Serum Drug Levels Research Articles

Preoperative Serum Vedolizumab Levels Do Not Impact Postoperative Outcomes in Inflammatory Bowel Disease (IBD)

BACKGROUND: Although biological therapy has revolutionized the medical management of IBD, a crucial concern is whether patients undergoing major abdominal surgery after drug exposure are at increased risk of early postoperative complications. Studies reporting on the association of preoperative vedolizumab therapy use and postoperative outcomes in IBD have been published with conflicting results. Serum levels of anti-TNF drugs have been used as a surrogate for biologic effect on inflammatory mechanisms and have been correlated with postoperative outcomes. In a similar fashion, we sought to clarify associations between serum vedolizumab levels and postoperative outcomes in IBD patients. METHODS: IBD patients on vedolizumab, with serum drawn within 7 days before surgery, were identified from a prospectively collected IRB-approved database. Serum vedolizumab levels were measured by investigators blinded to clinical outcomes using the homogenous mobility shift assay (Prometheus Laboratories Inc.). Patients were divided into 2 groups according to serum levels: Group 1 (undetectable vedolizumab levels; ≤1.8 mcg/ml)) and Group 2 (detectable serum vedolizumab levels; >1.8 mcg/ml). To assess whether a higher level of vedolizumab affected outcomes, Group 2 was divided further into high and low levels as determined by median detectable serum level. Postoperative outcomes, including the Comprehensive Complication index (CCI)), within 30 days of surgery were collected prospectively and compared among groups. Categorical variables were analyzed using Fisher's exact test and continuous variables analyzed with Student's t-test. RESULTS: The study cohort of 35 patients had a median age of 29 (range, 14-62) years and included 18 (51%) males. Indications for surgery were Crohn's disease (n=18;51%), ulcerative colitis (n=14;40%) or indeterminate colitis (n=3;9%). Index procedures included subtotal colectomy with ileostomy (n=10;29%), small bowel/ileocolic resection (n=9; 26%) and ileal pouch-anal anastomoses (n=8;23%). Serum vedolizumab levels were detectable in 23 (66%) patients and not detectable in 12 (34%) patients. Median detectable serum vedolizumab level at the time of surgery was 12.6 mcg/ml (range, 1.9-54.4). Twelve (34%) patients had low detectable levels and 11 (31%) had high detectable levels. Groups 1 and 2 were similar in all preoperative characteristics. There were no postoperative deaths. There were no significant differences between groups in regards to overall postoperative morbidity (13% vs. 42%; P=0.09), infectious complications (4% vs. 17%; P=0.26), 30-day readmission rates after surgery (13% vs. 33%; P=0.19), or CCI (1.9 vs. 5.1; P=0.07). Finally, among patients with detectable serum vedolizumab levels, there was no association between level of vedolizumab (high vs. low) and overall postoperative morbidity (18% vs. 17%; P=1), infectious complications (0% vs. 8%; P=1), 30-day readmission rates (18% vs. 8%; P=0.59) or CCI (0.79 vs 2.9; P=0.07) after surgery. CONCLUSION(S): This first-ever study of serum vedolizumab levels in surgical patients showed that the presence and magnitude of serum drug levels do not adversely influence postoperative outcomes in IBD patients. Contrary to other studies, there appears to be no deleterious effect of preoperative vedolizumab use in IBD patients requiring surgery.

Valproic Acid-Induced Hyperammonemia with Encephalopathy (VIHE): A Case Report

Valproic acid (VPA) is a wide spectrum antiepileptic medication indicated for seizure prophylaxis across the spectrum of epilepsy. Since coming into clinical use, VPA has also been recommended for the management of a variety of other pathologies, including, most notably, mood stabilization in the manic patient. VPA’s common adverse effects include gastrointestinal, influenza-like symptoms, headache, and difficulties with sleep; nonetheless, in rare instances, VPA has been noted to cause the severe and potentially lethal condition of hyperammonemia with encephalopathy (VIHE). VIHE is the result of a dose-independent increase in ammonia levels. Often the patient is asymptomatic; if symptoms reach clinical threshold, lethargy is most common, though seizures, focal neurologic deficits and even coma are possible. VIHE can occur in patients despite normal hepatic function, normal loading doses, chronic stable doses and normal free serum drug levels. Once the diagnosis is confirmed, the first approach for symptomatic patients is to discontinue VPA, start alternative mood stabilizer as indicated, and supplement hyperammonemia treatment with lactulose, carnitine or carglumic acid. Below is a case report of VIHE that developed in an adolescent girl with a history of Bipolar I Disorder who was hospitalized in our facility for stabilization of mania. As demonstrated below, early diagnosis of VIHE is pivotal in reducing morbidity and ultimately can be life-saving.
 Keywords: Valproic acid, Hyperammonemia, Encephalopathy

