scholarly journals P590 Which biomarkers have an effect on therapeutic vedolizumab drug levels? A retrospective analysis from a London Tertiary Centre

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S540-S540
Author(s):  
A Bancil ◽  
M Stevens ◽  
K Kok
Keyword(s):  
Drug Level ◽  
Albumin Level ◽  
Therapeutic Drug ◽  
Faecal Calprotectin ◽  
Drug Levels ◽  
Reactive Protein ◽  
Tertiary Centre ◽  
Trough Serum ◽  
Factor Α ◽  
Serum Crp

Abstract Background Vedolizumab is a humanised monoclonal antibody that binds to the α 4β 7 integrin and is an established treatment for both Crohn’s Disease (CD) and Ulcerative Colitis (UC). Drug levels for anti-tumour necrosis factor-α inhibitors such as infliximab and adalimumab have been used routinely for therapeutic drug monitoring (TDM). Target therapeutic levels for vedolizumab are yet to be established. Correlations with vedolizumab levels have been found in prospective and retrospective studies with a number of biomarkers such as C-Reactive Protein (CRP), albumin and Body Mass Index (BMI). However, these have failed to replicate consistently among studies of vedolizumab drug levels. Methods Trough serum vedolizumab drug levels were taken for 81 patients through a period of 3 months. These were analysed using a drug tolerant assay (IDKMonitor Drug level ELISA and IDKMonitor vedolizumab Free anti-drug antibody ELISA) run on a Dynex DS2 ELISA processor. These were collected from 33 CD patients, 46 UC patients and 2 patients with unclassified Inflammatory Bowel Disease (IBD-U). Faecal calprotectin (FCP) was collected in a subset of patients. Serum CRP, albumin, and haemoglobin (Hb) levels were also taken alongside levels. BMI was recorded at our infusion unit before receiving the infusion. Results 81 patients had drug levels taken: CD patients (mean drug level Q8w - 7.8 mcg/ml, Q4w - 18.6 mcg/ml, 9 patients with concomitant immunomodulators (CIM)), UC patients (mean drug level Q8w - 9.4 mcg/ml, Q4w – 22.0 mcg/ml, 5 patients with CIM), IBD-U (mean drug level Q8w - 15.2 mcg/ml, no patients with CIM). One patient developed anti-drug antibodies. Correlation was analysed using simple linear regression. A positive correlation was found with vedolizumab levels and albumin (correlation coefficient (r) = 0.11; p=0.03) but not with CRP (p=0.49), Hb (p=0.56), BMI (p=0.33) or FCP (p=0.08). Conclusion Our results indicate that albumin positively correlates with a higher vedolizumab drug level, which suggests that drug levels will be lower and perhaps less effective in patients with a low albumin level. Further studies should look at larger numbers of patients to identify whether the correlations identified with other biomarkers are significant and identify therapeutic target levels for vedolizumab. These will help guide TDM for patients and inform clinicians of when to switch as well as recognising likely non-responders and thus provide a personalised approach to biologic choice.

scholarly journals P414 Risk factors for the development of anti-drug antibodies to infliximab and adalimumab in Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S378-S379
Author(s):  
E Khoo ◽  
A Lord ◽  
K Hanigan ◽  
A Croft ◽  
G Radford-Smith
Keyword(s):  
Risk Factors ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Lower Risk ◽  
Smoking Status ◽  
Drug Level ◽  
Enzyme Linked Immunosorbent Assay ◽  
Therapeutic Drug ◽  
Drug Levels ◽  
Low Serum

