Serum Drug Levels Research Articles

Etanercept for patients with juvenile idiopathic arthritis: drug levels and influence of concomitant methotrexate: observational study

BackgroundEtanercept (ETN) is widely used tumour necrosis factor (TNF) blocker in the treatment of juvenile idiopathic arthritis (JIA) when traditional synthetic disease modifying antirheumatic drug (sDMARD) therapy is not sufficient. There is limited information about the effects of methotrexate (MTX) on serum ETN concentration in children with JIA. We aimed to investigate whether ETN dose and concomitant MTX would effect ETN serum trough levels in JIA patients, and whether concomitant MTX have an influence on the clinical response in patients with JIA receiving ETN.MethodsIn this study, we collected the medical record data of 180 JIA patients from eight Finnish pediatric rheumatological centres. All these patients were treated with ETN monotherapy or combination therapy with DMARD. To evaluate the ETN concentrations, blood samples of the patients were collected between injections right before the subsequent drug. Free ETN level was measured from serum.ResultsNinety-seven (54%) of the patients used concomitant MTX, and 83 (46%) received either ETN monotherapy or used sDMARDs other than MTX. A significant correlation was noted between ETN dose and drug level [r = 0.45 (95% CI: 0.33–0.56)]. The ETN dose and serum drug level were correlated (p = 0.030) in both subgroups – in MTX group [r = 0.35 (95% CI: 0.14–0.52)] and in non-MTX group [r = 0.54 (95% CI: 0.39–0.67)].ConclusionIn the present study, we found that concomitant MTX had no effect on serum ETN concentration or on clinical response. In addition, a significant correlation was detected between ETN dose and ETN concentration.

Effectiveness of golimumab intensification in ulcerative colitis: A multicentric prospective study.

Loss of response to golimumab occurs in nearly 40% of patients with ulcerative colitis (UC). Unlike others anti-TNF, no study has reported a correlation between serum golimumab level and response to drug intensification. The objective of this study was to evaluate the effectiveness and safety of golimumab intensification and to identify the best threshold of serum golimumab before drug intensification predictive of response. We included all consecutive patients with active UC with loss of response to golimumab in a prospective multicentric cohort study. Patients with loss of response at 50 mg q4 weeks (W) and 100 mg q4W underwent therapeutic intensification at 100 mg q4W and 100 mg q2W, respectively. Effectiveness and safety were assessed between Weeks 2 and 4 (visit 2) and between Weeks 4 and 8 (visit 3) after intensification. Serum level and anti-golimumab antibodies were evaluated at each medical visit (Lisa Tracker, Theradiag France). A total of 47 UC patients (Female, 50%; median age, 39 years (IQR, 27-52)) treated with golimumab for a median of 20.4 weeks (IQR, 10.7-38.3) were included. The median partial Mayo score was 6 (IQR, 5-7), and the median endoscopic Mayo score was 3 (IQR, 2-3). The median golimumab serum level before intensification was 2.23 μg/mL (IQR, 1.02-3.96) and only one patient (2.1%) had anti-drug antibodies. At Visit 2 (Week 2-4), 40% patients experienced clinical response, 10% clinical remission, 33% endoscopic response and 23% endoscopic remission. At Visit 3 (Week 4-8), 44% of patients had clinical response, 22% of patients had clinical remission, 45% of patients had endoscopic response, and 41% of patients had endoscopic remission. The median golimumab levels before intensification do not differ between responders and non-responders (2.13μg/ml (0.76-2.76) and 3.37μg/ml (IQR, 1.08-4.67), respectively; p= 0.14) assessed at Visit 3. Golimumab intensification to 100 mg q4W (vs q2W) (OR 1.98, 95% CI [1.06-3.70]; p= 0.032) was significantly associated with clinical remission at Visit 3. Serum drug level at baseline or the presence of antidrug antibodies were not associated with clinical or endoscopic remission/response. Two serious adverse events (one infection and one UC flare) were reported during the 24-week follow-up. In this prospective multicentric study, half of patients recaptured response following golimumab intensification in UC. Therapeutic drug monitoring did not predict response after optimisation of golimumab.