P717 Comparison of two different techniques to assess vedolizumab trough levels in adult patients with IBD

Vedolizumab (VLZ), an α4β7 integrin antagonist, is a therapeutic monoclonal antibody recently approved for use in moderate-to-severe Crohn's disease (CD) and ulcerative colitis (UC). Since loss of response to VLZ in patients with inflammatory bowel disease is likely due to low drug serum levels, modifying dosage on the basis of VLZ drug concentrations may improve patient outcomes. However, there are limited data on the diagnostic accuracy and utility of currently available assays for measuring VLZ levels. In this study, our aim was to compare serum VLZ concentrations using two different techniques. Up to November 2017, we assessed serum VLZ concentrations in 63 IBD patients (30 CD/33 UC). Serum VLZ trough levels were assessed using a sandwich principle-based enzyme-linked immunosorbent assay (ELISA; Berger et al., JCC 2017;11:S320) and an ultra-performance liquid chromatography (UPLC)-MS/MS system (Thermo Scientific, Waltham, MA, USA) with an H-ESI II ionisation source. Tryptic peptides for quantification were identified for VLZ using a selective reaction monitoring (SRM) mass spectrometry method (Christ et al. JCC 2016; 10: S380). VLZ trough levels were significantly lower in patients who experienced relapse compared with patients in remission, using both ELISA: 19.7 μg/ml vs. 33.9 μg/ml in CD (p = 0.002) and 15.6 μg/ml vs. 34.2 μg/ml in UC (p = 0.005) and LC-MS/MS: 12.3 μg/ml vs. 35.1 μg/ml in CD (p = 0.003) and 16.9 μg/ml vs. 36.2 μg/ml in UC (p = 0.004). There was a significant correlation between ELISA and LC-MS/MS VLZ trough levels at both week 48 (r = 0.691, p = 0.0003) and week 96 (r = 0.822, p = 0.0001). ELISA and LC-MS/MS are accurate methods to assess VLZ trough levels in both CD and UC patients and those who experience loss of response, offering effective and reliable tools for the monitoring and modification of individual treatment schedules. The preferential use of one of the two techniques should be based on local availability and the physician’s experience.

Correlation between HLA haplotypes and the development of antidrug antibodies in a cohort of patients with rheumatic diseases.

IntroductionThe aim of this study was to investigate the correlation between human leukocyte antigen (HLA) haplotypes and the development of antidrug antibodies (ADAs) in a cohort of patients with rheumatic diseases.Patients and methodsWe evaluated the presence of ADAs in 248 patients with inflammatory rheumatic diseases after 6 months of treatment with anti-TNF drugs: 26 patients were treated with infliximab (IFX; three with rheumatoid arthritis [RA], 13 with ankylosing spondylitis [AS], 10 with psoriatic arthritis [PsA]); 83 treated with adalimumab (ADA; 24 with RA, 36 with AS, 23 with PsA); 88 treated with etanercept (ETA; 35 with RA, 27 with AS, 26 with PsA); 32 treated with certolizumab (CERT; 25 with RA, two with AS, five with PsA); and 19 treated with golimumab (GOL; three with RA, seven with AS, nine with PsA). Serum drug and ADA levels were determined using Lisa-Tracker Duo, the ADA-positive samples underwent an inhibition test, and the true-positive samples underwent genetic HLA typing. To have a homogeneous control population, we also performed genetic HLA typing of 11 ADA-negative patients.ResultsAfter inhibition test, the frequency of ADAs was 2/26 patients treated with IFX (7.69%), 4/83 treated with ADA (4.81%), 0/88 treated with ETA (0%), 4/32 treated with CERT (12.5%), and 1/19 treated with GOL (5.26%). The frequency of HLA alleles in the examined patients was HLA-DRβ-11 0.636, HLA-DQ-03 0.636, and HLA-DQ-05 0.727. The estimated relative risks between the ADA-positive patients and the ADA-negative patients were HLA-DRβ-11 2.528 (95% CI 0.336–19.036), HLA-DQ-03 1.750 (95% CI 0.289–10.581), and HLA-DQ-05 2.424 (95% CI 0.308–15.449).ConclusionThis is the first study that shows an association between HLA and genetic factors associated with the occurrence of ADAs in patients with rheumatic diseases, but the number of samples is too small to draw any definite conclusion.