Abstract Background Anti-tumor necrosis factor-α (anti-TNFa) therapy have been established as an effective maintenance treatment for complicated Crohn’s Disease (CD). However, the efficacy of Infliximab (IFX) and Adalimumab (ADM) may be affected by low serum levels and/or the presence of anti-drug antibodies (ADA). This reinforces the importance of therapeutic drug monitoring (TDM). We aim to assess the clinical benefit of proactive vs. reactive TDM. Secondly, to assess the impact of TDM on clinical management. Thirdly, to identify risk factors for low serum drug levels and the development of ADA in CD patients. Methods This was a single-centred observational cohort study performed at a tertiary hospital, comprising of total 229 CD patients: 142 received IFX and 87 received ADM, who have had a trough drug level, tested using enzyme-linked immunosorbent assay. Demographic and clinical data were retrospectively collected from electronic medical records. Fisher’s Exact Test was used to determine if there are nonrandom associations between variables. A p-value of less than 0.05 was considered statistically significant. Results One hundred and fourteen patients (49%) receiving a standard anti-TNFa regimen had subtherapeutic drug levels (67 had IFX < 3 μg/ml and 47 had ADM < 5 μg/ml). Interestingly, almost half of this cohort were asymptomatic. Reactive TDM completed among symptomatic patients have shown to have a statistically significant benefit in detecting subtherapeutic drug level (p = 0.0001). Following these results, only fifty-two patients (46%) had a change of therapy (29 IFX, 25 ADM); while the remaining sixty-two patients (54%) continued the same dosing regimen with only one documented admission within 90-days following the drug level being taken. Eight patients (4%) were found to have positive ADA, all in the presence of subtherapeutic drug levels. Two of these had a subsequent flare of their disease. They were all switched to another class of biologic therapy. Non-smoking status at diagnosis and the concomitant use of immunomodulator were found to have statistically significant associations with a therapeutic drug level (p = 0.0176 and p = 0.0001, respectively). Similarly, both of these risk factors were associated with lower risk of ADA formation (p = 0.0057 and p = 0.0165, respectively). Conclusion This study suggests that a large proportion of patients have subtherapeutic drug levels at standard dosing schedules. However, low drug levels do not correlate with a higher risk of complications if patients are in clinical remission. The results of this study also indicate that non-smoking status at diagnosis and the concomitant use of immunomodulator are associated with higher serum drug levels and lower risk of developing anti-drug antibodies.

scholarly journals A101 USTEKINUMAB LEVELS MEASURED DURING INDUCTION ARE ASSOCIATED WITH CLINICAL AND BIOCHEMICAL OUTCOMES AT WEEK 12 OF TREATMENT IN CROHN’S DISEASE

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 117-118
Author(s):  
M Walshe ◽  
K Borowski ◽  
K Boland ◽  
S Rho ◽  
J Stempak ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Negative Correlation ◽  
Pearson Correlation ◽  
Significant Negative Correlation ◽  
Therapeutic Drug ◽  
Tertiary Referral Centre ◽  
Faecal Calprotectin ◽  
Drug Levels ◽  
Induction Dose

Abstract Background Therapeutic drug monitoring (TDM) helps guide use of anti-TNF drugs in IBD patients. In addition, higher anti-TNF levels during induction therapy have been shown to be associated with better clinical and endoscopic outcomes. The role of TDM for more novel biologics such as ustekinumab (an anti- IL-12/23 antibody used to treat Crohn’s disease) remains to be elucidated. Aims We set out to investigate correlations between ustekinumab drug levels measured during induction with clinical and biochemical outcomes in patients with Crohn’s disease. Methods Patients with Crohn’s disease commencing treatment with ustekinumab were recruited from a single tertiary referral centre. Standard weight-based induction dosing was used. TDM was performed at week 2 and week 6 following IV induction dose. A drug-tolerant assay (Prometheus) was used. Kruskal-Wallis test was used to examine association between induction dose and ustekinumab levels. CDAI, CRP, and faecal calprotectin (FCP) were measured at week 12. Pearson correlation co-efficient was used to assess the relationship between ustekinumab levels and i)CDAI ii)CRP and iii)FCP at week 12. Results A total of 38 ustekinumab levels in 21 patients were measured. Week 2 ustekinumab levels were available for 17 patients, 16 (94.1%) of whom had levels of greater or equal to 25μg/mL. (1 patient had a level of 19.5μg/mL.) Week 6 ustekinumab levels were available for 21 patients; median 15μg/mL (IQR 9.9–21.3). No patients had detectable antibodies to ustekinumab. There was no significant association between absolute induction dose and week 6 ustekinumab levels; p=0.46. Of the 21 patients with week 6 levels, CDAI, CRP and FCP were available for 18, 18 and 16 patients respectively; Median CDAI 103(IQR 42–249), median CRP 2.3mg/L(IQR 1.0–11.3), median FCP 269μg/g(IQR109-932). There was a significant negative correlation between week 6 ustekinumab levels and CDAI; r=-.609, p=0.007. A negative correlation between week 6 ustekinumab levels and FCP was also significant; r=-.526, p=0.037. There was no significant correlation between week 6 ustekinumab levels and CRP; r=-.259, p=0.298. Conclusions We have demonstrated inter-patient variation in drug pharmacokinetics at week 6 following induction dose of ustekinumab in patients with Crohn’s disease. Drug levels at week 6 are significantly associated with clinical and biochemical markers of disease activity (CDAI, faecal calprotectin) at week 12. Measurement of week 6 ustekinumab levels may aid early identification of patients at risk of primary non-response to ustekinumab. Funding Agencies Testing provided by Prometheus

