -1.00; 95% CI: -1.90, -0.10; P&lt;0.00001). Conclusion: Dapagliflozin, when given in combination, shows a major improvement in HbA1c and FBG levels and does not affect body weight. It was shown to be more effective when given in triple combination therapy.&#x0D; Keywords: Dapagliflozine, meta-analysis, Sexagliptine, Metformin, Type two diabetes mellitus (T2DM), Sodium-glucose Cotransporter-2 (SGLT2)

Pharmacokinetics of Antimicrobials in Children with Emphasis on Challenges Faced by Low and Middle Income Countries, a Clinical Review.

Effective antimicrobial exposure is essential to treat infections and prevent antimicrobial resistance, both being major public health problems in low and middle income countries (LMIC). Delivery of drug concentrations to the target site is governed by dose and pharmacokinetic processes (absorption, distribution, metabolism and excretion). However, specific data on the pharmacokinetics of antimicrobials in children living in LMIC settings are scarce. Additionally, there are significant logistical constraints to therapeutic drug monitoring that further emphasize the importance of understanding pharmacokinetics and dosing in LMIC. Both malnutrition and diarrheal disease reduce the extent of enteral absorption. Multiple antiretrovirals and antimycobacterial agents, commonly used by children in low resource settings, have potential interactions with other antimicrobials. Hypoalbuminemia, which may be the result of malnutrition, nephrotic syndrome or liver failure, increases the unbound concentrations of protein bound drugs that may therefore be eliminated faster. Kidney function develops rapidly during the first years of life and different inflammatory processes commonly augment renal clearance in febrile children, potentially resulting in subtherapeutic drug concentrations if doses are not adapted. Using a narrative review approach, we outline the effects of growth, maturation and comorbidities on maturational and disease specific effects on pharmacokinetics in children in LMIC.

Pitfalls and pearls with drug dosing in the critically ill obese patient: 10 statements to guide ICU practitioners.

Obesity is highly prevalent in ICU patients presenting a number of challenges, one of which is drug dosing. There are limited high-quality data describing drug dosing in obesity, which can lead to dosing strategies that are suboptimal. For example, inappropriately using the wrong weight for weight-based dosing can lead to supratherapeutic drug concentrations and an adverse drug event or subtherapeutic drug concentrations and treatment failure. A generalized framework for decision making specific for obese patients is available that describes a step-by-step approach for constructing dosing regimens. This manuscript will build on that framework by providing pitfalls and pearls for clinicians to consider when making dosing decisions in critically ill patients with severe obesity.

Variable Sequestration of Antifungals in an Extracorporeal Membrane Oxygenation Circuit.

Fungal infections are common and frequently associated with clinical failure in patients receiving extracorporeal membrane oxygenation (ECMO). Antifungal drugs have physicochemical characteristics associated with a higher likelihood of sequestration onto ECMO circuitry potentially leading to a subtherapeutic drug concentration. The percentage of sequestration of the antifungal drugs-caspofungin, posaconazole, and voriconazole-was determined using an ex vivo ECMO model. The circuits were primed with whole human blood, sodium chloride 0.9%, and human albumin solution. Serial 2 ml samples were taken at baseline, 0.5, 1, 2, 6, 12, and 24 hours after drug addition, paired with non-ECMO controls stored in a water bath at 37°C. Mean loss from the blood-primed ECMO circuits and controls at 24 hours relative to baseline were 80% and 61% for caspofungin ( p = ns), 64% and 11% for posaconazole ( p < 0.005), and 27% and 19% for voriconazole ( p < 0.05). Calculated AUC 0-24 showed a 44% for caspofungin ( p = ns), 30.6% posaconazole ( p < 0.005), and 9% loss for voriconazole ( p = 0.003) compared with the controls, suggesting therapeutic concentrations of these antifungal agents cannot be guaranteed with standard dosing in patients on ECMO. Posaconazole exhibited the greatest loss to the ECMO circuit correlating with both high lipophilicity and protein binding of the drug.

Nanocrystals as a master key to deliver hydrophobic drugs via multiple administration routes.