Increased Susceptibility for Atrial and Ventricular Cardiac Arrhythmias in Mice Treated With a Single High Dose of Ibrutinib

Atrial fibrillation is a side effect of ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase used for treatment of B-cell lymphoproliferative disorders. We determined if single (2 or 10 mg/kg), or chronic (14 days) oral ibrutinib followed by 24-hour washout conferred susceptibility to electrically induced arrhythmias in 1-month-old male C57BL/6 mice. A single higher dose of ibrutinib increased arrhythmia inducibility. There was no inducibility difference after chronic dosing with washout. This suggests that high serum drug levels might be responsible for the proarrhythmic effect of ibrutinib and that an altered dosing strategy might mitigate the side effects.

Antibiotic pharmacokinetic and pharmacodynamic parameters in pediatric clinical practice

Progress in the knowledge of antibiotic mechanisms of action allows to determine the pharmacodynamics/pharmacokinetic (PK/PD) parameters predictive of antibiotic efficacy in bacterial infections. According to the antibiotic compound, the bacterial species implicated, the location of the infection, and the severity of the disease, these parameters may vary. The PK/PD parameters described in this paper, focus only on blood compartments. These PK/PD parameters best predict efficacy in the most frequent infections (e.g., respiratory, bacteremia, skin and soft tissue infections and intra-abdominal infections). Furthermore, they contribute to the determination of doses and number of administrations per day as well as the determination of minimum inhibitory concentration (MIC) breakpoints. The time above the MIC (T> MIC) is the main criterion for β-lactams: free drug serum levels of these drugs should be above the MIC for at least 40%-50% of the dosing interval to produce adequate clinical and microbiological efficacy. Peak/MIC ratio is the major determinant of the activity of aminoglycosides: in general, peak/MIC ratios should exceed 8-10. Area under the MIC curve (AUC/MIC) is considered for quinolones, macrolides, and vancomycin as the best predictor of efficacy.

Effects of religiosity and religious coping on medication adherence and quality of life among people with epilepsy

The epidemiologic information demonstrates the importance of caring people with epilepsy (PWE). Indeed, the impaired quality of life (QoL) and medication nonadherence rate among PWE have been reported. However, religiosity and religious coping could be potential factors for clinicians to foster appropriate intervention on epileptic care. This study investigated two models to further understand the relationships between religiosity, religious coping (including positive and negative coping), medication adherence, and QoL in an Iranian sample with epilepsy. Eligible PWE (n=760) completed the religiosity scale (Duke University Religion Index; DUREL) at baseline; the religious coping scale (Brief Religious Coping Scale; Brief RCOPE) one month later; the medication adherence scale (Medication Adherence Report Scale; MARS-5) two months later; and the QoL scale (Quality of Life in Epilepsy; QOLIE-31) twelve months later. Their antiepileptic drug serum level was measured during the period they completed the MARS. Through structural equation modeling (SEM), we found that religiosity directly correlated with negative religious coping and medication adherence, and indirectly correlated with medication adherence through negative religious coping. Both positive and negative religious coping directly correlated with medication adherence and QoL. Therefore, religiosity and religious coping may be determinants of medication adherence and QoL in PWE; health professionals may consider asking PWE if religion is important to them and how they use it to cope with their epilepsy.

Interventions Targeting the Prescribing and Monitoring of Vancomycin for Hospitalized Patients: A Systematic Review Protocol.