scholarly journals P582 Adalimumab therapeutic drug monitoring: Does time of testing matter?

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S488-S488
Author(s):  
S Shields ◽  
J P Seenan ◽  
A Dunlop ◽  
P Galloway ◽  
J Macdonald
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Drug Level ◽  
Drug Dose ◽  
Therapeutic Drug ◽  
Drug Levels ◽  
Clinical Scenarios ◽  
Serum Drug Level ◽  
Inflammatory Bowel ◽  
Fourth Quartile

Abstract Background Whilst anti-TNF drugs such as adalimumab (ADL) have revolutionised the management of inflammatory bowel disease treatment outcomes are not universally favourable with 30% primary non-response (PNR) and 46% secondary loss of response (SLOR) rates reported.1,2 Therapeutic drug monitoring (TDM)—the measurement of serum drug levels and anti-drug antibodies—has become popular with clinicians who use it to optimise biologic therapy through serum drug-level guided dose adjustment. Conventionally TDM is based on the interpretation of trough drug levels (DL) which are obtained by drawing a blood sample immediately prior to the next drug dose. Obtaining an ADL trough DL can be challenging as the drug is administered as a subcutaneous injection usually in the patient’s own home. The aim of this project was to determine the current use of non-trough ADL TDM in clinical practice and determine whether timing of ADL TDM in relation to the next planned dose is clinically important. Methods All ADL DLs performed in 2018 in the Scottish Biologic TDM service3 were identified. DLs were included for patients in sustained clinical remission (SCR), on 40mg every other week dosing, and if the time from the last dose was ≤14 days. TDM performed during induction and for PNR or SLOR were excluded, as were patients on nonstandard dosing or with missing data on dose and interval. Results were analysed by quartile according to time from the last drug dose. Results 338 DLs were included. Median DL is 8µg/ml (range <0.4–36). Median time from last dose is 12 (range 0–14) days. The first quartile (n = 83, median 5 (range 0–7) days) had a median DL of 8.2µg/ml (<0.4–28.1). The second quartile (n = 90, median 11 (8–12) days) had a median DL of 7.9µg/ml (<0.4–36). The third quartile (n = 80, 13 days from last dose) had a median DL of 8µg/ml (<0.4 – 28.1). fourth quartile samples (n = 85, 14 days from last dose – true trough DLs) had a median DL of 8 µg/ml (<0.4–34.8). No relationship was identified between observed DL and the time of DL testing (ρ= -0.3162, p = 0.23). Conclusion It is not necessary to use trough DLs when performing ADL TDM for individuals in SCR. These data should give clinicians the confidence to use opportunistic ADL TDM testing in a clinical setting. Further work should be undertaken on non-trough testing of ADL DLs in other clinical scenarios. Disclosure Biogen GmbH contributed funding for this research. Authors had full editorial control and approval of all content. References

scholarly journals Comparison of Adalimumab Serum Drug Levels When Delivered by Pen Versus Syringe in Patients With Inflammatory Bowel Disease. An International, Multicentre Cohort Analysis