Relationships of Serum Illicit Drug Concentrations During Pregnancy to Maternal Nutritional Status

Findings reported are for a subset of African American subjects, residing in the urban area of Washington, D. C., who participated in a Program Project designed to study nutrition, other factors, and the outcome of pregnancy. Fasting blood samples, drawn during each trimester of pregnancy and at delivery, were screened for concentrations of cocaine, phencyclidine (PCP) and marijuana. Since substance abusers are expected to consume inadequate diets, these samples were also analyzed for serum folate, vitamin B12, ferritin and ascorbic acid. Data for these biochemical variables were compared for subjects whose serum values for drugs were either above or below the drug screening threshold concentrations established by ADAMHA/NIDA. Pearson's correlations were used to determine relationships between pregnancy outcome variables and maternal serum drug concentrations. Blood samples drawn at delivery showed higher maternal: cord ratios (mean +/- SEM) for marijuana (3.3 +/- 2.2) and PCP (2.9 +/- 1.0) than for cocaine (1.0 +/- 0.2). The subjects whose serum values were above the ADAMHA/NIDA ranges for marijuana, PCP and cocaine had concentrations of folate and ferritin that were significantly less than those of subjects with lower serum drug levels (P < or = 0.05). High maternal serum concentrations of illicit drugs were accompanied by a significant increase in leukocyte count (P < or = 0.05). The level of maternal cocaine during the third trimester was inversely correlated with birthweight (r = -0.29; n = 52; P = 0.038) and head circumference (r = -0.28; n = 52; P = 0.047).(ABSTRACT TRUNCATED AT 250 WORDS)

P785 A retrospective cohort study on vedolizumab trough levels in Crohn’s disease patients

Abstract Background Background: Vedolizumab (VDZ), an α47-integrin inhibitor, is approved for the treatment of moderate to severe Crohn’s disease (CD). Exposure-response relationship for VDZ is less evident in CD. Here, we are exploring associations between serum VDZ serum concentrations and clinical/biomarker-defined endpoints from a single center, real-world cohort. Methods Methods: Electronic health data records of CD patients during their first year of treatment with VDZ from January 2014 – July 2022 at our tertiary care center were obtained. Serum drug levels (TDL) and their correlation with outcomes were assessed at specified timepoints – weeks 12 (± 2), 26 (± 4) and 52 (± 6). Clinical remission was assessed by patient reported outcomes as suggested in STRIDE II guidelines (stool frequency ≤ 3 and abdominal pain ≤ 1). Fecal calprotectin (fCP) values ≤ 150 µg/g marked biomarker remission. Vedolizumab drug levels were measured with IDKmonitor Vedolizumab drug level ELISA kit (Immundiagnostik AG, Germany), In case of missing data patients were categorized as non-responders. For association modelling, multivariable fractional polynomials and generalised additive models were used (R statistical software, v4.1.2; R Core Team). Results Results: In total, 58 patients (females = 55.2%) with at least two available data points were included (Table 1). Sixteen individuals (16/58, 27.6%) were naive for biologics therapies. 98.3% (57/58) reached week 12 (± 2). Both at weeks 26 and 52 91.4% (53/58) subjects still were on drug. Clinical remission was achieved in 51.7% (30/58), 49.1% (26/53) and 45.2% (24/53) cases at weeks 12, 26 and 52, respectively, with biomarker remission rates of 24.1% (14/58), 35.8% (19/53) and 27.6% (16/53) patients reached biomarker remission. TDLs differed only between clinical remitters and non-remitters at week 26 (Mann-Whitney-U-test, p = 0.04). Also, there was no significant association between clinical and biomarker remission at defined timepoints and corresponding TDLs (for all p &amp;gt; 0.05). TDLs at week 2 and 6 were correlated with fCP values at the same time (rho: -0.327, p = 0.03 at week 2 and rho: -0.356, p = 0.02 at week 6). When TDLs at week 2 and week 6 were taken into consideration and associated separately with therapy outcomes in a univariate regression, only association between serum levels at week 6 and biomarker remission at weeks 26 and 52 was found (p = 0.02 and p = 0.03, respectively). Conclusion Conclusion: The only association between serum drug levels and remission was found between TDLs at week 6 and biomarker remission at weeks 26 and 52 suggesting a complex exposure-response relation for vedolizumab in CD patients.