IntroductionVancomycin remains one of our essential antibiotics after fifty years of treating serious infections such as methicillin-resistant Staphylococcus aureus. Vancomycin, unlike many other antibiotic agents, requires individualized dosing and monitoring of serum drug levels to ensure it is efficacious, to minimize toxicity, and to limit the development of antibiotic resistance. These issues have led to numerous vancomycin clinical practice guidelines being published in recent years including several key national guidelines. Significant resources are invested during the development of such guidelines; however, there is often little or no information about how such guidelines or other vancomycin practice improvement initiatives should be implemented. The aim of this systematic review is to identify and evaluate the effect of interventions using education, guideline implementation, and dissemination of educational resources that have sought to improve therapeutic drug monitoring and dosing of vancomycin.MethodsA systematic review of the literature will be conducted for RCTs and observational studies where a vancomycin guideline or practice improvement initiative has been implemented. Electronic databases to be searched are PubMed, Medline, CINAHL, EMBASE and the Cochrane Library of Systematic Reviews. The population will be patients who have had intravenous vancomycin prescribed and monitored in hospital. The interventions will be education, implementation of guidelines or protocols, dissemination of educational materials (printed or electronic) or multifaceted interventions of the above. The comparator will be patients who have had standard-care prescribing and monitoring of vancomycin. Outcomes will be changes in prescribing and ordering of vancomycin serum tests, and serum levels attained in patients as well as reported nephrotoxicity. Two reviewers will be involved in the quality assessment and extraction of data. The Scottish Intercollegiate Guidelines Network checklist for RCTs will be used. Studies that are not randomized will be assessed for quality using the validated ROBINS-I (risk of bias in non-randomized studies of interventions) tool.DiscussionThis systematic review will identify interventions that have been used to implement guidelines and clinical practice initiatives for vancomycin. The findings of this review may be informative to those involved with the implementation of vancomycin clinical practice guidelines. Systematic review registration: PROSPERO: CRD42016049147.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-017-0177-7) contains supplementary material, which is available to authorized users.

Correlation Between Serum Level of Antiepileptic Drugs and their side-effects

Phenytoin can cause a range of dose-related and idiosyncheratic adverse effects.

Infliximab Assay Used in Clinical Practice Validated for Measuring SB2 Infliximab Biosimilarʼs Serum Drug and Anti-drug Antibody Levels

Introduction: Study aimed to validate suitability of assays from THERADIAG (available in US via Miraca Life Sciences as InformTXTM, promoted as LISA-TRACKER (LT) outside of US) for monitoring of patients treated with Infliximab (IFX) biosimilar developed by Samsung Bioepis (SB2). LT has been developed to quantify IFX and Anti-IFX antibodies (Ab) in human serum/plasma for monitoring of patients treated with originator IFX (Remicade®). Methods: For IFX quantification, recombinant human TNFa on solid phase was used to catch IFX, and biotinylated anti-human-IgG for the detection step. For Anti-IFX quantification, IFX was coated on solid phase, and biotinylated IFX was used for the detection step. For both assays, conjugate and substrate were used before the reading of optical density (OD). Level of IFX or Anti-IFX was proportional to OD. 2 batches of SB2 were assessed. 3 human serum matrix were used to prepare spiked samples. 58clinical samples were collected from US patients treated with originator IFX. Inhibition assays were performed in using polyclonal Ab. Results:IFX ASSAY:SB2 spiked samples gave % of recovery between 81% and 105%. Coefficients of variation ranged from 2.2% to 10.3% for intra-run and from 4.4% to 12.7% for inter-run precision assay. Clinical samples with detectable levels of IFX spiked with SB2 or originator IFX gave similar results. IFX assay gave consistent results even if SB2 is quantified after storage of samples during 7 days at +2°C+8°C, or 3 days at room temperature, or after 5 freeze/thaw cycles. ANTI-IFX ASSAY:All clinical samples with a detectable level of Anti-IFX Ab were inhibited when originator IFX or SB2 were added to the samples. SB2 has the capacity to block detection of Anti-IFX Ab when added to detection reagent. Very good correlation was obtained when originator IFX or SB2 were used for reagents production: R2>0.97; 0.91 Conclusion: LT IFX assay gave high precision and accuracy for quantification of SB2. Behavior of SB2 and originator IFX in tested LT assays is similar. Results indicate that Anti-IFX Ab induced by SB2 should be detected with LT Anti-IFX assay. InformTXTM, or LT, are suitable for monitoring of patients treated with SB2. Study demonstrated that the assay can be used interchangeably for monitoring drug level and Anti-IFX for originator IFX and SB2.