2019 ◽  
Vol 13 (12) ◽  
pp. 1527-1536
Author(s):  
Robert D Little ◽  
Isabel E Chu ◽  
Esmerij P van der Zanden ◽  
Emma Flanagan ◽  
Sally J Bell ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Cohort Analysis ◽  
Drug Level ◽  
Delivery Device ◽  
Faecal Calprotectin ◽  
Drug Levels ◽  
Significant Difference ◽  
The Impact

Abstract Background Adalimumab is administered via a pre-filled syringe or spring-loaded pen. In a previous study in Crohn’s disease, higher drug levels were observed in syringe users. The aim of this study was to evaluate the impact of delivery device on adalimumab drug levels in patients with Crohn’s disease. Methods Consecutive Crohn’s disease patients treated with maintenance adalimumab [40 mg fortnightly] were recruited from five centres. The first recorded drug level with matched clinical and biochemical markers of disease activity was compared between pen and syringe users. Results Of 218 patients, 64% used pen, with a median faecal calprotectin 110 μg/g and serum C-reactive protein 4 mg/L. In comparison to pen, syringe users had higher albumin [39 vs 42 g/L; p = 0.016], lower Harvey-Bradshaw Index [2 vs 1; p = 0.017], and higher rates of concomitant immunomodulation [54% vs 71%; p = 0.014]. Drug levels were equivalent between pen and syringe users [median 5.3 vs 5.2 μg/ml; p = 0.584], even after controlling for disease activity and immunomodulation. Syringe users at Alfred Health had higher drug levels than pen [6.1 vs 4.5 μg/ml; p = 0.039]; a greater proportion achieved therapeutic levels [75% vs 44%; p = 0.045]. A higher proportion of pen users from Saint-Étienne had therapeutic levels [79% vs 42%; p = 0.027], yet no significant difference in drug levels [7.9 vs 4.5 μg/ml; p = 0.119]. Conclusions Delivery device does not appear to significantly affect adalimumab drug levels. Given differences between study sites, studies evaluating administration education and technique are warranted.

scholarly journals Therapeutic drug monitoring in epilepsy clinic: a multi-disciplinary approach

2014 ◽  
Vol 6 (4) ◽  
Author(s):  
Sunee Lertsinudom ◽  
Aporanee Chaiyakum ◽  
Supinya Tuntapakul ◽  
Kittisak Sawanyawisuth ◽  
Siriporn Tiamkao ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Public Health Problem ◽  
Clinical Information ◽  
Drug Level ◽  
Therapeutic Drug ◽  
Therapeutic Level ◽  
Drug Levels ◽  
Drug Level Monitoring ◽  
Level Monitoring