The poor aqueous solubility of many approved drugs and most new chemical entities poses a challenge to drug delivery scientists working in academic and industrial labs. Despite the high pharmacological activity these drugs may have, their limited water solubility leads to poor absorption and consequently to sub-therapeutic drug concentrations in target tissues. The formulation of drug nanocrystals (NCs) has emerged as one the most promising approaches for increasing the biopharmaceutical performance of hydrophobic drugs. Initially aimed at increasing the absorption of drugs administered orally, NCs have been increasingly utilised to allow drug delivery via multiple routes, namely, parenteral injections, transdermal, ocular, intranasal, and pulmonary. This review aims to describe the recent progress in the field and demonstrate how the NCs technology enabled the delivery of hydrophobic drugs through multiple administration routes.

P241

Abstract Background In recent decades, biological drugs targeting anti-tumour necrosis factor-α (TNF-α) have represented the cornerstone in the treatment of inflammatory bowel diseases. Currently, anti- TNF-α represents a breakthrough in patient care. However, 20–50% of patients experience primary or secondary loss of response. This may be due to pharmacodynamic and/or pharmacokinetic issues, resulting in subtherapeutic drug concentrations, frequently related to the development of anti-drug antibodies (ADA). In this context, therapeutic drug monitoring (TDM) is essential to patients’ management in order to pinpoint the basis of reduced efficacy. Indeed, a fast and reliable assessments of TDM is mandatory to allow rapid intervention, to avoid toxicity and improve treatment efficacy. In this study we assess the analytical performance of a novel fully automated chemiluminescent assay in measuring biological drugs levels and ADA serum concentration and to compare its performances to the current diagnostic method (ELISA). Methods Serum levels of biological drugs (Infliximab and Adalimumab) and their respective ADA were measured in twenty infliximab (IFX)-treated IBD patients and twenty adalimumab (ADL)-treated IBD patients using both the Promonitor® ELISA kits (Grifols) and the i-TRACKER chemiluminescent (CLIA) kits (Theradiag Results The CLIA method is a random-access platform that allows the continuous loading of samples, while the ELISA is a time-consuming manual method to be planned in advance to reduce expenses. Actually, in our laboratory is performed only twice a month. A very good correlation was observed both for Infliximab (Spearman r=0.9695, 95%CI = 0,92-0,99, p&amp;lt;0.0001) and Adalimumab serum levels (Spearman r=0.9476, 95%CI = 0,86-0,98, p&amp;lt;0.0001). Among the patients with undetectable IFX serum levels, 6/8 (75%) resulted ADA positive by ELISA versus 8/8 (100%) by CLIA. Moreover, CLIA disclosed very high ADA concentration in 3 samples compared to borderline results by ELISA. Regarding ADL, all the 9 patients with undetectable serum levels presented similar ADA concentration as tested with ELISA or CLIA. Conclusion In conclusion, the i-TRACKER CLIA Infliximab and Adalimumab assays showed a very good correlation for serum-based drugs level quantification as compared to the related ELISA methods. Furthermore, a good agreement was observed for ADA analysis, with a higher sensitivity against anti-IFX antibodies by CLIA compared to ELISA. Our data clearly highlighted that a fully automated assay for TDM would certainly reduce costs and significantly improve the management of IBD patients in terms of a shorter turn-around time.

Augmented Renal Clearance: What Have We Known and What Will We Do?

Augmented renal clearance (ARC) is a phenomenon of increased renal function in patients with risk factors. Sub-therapeutic drug concentrations and antibacterial exposure in ARC patients are the main reasons for clinical treatment failure. Decades of increased research have focused on these phenomena, but there are still some existing disputes and unresolved issues. This article reviews information on some important aspects of what we have known and provides suggestion on what we will do regarding ARC. In this article, we review the current research progress and its limitations, including clinical identification, special patients, risk factors, metabolism, animal models and clinical treatments, and provide some promising directions for further research in this area.

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy and haemopoietic stem cell transplant recipients, 2021.