Retrospective analysis of goal drug level attainment of posaconazole for invasive fungal infection prophylaxis in patients with acute myeloid leukemia pre- and post-switch to tablet formulation.

Posaconazole is approved for invasive fungal infection prophylaxis in patients with hematologic malignancies. Posaconazole suspension is plagued by poor oral absorption and dietary requirements that are difficult for patients to meet. The delayed-release tablet formulation of posaconazole may be taken without regards to meals and has significantly better oral absorption than posaconazole suspension. We sought to determine if a switch to posaconazole tablets improved steady-state drug level attainment for invasive fungal infection prophylaxis in patients with acute myeloid leukemia. All adult inpatients with acute myeloid leukemia undergoing chemotherapy, who received posaconazole for invasive fungal infection prophylaxis between 2012 and 2015, were included. The primary outcome was proportion of patients with first posaconazole level greater than 700 ng/mL. Secondary outcomes included proportion of patients with first posaconazole level greater than 1000 ng/mL, invasive fungal infection within 100 days, and adverse drug events. Forty patients received posaconazole tablets and 34 patients received suspension. Posaconazole levels were significantly higher at first measurement in patients receiving tablet than suspension (1296 ng/mL vs. 788 ng/mL, p < 0.01). Thirty-seven patients receiving tablets had a serum drug level greater than 700 ng/mL on first measurement versus 18 receiving suspension (p < 0.01). Patients receiving tablets were also more likely to have a serum drug level over 1000 ng/mL on first measurement (26 vs. 11, p < 0.01). Rates of invasive fungal infection and adverse events were not statistically different. Patients receiving posaconazole tablets attained significantly higher serum drug levels than those receiving suspension.

Correlation between trough serum levels of adalimumab and absolute PASI score in a series of patients with psoriasis

Background: The possibility of monitoring serum drug levels has opened the door to optimising biologic therapy. To consolidate this advance, it is imperative to demonstrate an adequate correlation between serum drug levels and clinical course.Objectives: To investigate whether a correlation exists between adalimumab levels and clinical response measured as absolute PASI.Methods: In a prospective cohort study, we enrolled 51 patients with psoriasis treated with adalimumab for at least 16 s. Patients received approved doses of adalimumab, but after 52 s the dosing interval could be modified according to clinical criteria. Excellent response was defined as PASI ≤3, appropriate response as PASI >3 and ≤5 and inappropriate response as PASI> 5. Correlations were calculated using Spearman’s correlation test.Results: A total of 92 serum samples from 51 patients were analysed. Significant differences were found in serum trough levels between patients achieving an excellent response (6.46 μg/mL), versus an appropriate (2.5 μg/mL) and an inappropriate response (2 μg/mL). The therapeutic range for adalimumab serum levels was from 3.30 to 7.30 μg/mL.Conclusions: We found an adequate correlation between drug serum levels and PASI scores. Monitoring of absolute PASI and serum levels can provide a personalised and cost-effective evaluation.

Predictive Value of Serum Infliximab Levels at Induction Phase in Rheumatoid Arthritis Patients.