Epilepsy is a common public health problem and needs multi-disciplinary treatment. Therapeutic drug monitoring (TDM) is one of step of the multi-disciplinary treatment in epilepsy at Epilepsy clinic, Khon Kaen University (Thailand). The TDM service has been established since 2008. Here, we aimed to study the roles of TDM order and epilepsy control. This is a prospective descriptive study in which data collection was done from January 1 to December 31, 2010, the period when pharmacists took part in assessing the appropriateness in measurement and interpretation of TDM in order to provide suggestions for physicians. The 112 patients under study had an average age of 38.21±15.36 years; 254 samples were collected for therapeutic drug monitoring; phenytoin was submitted mostly for drug monitoring at 46.46%; 44.49% of sub-missions for drug level monitoring were made owing to a suspected sub-therapeutic level. Associations were found between reasons of sending samples for drug level monitoring and the measured drug levels, <em>i.e.</em>, 66.67% of drug levels found was so low that they were undetectable in sample for patients’ compliance investigation and 38.94% of the drug levels were found to be sub-therapeutic as for the case where submission of samples was done because of suspected sub-therapeutic level, 40% of the cases were found to be in toxicity range in the cases with suspected over-therapeutic levels and monitoring levels, 58.25% were found to be within the therapeutic range. Pharmacists used the interpreted results in patients’ care by recommending physicians to monitor therapeutic drug closely, to adjust the dosage of drugs, and to recommend checking patients’ compliance in their use of drugs at 56.5, 38.9, and 4.3%, respectively. Physicians’ responses were found to be absolute follow, partial follow and not follow at 77.95, 11.03, and 7.48%, respectively. In conclusion, associations were found between reasons of TDM order and measured drug level. Therapeutic drug monitoring services at the Epilepsy Clinic was useful in supporting clinical information queries. Pharmacists could make use of interpreted drug level information by recommending physicians to monitor drug levels and adjust individual dosage regimen accordingly. It should be noted that physicians accepted pharmacists’ recommendation, denoting multi-disciplinary care team that would lead to greater efficiency.

scholarly journals Therapeutic Drug Monitoring in Rheumatic Diseases

2016 ◽  
Vol 16 (2) ◽  
pp. 33-37
Author(s):  
Alexandra NG Hoi-Yan ◽  
Chi Chiu Mok
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Tumor Necrosis ◽  
Drug Efficacy ◽  
Drug Level ◽  
Therapeutic Drug ◽  
Drug Levels ◽  
Underlying Diseases ◽  
Individual Pharmacokinetics ◽  
Necrosis Factor

Abstract The ultimate goal of treating rheumatic disease is to achieve rapid suppression of inflammation, while at the same time minimizing the toxicities from rheumatic drugs. Different patients have different individual pharmacokinetics that can affect the drug level. Moreover, different factors, such as renal function, age or even different underlying diseases, can affect the drug level. Therefore, giving the same dosage of drugs to different patients may result in different drug levels. This article will review the usefulness of therapeutic drug monitoring in maximizing drug efficacy, while reducing the risk of toxicities in Hydroxychloroquine, Mycophenolate Mofetil, Tacrolimus and Tumor Necrosis Factor inhibitors (TNF Inhibitors).

scholarly journals Biomarker Value in the Diagnosis of Community-Acquired Pneumonia with Concomitant Chronic Heart Failure

2021 ◽  
Vol 10 (19) ◽  
pp. 4570
Author(s):  
Svetlana Rachina ◽  
Andrey Bobylev ◽  
Pavel Lazarev ◽  
Vladimir Mladov ◽  
Florence Carrouel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Roc Curves ◽  
Community Acquired Pneumonia ◽  
Control Group ◽  
Reactive Protein ◽  
Factor Α ◽  
Serum Crp ◽  
Necrosis Factor ◽  
Control Study

The diagnosis of community-acquired pneumonia (CAP) with chronic heart failure (CHF) is associated with objective difficulties. Our case–control study aims to establish whether established serum inflammatory biomarkers are relevant to the diagnosis of CAP in patients with CHF. Seventy inpatients with previously diagnosed CHF and suspected non-severe CAP were recruited and then stratified into two subgroups with confirmed and rejected diagnosis of CAP. C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and brain natriuretic peptide (BNP) were measured. The value of biomarkers was determined using logistic regression, and their discriminatory efficacy was assessed by analyzing receiver operating characteristic (ROC) curves. Significantly higher levels of CRP 50.0 (35.5–98.5) mg/L, PCT 0.10 (0.05–0.54) ng/mL and IL-6 46.1(21.4–150.3) pg/mL in cases were identified as compared to the control group—15.0 (9.5–25.0) mg/L, 0.05 (0.05–0.05) ng/mL and 13.6 (9.5; 25.0) pg/mL, respectively. The Area Under the ROC Curve (95% CI) was the highest for CRP—0.91 (0.83–0.98), followed by PCT—0.81 (0.72–0.90) and IL-6—0.81 (0.71–0.91). A CRP value of >28.5 mg/L had an optimal sensitivity and specificity ratio (85.7/91.4%). In conclusion, the measurement of serum CRP, PCT and IL-6 levels can be useful for the diagnosis of CAP in patients with CHF. CRP showed optimal diagnostic utility in this population.