Antifungal agents can have complex dosing and the potential for drug interaction, both of which can lead to subtherapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy and haemopoietic stem cell transplant recipients. Antifungal agents can also be associated with significant toxicities when drug concentrations are too high. Suboptimal dosing can be minimised by clinical assessment, laboratory monitoring, avoidance of interacting drugs, and dose modification. Therapeutic drug monitoring (TDM) plays an increasingly important role in antifungal therapy, particularly for antifungal agents that have an established exposure-response relationship with either a narrow therapeutic window, large dose-exposure variability, cytochrome P450 gene polymorphism affecting drug metabolism, the presence of antifungal drug interactions or unexpected toxicity, and/or concerns for non-compliance or inadequate absorption of oral antifungals. These guidelines provide recommendations on antifungal drug monitoring and TDM-guided dosing adjustment for selected antifungal agents, and include suggested resources for identifying and analysing antifungal drug interactions. Recommended competencies for optimal interpretation of antifungal TDM and dose recommendations are also provided.

The effect of weight reduction surgery on the efficacy and tolerability of epilepsy pharmacotherapy

BackgroundBariatric surgery is an increasingly utilized procedure among patients with obesity-related medical complications. The impact of bariatric surgery on seizure frequency and antiseizure drug (ASD) levels are not well described. MethodsWe conducted a retrospective chart review of adult patients with a history of epilepsy or seizures undergoing bariatric surgery for morbid obesity from September 1997–September 2019. The median follow-up was 60 months [range 9–220 months]. ResultsForty-six patients with a history of seizures were identified (38 female); 44 patients had recurrent and unprovoked seizures. Seventeen sets of pre- and post-surgery drug concentrations from 14 patients were reviewed. The median age at surgery was 44 years (range, 19–68). Thirty-three patients were prescribed ASDs at the time of bariatric surgery (median 1 drug [range, 1–3]). Laparoscopic Roux-en-Y was performed in 40 patients, and sleeve gastrectomy in 6 patients. Median pre-surgery weight was 120.75 kg (range, 71–230) and BMI 44.4 kg/m2 (range, 34–77.6). Six months following surgery the median weight was 89.5 kg (range, 58.2–202) and BMI 34.2 kg/m2 (range, 24.5–61.9).Nine patients (19.6%) had a worsening of seizure control on long-term follow-up (median 60, range 9–220 months) following bariatric surgery, including five (10.8%) who suffered seizures within 6 months of bariatric surgery. Five patients developed ASD-associated side effects following bariatric surgery including irritability in two patients (levetiracetam and phenytoin) and one patient each suffering from somnolence (phenytoin), hyperammonemic encephalopathy (sodium valproate), and nausea and vomiting (carbamazepine). Subtherapeutic post-surgery drug concentrations were identified in 5 patients and supratherapeutic concentrations in one patient. In the initial 6 months following surgery, ASD doses were increased in five patients and reduced in five. ConclusionsThe majority of patients with epilepsy who undergo bariatric surgery have no change in seizure frequency. However, a significant minority of patients may experience medication side effects or an increase in seizure tendency due to the impact of bariatric surgery on ASD drug absorption and metabolism leading. Pre- and post-surgical serum concentrations should be measured in patients with seizures or epilepsy receiving ASDs.

Vascular priming with RRx-001 to increase the uptake and accumulation of temozolomide and irinotecan in orthotopically implanted gliomas

Vascular normalisation refers to a ‘remodeling’ of the dysfunctional tumour capillary network, which regresses under the influence of anti-VEGF treatment, resulting in improved blood flow and oxygenation. RRx-001 is an anti-CD47-SIRPα small molecule with vascular normalising properties under investigation in clinical trials for the treatment of glioblastoma, brain metastases, lung cancer and colorectal cancer, with FDA Orphan Drug Designation in glioblastoma and other tumour types. This study investigated whether the improved oxygenation and perfusion that has been previously observed with RRx-001 both preclinically and clinically in the context of a brain metastasis trial was correlated with increased penetration and accumulation of the cytotoxic chemotherapies, irinotecan and temozolomide, in orthotopically implanted gliomas, priming tumours for improved response. The experiments demonstrate that administration of RRx-001 prior to temozolomide or irinotecan results in significantly increased uptake of irinotecan and temozolomide in orthotopic glioma tumours. Since the success of chemotherapy in the brain (and outside of it) is limited by subtherapeutic tumoral drug concentrations, vascular normalisation-enhanced delivery of standard cytotoxics as demonstrated with RRx-001 may mitigate or reverse clinical drug resistance and thereby improve the outcome of cancer therapy, particularly in the brain.