P730 Anti tumor necrosis factor treatment in Ulcerative Colitis: Real-world data and evaluation of current treatment targets (STRIDE II)

Abstract Background In 2021, the Selection of Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative proposed updated recommendations for treatment targets for ulcerative colitis (UC) patients. The recommendations introduce clinical remission as a short/medium term target, normalisation of CRP and Fecal Calprotectin (FC) as an intermediate target, and advice that change of treatment should be considered if targets are not met. In this single-centre study, we report real-world experience with proactive therapeutic drug monitoring (TDM) strategy for UC patients with first-line anti tumor necrosis factor (TNFi) treatment, and reflect on how implementation of the STRIDE II recommendations might affect clinical practice. Methods Adult, biologically naïve UC patients starting TNFi between 2014 and 2021 at Oslo University Hospital were included in a medical chart review study, and data were recorded at three and twelve months. Clinical remission was defined as a patient-recorded outcome (PRO-2) ≤1. Biochemical remission was defined as CRP &amp;lt;5 mg/L and FC &amp;lt; 250 µg/g. Combined remission was defined as clinical and biochemical remission. Target serum drug levels were defined as ≥7.5 mg/L (adalimumab [ADA]) and ≥5 mg/L (infliximab [IFX]). Logistic regression was applied for association analyses. Results A total of 141 patients were included. Of these, 60% were male, median age was 25 years. In total, 67% received IFX and 32% received ADA. One third (n=39) patients discontinued TNFi or added a second biologic agent during follow-up and were considered in non-remission, resulting in 102 (72%) persistent patients. Percentages [95% CI] in remission at 3 and 12 months are summarized in Table 1, and for drug-persistent patients in Table 2. Target drug level at 3 months was associated with clinical remission at 12 months (OR 2.97, 95% CI [1.24 – 7.12]), biochemical remission at 12 months (OR 2.64, 95% CI [1.03 – 6.77]) but not with combined remission. In total, 125 dosage adjustments were recorded. Of these, 70 (56%) were classified as adjustments related only to serum drug levels. Conclusion Combined remission rates at 3 and 12 months for persistent patients suggest that 60% and 46% of our cohort should have been considered for a change of treatment according to the STRIDE II recommendations. A majority of dosage adjustments were made proactively, and as target drug levels at 3 months were associated with remission outcomes at 12 months, our data support the use of a proactive TDM strategy.

Assessment of the influence of Fc-γ receptor polymorphisms on biologics' pharmacokinetics in Tunisian rheumatoid arthritis patients.

This study aims to determine whether a modification in Fc-γ receptors' (FcgRs) affinity to Fc portion, caused by single nucleotide polymorphisms such as rs1801274-R131H FcgRIIa, rs396991-F158V FcgRIIIa and NA1/NA2-FcgRIIIb, might impact clearance of therapeutic monoclonal antibodies and thus serum drug levels and the development of anti-drug antibodies. A cross sectional, multicentral and noninterventional study was conducted in Tunisian RA patients treated with rituximab (RTX), etanercept (ETA), infliximab (IFX) and adalimumab (ADL). Serum drug level (SDL) of the different biologics and ADA against them were measured. All patients were genotyped for the 3 FcgR single nucleotide polymorphisms. A total of 81 patients were included: 47 were under tumour necrosis factor inhibitors (18 ETA, 13 ADL and 16 IFX), and 34 were under RTX. Regardless of the type of biotherapy, SDL was in therapeutic range, in 35 patients (43.2%), of whom only 1 was treated with RTX. Fourteen patients (22.2%) developed ADA, but none of the patients treated with ETA had detectable ADA levels. There was no association between SDL positivity and FcgR polymorphisms. However, the high affinity FcgR2A 131 H/H receptor was statistically more prevalent in patients with detectable ADA treated with ADL, IFX and RTX (P = .018). The same result was obtained in the monoclonal antibody tumour necrosis factor inhibitor subgroup (n = 29, P = .022) as well as in patients treated only with IFX (n = 16, P = .029). Our work supports the hypothesis of an impact of FcgR single nucleotide polymorphisms on biologics' immunogenicity, particularly FcgR R131H polymorphism, but further studies with larger cohorts need to be undertaken to confirm these results.