Background:The Infliximab, has proven effective in treating rheumatoid arthritis (RA). A good clinical response is usually associated with high serum drug levels. Development of antibodies toward Infliximab (ATI) can increase drug clearance, leading to treatment failure.Aims:To analyze whether serum Infliximab trough levels (ITL) at the induction phase are associated with Infliximab clearance and clinical outcomes at week(W) 54 and to investigate the association with immunogenicity development.Methods:Observational retrospective study in which ITL from 66 RA patients were measured by capture ELISA at W0, W2, W6, W14 and 22. Patients were classified as ITLpos if Infliximab was detectable at W54 and ITLneg otherwise. ATI were assayed by bridging ELISA and by two drug-tolerant assays. ITL cut-off values were established by ROC curves. The association between ITL at early-stage and clearance of Infliximab at W54 was analyzed by univariable and multivariable logistic regression.Results:ITLneg patients (n=25) always had significantly lower Infliximab levels than ITLpos (n=41). An ITL value of 4.4 μg/mL at W6 best predicted W54 Infliximab absence. In the multivariable analysis, only ITL below the cut-off at W6 (OR: 86.6; 95%CI: 6.58-1139.99) and non-use of methotrexate (OR: 6.9; 95%CI: 1.04-45.84) remained significantly associated with W54 Infliximab absence. ATI were more frequent in patients with ITL below the cut-off at W6.Conclusions:In RA, ITL at induction phase are inversely associated with Infliximab clearance and clinical outcomes at W54. ATI was the main reason for low early ITL. A predictive value of ITL at W6 was found as a useful prognostic measure of treatment efficacy.

Importance of TDM During Pregnancy and Breastfeeding

Therapeutic drug monitoring (TDM) is specific method of clinical pharmacology for monitoring of the therapy using measurement of drugs serum concentrations followed by interpretation and good cooperation with clinicians. Almost every pregnant woman is exposed to some type of medication during pregnancy. It was found a significant correlation between teratogenic effects and maternal or umbilical cord concentrations of some drugs, but not dose. For this reason, TDM in mother during pregnancy is more valuable than the given dose for estimating and possibly obviating the teratogenic risk of these drugs on the fetus. However, the data relating to the transplacental passage for most of drugs remain sparse. It was reported that analytical models should also take into account not only type and dose, but also levels of drugs in the mother and the neonate at birth as a closer surrogate marker for fetal exposure. Measuring the umbilical cord/maternal serum drug level ratio at birth is the method recommended to assess transplacental transfer. The decline in plasma concentrations during pregnancy was also observed with a considerable interindividual variability in the effect of pregnancy on kinetics of some drugs. Therefore, frequent TDM during pregnancy and after delivery is necessary to optimize treatment in women taking these drugs in the period of instable kinetics. The data on the transfer of drugs to the milk and the risk of exposure to the breastfed infants remain also sparse and only a limited number of studies have actually measured the infant blood levels. It was reported that the monitoring of breastfed infant’s concentrations appears to be the most relevant method for analysis of drugs exposure in breastfed infants (especially in those with some clinical problems such as sedation, poor suckling, and life-threatening rashes), overriding any other calculation.

Importance of TDM During Pregnancy and Breastfeeding

Therapeutic drug monitoring (TDM) is specific method of clinical pharmacology for monitoring of the therapy using measurement of drugs serum concentrations followed by interpretation and good cooperation with clinicians. Almost every pregnant woman is exposed to some type of medication during pregnancy. It was found a significant correlation between teratogenic effects and maternal or umbilical cord concentrations of some drugs, but not dose. For this reason, TDM in mother during pregnancy is more valuable than the given dose for estimating and possibly obviating the teratogenic risk of these drugs on the fetus. However, the data relating to the transplacental passage for most of drugs remain sparse. It was reported that analytical models should also take into account not only type and dose, but also levels of drugs in the mother and the neonate at birth as a closer surrogate marker for fetal exposure. Measuring the umbilical cord/maternal serum drug level ratio at birth is the method recommended to assess transplacental transfer. The decline in plasma concentrations during pregnancy was also observed with a considerable interindividual variability in the effect of pregnancy on kinetics of some drugs. Therefore, frequent TDM during pregnancy and after delivery is necessary to optimize treatment in women taking these drugs in the period of instable kinetics. The data on the transfer of drugs to the milk and the risk of exposure to the breastfed infants remain also sparse and only a limited number of studies have actually measured the infant blood levels. It was reported that the monitoring of breastfed infant’s concentrations appears to be the most relevant method for analysis of drugs exposure in breastfed infants (especially in those with some clinical problems such as sedation, poor suckling, and life-threatening rashes), overriding any other calculation.