Enhanced efficacy and drug delivery with lipid coated mesoporous silica nanoparticles in cancer therapy

The exposure of cancer cells to subtherapeutic drug concentrations results in multidrug resistance (MDR). The uniqueness of mesoporous silica nanoparticles (MSNPs) with larger surface area for higher drug loading can solve the issue by delivering higher amounts of chemotherapeutics to the cancer cells. However, premature drug release and lower biocompatibility remain challenging. Lipid coating of MSNPs at the same time, can enhance the stability and biocompatibility of nanocarriers. Furthermore, the lipid coating can reduce the systemic drug release and deliver higher amounts to the tumor site. Herein, lipid coated MSNPs were prepared by utilizing cationic liposomes and further investigations were made. Our studies have shown the higher entrapment of doxorubicin (Dox) to MSNPs due to availability of porous structure. Lipid coating could provide a barrier to sustain the release of drug along with reduced premature leakage. In addition, the biocompatibility and enhanced interaction of cationic liposomes to cell membranes resulted in better cellular uptake. Lipid coated silica nanoparticles have shown higher cellular toxicity as compared to non-lipid coated particles. The increase in cytotoxicity with time supports the hypothesis of sustained release of drug from lipid coated MSNPs. We propose the Lip-Dox-MSNPs as an effective approach to treat cancer by delivering and maintaining effective concentration of drugs to the tumor site without systemic side effects.

Issue Highlights

Although the introduction of biologics for the treatment of Crohn’s in 1998 revolutionized our approach to this disease, primary non-response and secondary loss of response remain vexing problems for a large subset of patients in clinical practice. For anti-TNF agents, common reasons for loss of response include subtherapeutic drug concentrations and development of neutralizing anti-drug antibodies. Therapeutic drug monitoring, dose escalation and interval shortening are approaches with demonstrated effectiveness recapturing response to these agents and are commonly employed in clinical practice. 1 Papamichael K. Cheifetz A.S. Melmed G.Y. et al. Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2019; 17: 1655-1668.e3 Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Shortening the dose interval or dose intensification for Vedolizumab has also been shown to permit recapturing of response in some patients, 2 Peyrin-Biroulet L. Danese S. Argollo M. et al. Loss of response to vedolizumab and ability of dose intensification to restore response in patients with crohn's disease or ulcerative colitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019; 17: 838-846.e2 Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar but whether this approach can be extrapolated to Ustekinumab remains unclear. This retrospective study by Ollech et al 3 Ollech J.E. Normatov I. Peleg N. et al. Effectiveness of Ustekinumab dose escalation in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2021; 19: 104-110 Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar is the first to evaluate real-world effectiveness of interval shortening from 8- to 4-week dosing for Ustekinumab. The authors describe pre- and post-dose escalation parameters including Harvey Bradshaw Index (HBI), C-reactive protein (CRP), and fecal calprotectin for a subset of 110 patients not responding to Ustekinumab every 8 weeks. Although not all patients in the subset had all parameters pre- and post-dose increase, of the 78 patients (71%) with pre-and post-HBI metrics, the median HBI decreased from 4.5 to 3 (P = .002). Of 60 patients (55%) with CRP measurements, median CRP decreased from 8 mg/L to 3 mg/L (P = .031). Among patients with HBI >4, CRP ≥5 mg/L, fecal calprotectin >250 μg/g, or endoscopic evidence of active disease, 28% achieved clinical remission (HBI<4), 22% normalized CRP, and 36% endoscopic remission with a median follow up of 9 months post-dose increase. 38% of patients on steroids were able to discontinue, and 45% with active perianal disease reported resolution within 6 months of dose-escalation. Twenty-three patients (20.9%) discontinued therapy following dose escalation, most (78%) due to lack of response; only 1 due to side effects (rash). This is the first study to demonstrate improvement in objective measures of Crohn’s disease activity with dose-intensification of Ustekinumab from 8- to 4-week intervals. Effectiveness of Ustekinumab Dose Escalation in Patients With Crohn’s DiseaseClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewA subset of patients with Crohn’s disease (CD) do not respond to ustekinumab at the standard dose of 90 mg every 8 weeks. Little is known about the efficacy of shortening the interval between doses. Full-Text PDF Type 2 Diabetes and Metformin Use Associate With Outcomes of Patients With Nonalcoholic Steatohepatitis–Related, Child–Pugh A CirrhosisClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewFactors that affect outcomes of patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis are unclear. We studied associations of type 2 diabetes, levels of hemoglobin A1c (HbA1c), and use of antidiabetic medications with survival and liver-related events in patients with NASH and compensated cirrhosis. Full-Text PDF Intragastric Balloon Placement Induces Significant Metabolic and Histologic Improvement in Patients With Nonalcoholic SteatohepatitisClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewObese patients with nonalcoholic steatohepatitis (NASH) are at risk for cirrhosis if significant weight loss is not achieved. The single fluid-filled intragastric balloon (IGB) induces meaningful weight loss and might be used in NASH treatment. We performed an open-label prospective study to evaluate the effects of IGB placement on metabolic and histologic features of NASH. Full-Text PDF Serum Levels of α-Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular CarcinomaClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewUltrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. Full-Text PDF