Antidrug Antibodies to Tumor Necrosis Factor α Inhibitors in Patients With Noninfectious Uveitis

Tumor necrosis factor inhibitors (TNFis) can induce antidrug antibody (ADA) formation and loss of therapeutic response. However, the utility of ADA testing and the association between ADAs and treatment response in patients with noninfectious uveitis (NIU) is not well understood. To assess the frequency of ADAs and their association with drug levels and clinical response in patients with NIU treated with adalimumab or infliximab. This retrospective cross-sectional study included patients diagnosed with NIU who received adalimumab or infliximab and underwent testing for serum drug level and ADAs at the National Eye Institute from September 2017 to July 2021. Serum drug level testing with reflex testing for ADA levels was performed. The main outcome was the association between drug levels and ADAs, clinical response, and concurrent antimetabolite use in patients treated with TNFis for NIU. Of 54 patients included in the study, 42 received adalimumab (mean [SD] age, 43.6 [19.6] years; 25 [59.5%] female) and 12 received infliximab (mean [SD] age, 42.7 [20.4] years; 7 [58.3%] male). In the adalimumab group, mean (SD) drug level was 9.72 (6.82) μg/mL, mean (SD) ADA level was 84.2 (172.9) arbitrary units/mL, and ADA frequency was 35.7% (15 of 42 patients). Mean drug level was lower in those with ADAs compared with those without ADAs (mean [SD], 2.8 [2.6] μg/mL vs 13.6 [5.2] μg/mL; difference: 10.8 μg/mL; 95% CI, 8.3-13.2 μg/mL; P < .001). There was a higher mean drug level with concurrent antimetabolite use compared with monotherapy (mean [SD], 11.0 [7.3] μg/mL vs 6.8 [4.5] μg/mL; difference: -4.2 μg/mL; 95% CI, -8.7 to 0.2 μg/mL; P = .06). Multivariable modeling showed that a 1-arbitrary unit increase in ADAs was associated with a -0.02 μg/mL (95% CI, -0.01 to -0.34 μg/mL) difference in mean drug level (P < .001). Favorable clinical response was associated with a threshold drug level above 2.7 μg/mL or an antibody level below 15.2 μg/mL. The mean (SD) drug level in the infliximab group was 27.02 (18.15) μg/mL, and no ADAs were detected. In this study, 35.7% of adalimumab-treated patients with NIU had ADAs. The presence of ADAs was associated with lower drug levels, and higher ADA levels were associated with increased risk of TNFi treatment failure. Although limited by the retrospective design, our results suggest that therapeutic drug monitoring may be considered among patients experiencing therapy failure to help exclude ADAs as a potential cause of treatment failure.