scholarly journals P491 De-escalation of dose-intensified anti-TNF therapy in IBD patients in sustained deep remission

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S430-S431
Author(s):  
I Chu ◽  
R Little ◽  
M Sparrow ◽  
M Ward
Keyword(s):  
Clinical Trial ◽  
Drug Level ◽  
Time To Failure ◽  
Faecal Calprotectin ◽  
Patient Demographics ◽  
Reactive Protein ◽  
Disease Characteristics ◽  
Significant Difference ◽  
Success Group

Abstract Background Data on outcomes following de-intensification of anti-TNF therapy in inflammatory bowel disease (IBD) are limited and concerns about relapse limit the willingness to de-escalate. This study aimed to evaluate rates of successful de-escalation at 12 months and to determine factors that may predict success. Methods Single-centre retrospective study of IBD patients on dose-intensified infliximab (IFX) or adalimumab (ADA) for secondary loss of response. De-escalation was considered in patients achieving sustained biomarker normalisation. Patients were followed for 12 months post-de-escalation and classified as ‘successes’ if remaining on reduced dose anti-TNF or ‘failures’ if requiring re-escalation, steroids, surgery or enrolment into a clinical trial. Patient demographics, disease characteristics, biomarkers (faecal calprotectin (FCP), C-reactive protein (CRP), albumin), anti-TNF drug levels and thiopurine metabolites were collected. Results Of 24 patients (20 CD, 4 UC), 18 received IFX and 6 received ADA. Patients on IFX were de-escalated to 5 mg/kg 8-weekly (89%) or 10 mg/kg 6-weekly (11%), while patients on ADA were de-escalated to 40 mg fortnightly (83%) or 40 mg weekly (17%). Fifteen out of 24 (63%) patients were successes 12 months post-de-escalation. Of the 9 failures, median time to failure was 6 months (IQR 4.6–9.9) – 6/9 failures required re-escalation of anti-TNF therapy and 3/9 entered a clinical trial. Re-escalation successfully recaptured response in 6/6 (100%) patients after a median of 1.4 years follow-up (IQR 1.1–2.3). Albumin at de-escalation was higher in the success group compared with failures (38 g/l vs. 36 g/l, p = 0.025). There was no significant difference in CRP, FCP, anti-TNF drug level or 6-TGN level between the two groups. There was no difference in IFX levels between successes and failures at the time of de-escalation (5.5 vs. 7.5, p = 0.524) as well as 6 months (3.1 vs. 5.1, p = 0.628) and 12 months (3.2 vs. 6.1, p = 0.457) post de-escalation. There were insufficient data for ADA drug level comparison post-de-escalation. Conclusion Nearly two-thirds of patients remained on reduced anti-TNF dosing at 12 months post-de-escalation. All patients who failed de-escalation were recaptured after dose re-escalation. Other than albumin, no baseline predictors for the success or failure of de-escalation could be identified, although cohort size is small, follow-up was short and the majority of patients achieved sustained biomarker normalisation prior to de-escalation. De-escalation may be considered in patients on intensified anti-TNF therapy in sustained deep remission.

scholarly journals P483 Infliximab but not adalimumab drug levels predict faecal calprotectin response in Inflammatory Bowel Disease patients on dose-intensified anti-TNF therapy

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S471-S472
Author(s):  
S Noack ◽  
R Little ◽  
K Vaz ◽  
M Ward ◽  
M Sparrow
Keyword(s):  
Roc Curves ◽  
Drug Level ◽  
Rank Tests ◽  
Dose Intensification ◽  
Post Dose ◽  
Faecal Calprotectin ◽  
Drug Levels ◽  
Loss Of Response ◽  
Signed Rank ◽  
Inflammatory Bowel