Bioequivalence of Two Oral Ciprofloxacin Extended-Release Formulations in Healthy Mexican Volunteers

Introduction. Oral ciprofloxacin extended-release formulation decreases the risk of treatment failure and prevents the development of antimicrobial resistance. However, non-equivalent formulations lead to subtherapeutic plasma drug concentrations, increasing the risk of such problems. Objective. To determine the bioequivalence of two oral ciprofloxacin extended-release tablet formulations (1,000 mg) in healthy Mexican volunteers. Material and Methods. In this open-label 2 × 2 crossover design study, 26 healthy volunteers were randomly allocated to receive a single dose of the reference drug Cipro XR® (Bayer, Mexico) and the test formulation Ciproflox DM® (Senosiain Laboratories, Mexico). Blood samples were obtained for 24 hours. Ciprofloxacin plasma levels were quantified using a validated liquid chromatography method. Pharmacokinetic parameters were obtained by standard non-compartmental analysis. In order to determine bioequivalence, log-transformed test/reference ratios of Cmax, AUC0-t, and AUC0-inf were compared by an analysis of variance, followed by the 90 % confidence intervals and the Schuirmann bilateral test. Results. The 90 % confidence intervals ranged from 85.69 to 114.31 % for Cmax, 85.16-115.84 % in AUC0-t, and 85.39-114.61 % for AUC0-inf, all cases were within bioequivalence acceptance criteria (80-125 %). Schuirmann test verified the probability that the values were within these criteria (p &lt; 0.05). No side-effects were observed with any treatment. Conclusions. The results obtained demonstrate bioequivalence between the analyzed formulations.

Mastitis and/or plugged ducts? How to differentiate, help and treat?

Mastitis is one of the most common pyoinflammatory processes that occur in the postpartum. The mastitis incidence varies from 0.5% to 33%. Due to lack of standard algorithms, approaches to diagnosis and treatment of lactational mastitis vary between pediatricians and obstetrician-gynecologists. Plugged ducts is the basic factor that predisposes a woman to plugged milk ducts, which can lead to mastitis. Unfortunately, frequently prescribed antibacterial treatment has an adverse effect on human milk microbiota and creates subtherapeutic drug concentration in milk, which leads to antibiotic resistance in infants. Effective expression of breast milk is a key method to prevent and fight mastitis and plugged ducts. Recommendations for preferred method of breast milk expression require a personalized approach, the first of which depends on the assessment of breast nipples condition. According to some reports, 80–90% of breast-feeding women develop soreness and cracked nipples, which cause delayed or missed breastfeeding. Teaching correct breast-feeding techniques can prevent the chain of these adverse events:cracked nipples – plugged duct – lactation mastitis.Ideally, a healthy mature infant with active sucking reflex, who is breastfed effectively with a good technique, may perfectly ensure a problem-free lactation period.