188: PHARMACOKINETIC ANALYSIS OF ANTIMICROBIAL THERAPY IN VENTRICULAR ASSIST DEVICE-SUPPORTED PATIENTS

Introduction: As a result of underlying heart failure, the utilization of left ventricular assist devices (VAD) has increased as a means of offloading the failing ventricle to improve cardiac output. Importantly, after device implantation and once end-organ perfusion has been enhanced, new pharmacokinetic alterations may acutely develop which may require pre-emptive dose adjustments for several pharmacotherapies. Currently, there are limited data in patients with VADs to determine patient and population-specific antimicrobial disposition. The purpose of this study is to assess perioperative pharmacokinetic changes in patients during VAD implantation receiving prophylactic antibiotics. Methods: Patients will be prospectively enrolled to collect blood samples peri-operatively and post-operatively. Blood samples will be used to analyze the antimicrobial concentrations using a validated high-performance liquid chromatography (HPLC-UV) assay. Results: To date, 11 patients have been enrolled in this study. Enrollees are on average 63 years of age, predominately male (82%), with nonischemic cardiomyopathy (64%). LVAD implantation consisted of HeartMate3 (n=9), and HVAD devices (n=2). Standard prophylactic regimens for LVAD implantation include ceftazidime and vancomycin. Intra-operatively, all patients received one prophylactic dose of ceftazidime 2 grams from which samples were collected thereafter. The median samples collected intra-operatively was 4 (IQR 3,6). Post-operatively, ceftazidime prophylaxis was continued for 36 hours, and samples were typically collected after the third ceftazidime dose. The median samples collected post-operatively was 4 (IQR 4,5). Antimicrobial plasma concentrations are currently pending processing and analysis. The drug concentration in the serum will be analyzed to determine the maximum concentration, area under the concentration-time profile for the dosing interval, half-life, clearance, and volume of distribution. Conclusions: In this medically complex heart failure patient population, use of narrow therapeutic index drugs can have detrimental consequences if they are not dosed appropriately. This study will provide practitioners more insight in perioperative dosing regimens for VAD patients by understanding how serum drug levels may be altered with VAD therapy.

Effects of dopamine D2/3 and opioid receptor antagonism on the trade-off between model-based and model-free behaviour in healthy volunteers.

Human behaviour requires flexible arbitration between actions we do out of habit and actions that are directed towards a specific goal. Drugs that target opioid and dopamine receptors are notorious for inducing maladaptive habitual drug consumption; yet, how the opioidergic and dopaminergic neurotransmitter systems contribute to the arbitration between habitual and goal-directed behaviour is poorly understood. By combining pharmacological challenges with a well-established decision-making task and a novel computational model, we show that the administration of the dopamine D2/3 receptor antagonist amisulpride led to an increase in goal-directed or 'model-based' relative to habitual or 'model-free' behaviour, whereas the non-selective opioid receptor antagonist naltrexone had no appreciable effect. The effect of amisulpride on model-based/model-free behaviour did not scale with drug serum levels in the blood. Furthermore, participants with higher amisulpride serum levels showed higher explorative behaviour. These findings highlight the distinct functional contributions of dopamine and opioid receptors to goal-directed and habitual behaviour and support the notion that even small doses of amisulpride promote flexible application of cognitive control.

Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial

PurposeIndividualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.MethodsThis multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.ResultsIn total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55–71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96–1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.ConclusionsWe could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.

Reduced prescription of TNF-inhibitors in chronic arthritis based on therapeutic drug monitoring: A randomized controlled trial

Objective Dosing of tumour necrosis factor-α inhibitors (TNFis) is not personalized causing interindividual variation in serum drug levels; however, dose optimization is not widely implemented. We hypothesized that some patients areoverdosed; thus, drug prescription could be reduced by therapeutic drugmonitoring (TDM). Method Independent of disease activity, 239 adults treated for rheumatoid arthritis (n = 99), psoriatic arthritis 15 (n = 48), or spondyloarthritis (n = 92) were recruited for a 48-week prospective, randomized open-label trial. Standard care alone or plusTDM was applied in chronic arthritis patients treated with infliximab (IFX), (n= 81), etanercept (ETN) (n = 79), or adalimumab (ADA) (n = 79). Serum TNFitrough levels assessed at inclusion and every 4 months determined patientswithin/outside predefined therapeutic intervals, supporting change inprescription or drug switch. The primary endpoint was reduced drugprescription. Results Compared to standard care, TDM reduced prescribed IFX [−12% (95% confidence interval −20, −3); p = 0.001] and ETN (−15% (−29, 1); p = 0.01], and prolonged the interdosing intervals of ETN [+235% (38, 432); p = 0.02] and ADA [+28% (6, 51); p = 0.04]. Time to drug switch was accelerated (χ2 = 6.03, p = 0.01). No group differences in adverse events, disease activity, or self-reported outcomes were shown, indicating equally sustained remission. Conclusions TDM reduced prescription of IFX, ETN, and ADA and identified patients benefiting from accelerated drug switch, thereby minimizing treatment failure, risk of toxicity, and unnecessary adverse events.