Metformin to treat prostate cancer (PCa) and prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Results of a randomized double-blind placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced PCa.

e16502 Background: ADT results in metabolic syndrome, characterized by hyperinsulinemia, insulin resistance and obesity. The hyperinsulinemia may result in ADT resistance; therefore preventing metabolic syndrome could have a therapeutic impact on PCa. In diabetes, metformin (MET) decreases glucose &amp; insulin by inhibiting hepatic gluconeogenesis. There is preclinical evidence for additional antineoplastic activity due to mTOR inhibition secondary to AMPK activation. Methods: Men with biochemical relapse or advanced PCa due to receive ADT were randomized 1:1 in a double blind manner to MET (500mg TID) or placebo (P). Subjects required normal oral glucose tolerance test at baseline, with fasting serum insulin/glucose, PSA, MET, weight and waist circumference (WC) monitored at baseline, week 12 and 28. The primary endpoint of study was the metabolic consequences of MET vs P. Secondary endpoints were PSA response and PBMC analysis of downstream target of mTOR, phospho-S6 kinase. Results: 36 men were randomized to MET or P, mean age 68.4; biochemical failure (n = 15) &amp; metastatic disease (n = 21). Mean weight, WC and insulin at baseline in MET cohort was 187 lbs, 41.14 cm and 10.03 mIU/L respectively, and 177.65 lbs, 40.52 cm and 8.02 mIU/L in P cohort. An increase in mean weight, WC and insulin levels was seen in both cohorts. At wk 12 and 28, no statistical difference in weight, WC and insulin was observe in either cohort. 4 men randomized to MET had undetectable serum drug levels despite drug-diary suggesting compliance; excluding them did not result in significant metabolic change. Assessing efficacy, 50% in MET and 53.3% in P cohort achieved undetectable PSA at wk 28; difference not statistically significant. PBMC analysis demonstrated variable down-regulation of phospho-S6 kinase in the metformin cohort. Conclusions: This study detected no impact of MET addition to ADT on the risk of metabolic syndrome and no additional anti-tumor effects. Control of hyperinsulinemia related to diabetes by MET does not necessarily imply MET has a similar action on hyperinsulinemia due to ADT. Clinical trial information: NCT02620423.

Anti-TNFα Treatment After Surgical Resection for Crohnʼs Disease Is Effective Despite Previous Pharmacodynamic Failure

The outcome of patients with Crohn's disease who failed anti-tumor necrosis factor alpha (anti-TNFα) therapy despite adequate serum drug levels (pharmacodynamic failure) is unclear. We aimed to assess such pediatric patients who underwent intestinal resection and were re-treated with the same anti-TNFα agent postoperatively. Pediatric patients with Crohn's disease who underwent intestinal resection and were treated with anti-TNFα agents postoperatively were assessed retrospectively. Patients were stratified to those with preoperative anti-TNFα pharmacodynamic failure and those with no preoperative anti-TNFα treatment. A total of 53 children were included, 18 with pharmacodynamic failure and 35 controls. Median age at intestinal resection was 14.8 years with 23 (43%) girls. The median time from intestinal resection to anti-TNFα initiation was 8 months (interquartile range 4-14 months). At the time of postoperative anti-TNFα initiation there were no differences in clinical, laboratory, and anthropometric measures between groups. Similar proportions of patients from both groups were in clinical remission on anti-TNFα treatment after 12 months and at the end of follow-up (1.8 years, interquartile range, 1-2.9 years): 89% versus 88.5% and 83% versus 80% for pharmacodynamic failure patients and controls, respectively; P = 0.9. No significant differences were observed at 14 weeks and 12 months of postoperative anti-TNFα treatment including endoscopic remission rate and fecal calprotectin. Both groups significantly improved all measures during postoperative anti-TNFα treatment. Pediatric patients with Crohn's disease who failed anti-TNFα therapy despite adequate drug levels and underwent intestinal resection can be re-treated with the same agent for postoperative recurrence with high success rate similar to that of anti-TNFα naive patients.