Development of Infliximab Target Concentrations During Induction in Pediatric Crohn Disease Patients.

Subtherapeutic drug concentrations contribute to both primary and secondary nonresponse to infliximab in children with Crohn disease (CD). The aim of this study was to evaluate treatment outcomes and infliximab concentrations at infusions 2 and 3 with an objective to establish infliximab targets during induction for primary responders. Single-center, prospective cohort of anti- tumor necrosis factor-alpha naïve CD patients younger than 22 years starting infliximab. Clinical response was defined with the weighted pediatric CD activity index at the fourth infusion. Rates of biological response (>50% improvement in fecal calprotectin) and maintenance concentrations ≥5 μg/mL were secondary outcomes. We enrolled 72 patients with CD with 70 of 72 receiving infliximab monotherapy. Clinical response, biological response, and start of maintenance concentrations ≥5 μg/mL were achieved in 64%, 54%, and 22%, respectively. The median (interquartile range) infliximab concentrations at infusion 2 and 3 in clinical responders were 27.8 μg/mL (19.5-40) and 14 μg/mL (8.3-24) compared to 18.8 μg/mL (9.1-23, P < 0.001) and 7.8 μg/mL (4-13.2, P < 0.01) in nonresponders. Receiver operating characteristic analysis determined that an infliximab concentration ≥15.9 μg/mL at infusion 3 was associated with clinical response (area under the curve [AUC] 0.73), whereas an infusion 3 level ≥18 μg/mL was associated with a start of maintenance concentration >5 μg/mL (AUC 0.85). Independent predictors for infusion 3 levels <18 μg/mL included pretreatment prednisone, low body mass index, elevated erythrocyte sedimentation rate and C-reactive protein, hypoalbuminemia, and an infusion 2 infliximab level <29 μg/mL. We found that infusion 2 (≥29 μg/mL) and infusion 3 (≥18 μg/mL) infliximab concentrations were strongly associated with improved early outcomes and higher first maintenance dose levels.

Assessment of Antiepileptic Drug Concentrations in HIV-Infected versus HIV-Negative Patients: A Retrospective Analysis.

A higher rate of subtherapeutic psychotropic drug concentrations was recently found in HIV-infected versus HIV-negative patients. In this study, we sought to investigate if this trend could also apply to antiepileptic drugs. Overall, 700 HIV-infected patients were screened during the first 2years after the introduction of our outpatient polytherapy management service (Gestione Ambulatoriale Politerapie [GAP]) in the search for subjects with antiepileptic drug trough concentration assessments. The distribution of such concentrations was compared with that in HIV-negative patients monitored over the same period. The search identified 97 HIV-infected patients concomitantly receiving antiretroviral and antiepileptic drugs, for a total of 310 drug measurements. Overall, 30%, 64% and 6%, versus 28%, 65% and 7%, of the antiepileptic concentrations measured in HIV-infected versus HIV-negative patients (1090 patients, for a total of 3488 antiepileptic concentrations measured) were below, within, or above the therapeutic targets, respectively. The antiepileptic drug valproate was associated with the highest risk of subtherapeutic drug concentrations, with 57% and 46% of determinations below the therapeutic range in HIV-positive and HIV-negative patients, respectively. Remarkably, the concentrations of valproate were significantly lower in HIV-infected versus HIV-negative patients (47.9±21.2 versus 53.9±21.6 mg/L; p<0.05). In our retrospective study, most HIV-infected patients had antiepileptic drug concentrations falling within the therapeutic targets, with the exception of valproate, which was associated with a higher rate of subtherapeutic concentrations compared with other antiepileptic drugs.