CML-362 Study to Evaluate the Effect of Fatty Meals on Nilotinib Drug Levels in Patients of Chronic Myeloid Leukemia–Chronic Phase and Correlate Its In-Vivo Activity With STAT1, STAT5, and AKT 1 Levels

Nilotinib is an oral tyrosine kinase inhibitor recommended to be administered in a fasting state (meals taken either 2 hours after or 1 hour before a dose). Fat-rich food has shown to increase the bioavailability of drugs. However, if the drug is allowed to be taken with food, it decreases the dose required to produce the desired clinical efficacy, lowering the cost of treatment and enhancing quality of life. Downstream pathway assessment will be helpful in evaluating the pharmacodynamics of the drug. To assess the effect of fatty meals on nilotinib drug levels and correlate its in-vivo activity with STAT1, STAT5, and AKT1 levels. Design/Setting/Patients/Intervention: This single-center, open-label, pharmacokinetic /pharmacodynamic study included 30 patients with newly diagnosed CML-chronic phase. There were 5 cohorts with 6 patients enrolled in each. The dose of nilotinib in each cohort was 150 mg OD, 200 mg OD, 150 mg BD, 200 mg BD, and 300 mg BD. The drug was given on an empty stomach for the initial 8 days and with fatty meals for the next 8 days. Fatty meals were defined as 2 slices of bread with 10 g butter. Blood (2 mL) was withdrawn at specified time points: 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 hours on day 1 and 0 and 3 hours on day 8. Nilotinib drug levels were estimated by liquid chromatography mass spectrometry. For assessment of the downstream signaling pathway, blood samples were drawn on days 1 and 8 of drug intake without food and day 8 of drug intake with food, and levels were assessed by ELISA. To assess serum drug levels of nilotinib along with STAT5, STAT1, and AKT1 levels in fasting and post-meal status. Nilotinib had a significant dose-dependent food interaction, and higher doses showed greater increases in AUC and Cmax. The protein expression of the native form of STAT1 increased in the group of drug intake with food. The increase might have resulted from inhibition of STAT1 phosphorylation by nilotinib. The study is funded by a research grant from ICMR, New Delhi.

P60 A case of autoimmune inflammatory myositis in a patient with SLC29A3 spectrum disorder