Abstract Background Secondary loss of response (SLOR) to infliximab (IFX) and adalimumab (ADA) is common and dose intensification is effective in a proportion of patients. Drug level targets associated with response as measured by faecal calprotectin (FCP) after anti-TNF intensification have not been well established. Methods Retrospective observational study of consecutive adult patients with Crohn’s disease (CD) or ulcerative colitis (UC) with SLOR commenced on dose-intensified IFX (5mg/kg 6 weekly) or ADA (40mg weekly) between May 2013-August 2020. Patients were managed via a protocolised virtual clinic. Trough anti-TNF drug levels and FCP were measured at baseline, and at 6 and 12 months post dose intensification. FCP response was defined as ≤150μg/g. Inter-group and longitudinal comparisons used Mann-Whitney U and Wilcoxon signed-rank tests, respectively. ROC curves evaluated anti-TNF drug levels predictive of FCP response. Results Of 78 patients (56% male, median age 40 years), 60 had CD (58% on IFX) and 18 had UC (100% on IFX). There were no significant differences in patient or disease demographics between FCP responders and non-responders at 6 or 12 months. At 6 months, median IFX level and increment in level from baseline were higher in FCP responders than non-responders in both CD and UC (Table 1). At 6 months, achieving an IFX level ≥5.7μg/mL in CD (AUC 0.82, sensitivity 88%, specificity 65%, p=0.012; Figure 1A) and an IFX level ≥5.2μg/mL in UC (AUC 0.89, sensitivity 100%, specificity 73%, p=0.015; Figure 1B) best predicted FCP response. ADA levels at 6 months and both IFX and ADA levels at 12 months were not predictive of FCP response in any cohort. Conclusion After dose-intensified IFX, CD and UC patients achieving FCP response had greater absolute and increment in drug levels than those with elevated FCP. IFX levels ≥5.7μg/mL and ≥5.2μg/mL at 6 months are predictive of FCP response in CD and UC, respectively. ADA levels were not predictive of FCP response.

scholarly journals The dose response of inhaled LPS challenge in healthy subjects

2018 ◽  
Vol 16 ◽  
pp. 205873921878482 ◽  
Author(s):  
Alex Mulvanny ◽  
Natalie Jackson ◽  
Caroline Pattwell ◽  
Sophie Wolosianka ◽  
Thomas Southworth ◽  
...  
Keyword(s):  
Dose Response ◽  
Good Manufacturing Practice ◽  
Post Challenge ◽  
Reactive Protein ◽  
Lps Challenge ◽  
Cell Counts ◽  
Neutrophil Percentage ◽  
Tnf Α ◽  
Factor Α ◽  
Serum Crp

Lipopolysaccharide (LPS) inhalation causes neutrophilic airway inflammation. We used LPS produced to Good Manufacturing Practice (GMP) standards to characterise the dose response. A total of 15 healthy non-smoking subjects inhaled 5-, 15- and 50-µg LPS. Whole blood cell counts and serum C-reactive protein (CRP) were measured at baseline and up to 24 h post challenge. Sputum was induced at baseline and 6 h post challenge for cell counts and quantification of myeloperoxidase (MPO), interleukin (IL)-1β, IL-6, IL-8 and tumour necrosis factor α (TNF-α) in supernatants. LPS inhalation was well tolerated. Blood neutrophil counts increased at 6 h post LPS with all doses. Serum CRP significantly increased with 15- and 50-µg LPS. All LPS doses significantly increased sputum neutrophil percentage ( P < 0.001). IL-1β, IL-6 and TNF-α were significantly increased in sputum supernatant following challenge with 50-µg LPS, there was no change in MPO or IL-8. The 50-µg LPS was well tolerated and produced a robust inflammatory response. This study supports the use of 50-µg GMP-grade LPS as a suitable challenge agent in clinical trials.

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