Thermosensitive Gel–Based Formulation for Intratumoral Delivery of Toll-Like Receptor 7/8 Dual Agonist, MEDI9197

Toll-like receptor (TLR) agonists TLR 7/8, MEDI9197, is a imidazoquinoline analogue that can be used for cancer immunotherapy based on its efficacy toward a variety of tumors. Systemic administration of TLR agonists results in stimulation of the immune system throughout the entire body causing undesirable side effects. To minimize these adverse events, local administration of TLR agonists including intratumoral (IT) delivery has been introduced. Here, a poloxamer 407 thermogel formulation for IT delivery of a TLR 7/8 dual agonist, MEDI9197, is described in which the combination of the aqueous thermogel and the ethanolic TLR 7/8 dual agonist, MEDI9197, solution leads to precipitated drug particles within the gel. The in vitro release profile showed an initial burst followed by sustained release. A B16-OVA mouse tumor model was used to assess the in vivo pharmacokinetics, efficacy, and systemic cytokine and chemokine (cytokine) production of the poloxamer 407–based thermogel formulation. The pharmacokinetic evaluation showed that the agonist level within the tumor was reduced by ∼70% over 14 days while serum agonist levels indicated an initial burst at the 6-h time point followed by a drop in serum drug levels over the 14 days of the experiment. The tumor growth inhibition, survival, and serum cytokines for post-IT injection of the poloxamer 407 formulation showed that it slowly released TLR 7/8 agonist, MEDI9197, resulting in more efficacious tumor growth inhibition compared with control groups. In addition, the cytokine levels in circulation indicated that a dose increase led to a decrease in the serum inflammatory and interferon-inducible cytokines levels. This observation could be due to a reduction of drug diffusion and escape from the tumor site due to the precipitation of the drug inside the tumor leading to sustained release. IT delivery of TLR 7/8 dual agonist, MEDI9197, via a thermosensitive gel–based formulation was efficacious and could offer an alternate method of local drug delivery.

Prediction of successful dose reduction or discontinuation of adalimumab, etanercept, or infliximab in rheumatoid arthritis patients using serum drug levels and antidrug antibody measurement

ABSTRACTBackground: To evaluate if TNF inhibitor serum drug levels (DL) or anti-drug antibodies (ADAb) can predict successful dose reduction (in patients with high DL) or discontinuation (in patients with no/low DL or ADAb) in rheumatoid arthritis (RA) patients.Research design and methods: RA patients that were using adalimumab (n = 42), etanercept (n = 76) or infliximab (n = 51) and were doing well, were tapered until discontinuation or flare (1–1.5 year follow up). Random timed DL for adalimumab and etanercept and trough DL for infliximab were measured before dose reduction: Receiver-Operator-Curves (ROC) analyses with optimal cut-off DL were determined.Results: No predictive value of adalimumab and infliximab DL for all outcomes were found, except for an inverse association of lower etanercept DL and higher chance for successful dose reduction (Area Under the Curve (AUC) 0.36, 95% CI 0.23–0.49; cut-off <2.6 mg/l). In sub analyses, higher adalimumab trough DL predicted successful dose reduction (AUC 0.86, 0.58–1.00; cut-off >7.8). ADAb were infrequent and not predictive of successful discontinuation.Conclusions: No predictive value of baseline adalimumab, etanercept and infliximab DL or ADAb for successful dose reduction or discontinuation in RA was found in this context, with the possible exception of high adalimumab trough levels for successful dose reduction.

AZ1366: An Inhibitor of Tankyrase and the Canonical Wnt Pathway that Limits the Persistence of Non-Small Cell Lung Cancer Cells Following EGFR Inhibition.

Purpose: The emergence of EGFR inhibitors such as gefitinib, erlotinib, and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors.Experimental Design: We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its antitumor activity, impingement on canonical Wnt signaling, and effects on gene expression. We performed pharmacokinetic and pharmacodynamic profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model.Results: In combination with EGFR inhibitors, AZ1366 synergistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. Pharmacokinetic and pharmacodynamic profiling of AZ1366-treated orthotopic tumors demonstrated clinically relevant serum drug levels and intratumoral target inhibition. Finally, coadministration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model.Conclusions: Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a cotreatment strategy with EGFR inhibition in an identifiable subset of EGFR-driven NSCLC. Clin Cancer Res; 23(6); 1531-41. ©2016 AACR.