Introduction/BackgroundThe SLC29A3 gene encodes the equilibrative nucleoside transporter hENT3. SLC29A3 spectrum disorder, an autosomal recessive disorder caused by mutations in this gene, is a rare multisystem disorder resulting in cutaneous manifestations (hyperpigmented, hypertrichotic and indurated patches of skin) and a variety of systemic features, with variable phenotypic expression. Along this spectrum are H syndrome and pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome. The majority of cases reported in the literature have been in patients of Arab descent. We report a case of a patient with SLC29A3 mutation who later developed features of autoimmune disease and myositis.Description/MethodAn 11-year-old girl with an established diagnosis of SLC29A3 mutation, dysosteosclerosis, camptodactyly and type 1 diabetes mellitus presented with a three-week history of intermittent fever, myalgia, muscle weakness and cervical lymphadenopathy. She had a non-specific rash over her eyelids, interphalangeal joints of both hands, torso and limbs. Her movements were restricted due to myalgia. She had no evidence of arthritis. Her creatine kinase was elevated (>1400 units/litre) and MRI of her thighs revealed evidence of myositis not akin to Juvenile Dermatomyositis distribution. An extensive investigation screen showed no evidence of infections. The bone marrow was hypocellular but there was no evidence of malignancy or histiocytosis. An autoinflammatory disease was suspected and the patient was treated with three pulses of IV methylprednisolone, to which she initially responded well but soon relapsed. Anakinra was trialled but this failed as the patient’s daily fevers persisted and her muscle weakness continued to worsen. Methotrexate was commenced and did not result in the desired reduction in prednisolone dose, so the patient was started on 4-weekly infliximab infusions. Following commencement of infliximab, the patient’s fever and rash resolved; her energy levels and muscle power improved and her muscle enzymes began to normalise. Repeat MRI showed her myositis was in remission. Infliximab was stopped after 13 doses due to side effects at the end of the infusions (tachycardia, hypertension and pyrexia). In addition, it was found that she had developed antibodies against infliximab and measured serum drug levels were low. Methotrexate was eventually stopped. The patient is now off all rheumatological treatment (as of February 2019) and she has not had reactivation of any of her symptoms.Discussion/ResultsThe patient we report had insulin-dependent diabetes mellitus, dysosteosclerosis and camptodactyly, three systemic features associated with SLC29A3 mutation. She presented concomitantly with signs of autoinflammatory disease and myositis. While up to 25% of patients with SLC29A3 mutation develop autoinflammatory features, to our knowledge, this is the first reported case of myositis in a patient with this mutation. Both the inflammatory features and myositis resolved following treatment with infliximab infusions. A number of case reports have described successful treatment of inflammation in SLC29A3 mutation with IL-6 inhibitors such as tocilizumab. The complete remission demonstrated in this case following infliximab infusions points to TNF-α inhibition as another potential therapeutic target. It is also interesting to note that our patient is now off all rheumatological treatment, which contrasts with other case reports in the literature where the patients have typically required maintenance immunomodulation therapy to remain asymptomatic. This case may therefore represent a new clinical subtype of SLC29A3 mutation with an autoimmune inflammatory myositis, rather than autoinflammatory as initially suspected, that carries a better prognosis. Further case reports of myositis in SLC29A3 mutation would help to build a clearer picture of its clinical presentation, prognosis and response to biologic therapies.Key learning points/Conclusion1. SLC29A3 spectrum disorder is a rare multisystem disorder that has only recently been recognised. By presenting this case report we hope to increase awareness of this condition and network with other clinicians who have encountered inflammatory disease associated with SLC29A3 mutation, either in their clinical practice or research.2. Up to a quarter of patients with SLC29A3 mutation present with autoinflammatory disease.3. We report on the first case of autoimmune inflammatory myositis in a patient with SLC29A3 mutation, to our knowledge.4. Our patient demonstrated complete remission of her inflammatory disease following treatment with infliximab, which may represent a new clinical subtype of SLC29A3 mutation with an autoimmune, rather than autoinflammatory, myositis that carries a better prognosis.

P31 Chicken or egg: Inflammatory bowel disease in ankylosing spondylitis

P31 Chicken or egg: Inflammatory bowel disease in ankylosing spondylitis

Fitness, performance, and cardiac autonomic responses to exercise in people with epilepsy

People with epilepsy (PWE) are less fit and have an increased risk of sudden cardiac death. Imbalances within the autonomic nervous system (ANS) are believed to mediate some of those effects. However, results are mostly derived from patients whose seizures are refractory to medical therapy. In this study, an exhaustive bicycle ergometer test was delivered to 25 PWE (19 seizure free in the last 6 months) recruited in a community-based setting and 25 age-, sex-, and BMI-matched healthy controls. During the exercise test a 12-channel ECG was recorded and spirometry was carried out to determine the maximal oxygen uptake (VO2peak) as the gold standard to assess fitness. Before and after exercise, heart rate variability (HRV) and electrodermal activity (EDA) were measured along with an electroencephalogram (EEG). Blood samples were collected to determine anti-seizure drug (ASD) serum levels and physical activity of daily living was evaluated via the International Physical Activity Questionnaire (IPAQ). People with epilepsy and healthy controls were similarly fit and physically active. However, PWE had a lower maximum heart rate, a lower heart rate reserve, and a lower chronotropic index. The ratio between low- to high-frequency HRV changes (LF/HF ratio) was lower in PWE. Two patients with idiopathic genetic epilepsies revealed generalized interictal epileptiform discharges only after, but not before exercise. However, post-exercise EEG measurement was three times longer than pre-exercise and those patients did not report exercise induced seizures in the history. Besides epileptogenesis, anti-seizure medications may also contribute to those autonomic differences.

Comparing the effect of different loading doses of phenobarbitone on serum phenobarbitone levels in babies with neonatal seizures and effect of therapeutic hypothermia on phenobarbitone levels.

With current recommendation for phenobarbitone dosing, we have noted that babies are extremely sedated with elevated serum phenobarbitone levels. We postulate that asphyxiated neonates with hypoxic liver injury have impaired drug metabolism and renal injury affects drug elimination, thus elevating serum drug levels. Therapeutic hypothermia (TH) could further affect the drug levels. To determine the serum levels of the phenobarbitone in babies receiving different loading doses of phenobarbitone for neonatal seizures and to study the effect of asphyxia and TH on drug levels. Prospective observational cohort study. Term neonates with seizures of any cause were given phenobarbitone up to a maximum loading of 40 mg/kg followed by maintenance dose of 5 mg/kg/day. Serum phenobarbitone levels were assessed after 4 h of the initial loading dose and subsequently at 24, 48 and 72 h from the time after maximum loading dose. Babies were divided into three groups Group 1 (HIE + TH-hypoxic ischemic encephalopathy undergoing TH), Group 2 (HIE - TH-hypoxic ischemic encephalopathy without TH) and Group 3 (non-HIE group). A total of 47 babies completed the study. Twenty-three (49%) received 20 mg/kg, 14 (30%) received 30 mg/kg and 10 (21%) received 40 mg per kg of phenobarbitone as loading dose. HIE was the major cause of seizures 28 (59%) followed by hypoglycemia 7 (14%), cerebral malformations 4 (8%), inborn errors of metabolism 2 (4%) and hypocalcemia 1 (2%) while the cause of seizures was not known in 6 (13%). Median (IQR) Phenobarbitone levels at 72 h in babies who received 20 mg/kg loading dose of phenobarbitone was 46.72 (44.02-50.49) mcg/ml in HIE + TH group, 40.53 (28.66-65.09) mcg/ml in HIE - TH group and 49 (37-65) mcg/ml in non-HIE group. After a loading dose of 30 mg/kg, phenobarbitone level was 63.76 (59.5-65.94) mcg/ml in HIE + TH group, 42.5 (34.75-48.75) mcg/ml in HIE - TH group and 42.07 (40-49.05) mcg/ml in non-HIE group. After 40 mg/kg loading dose, it was 62.3 (60.2-64.9) mcg/ml in HIE + TH group, 57.0 (49.8-60.2) mcg/ml in HIE - TH group and 48.15 (40.8-50.97) mcg/ml in non-HIE group. In babies who received &gt;20 mg/kg loading dose, 100% of HIE + TH, 80% of HIE - TH and 60% of non-HIE had supratherapeutic levels of phenobarbitone. At higher loading doses of 30 and 40 mg/kg, steady state concentration of serum phenobarbitone is higher in babies with hypoxic ischemic encephalopathy who underwent TH than in babies with non-HIE causes of seizures. Loading dose beyond 20 mg/kg should be used with close monitoring of serum drug level.

Patient-centered dupilumab dosing regimen leads to successful dose reduction in persistently controlled atopic dermatitis.

At present, no real-world studies are available on different dupilumab dosing regimens in controlled atopic dermatitis (AD). The aim of this study was to clinically evaluate a patient-centered dupilumab dosing regimen in patients with controlled AD and to relate this to serum drug levels and serum biomarkers. Ninety adult AD patients from the prospective BioDay registry were included based on their dupilumab administration interval according to a predefined patient-centered dosing regimen. Group A (n=30) did not fulfill the criteria for interval prolongation and continued using the standard dupilumab dosage (300 mg/2 weeks), group B (n=30) prolonged dupilumab interval with 50% (300 mg/4 weeks), and group C (n=30) prolonged dupilumab interval with 66%-75% (300 mg/6-8 weeks). AD severity score, patient-reported outcomes, serum dupilumab levels, and serum biomarkers were analyzed over time. Disease severity scores did not significantly change over time during the tapering period in any of the groups. In groups B and C, the Numeric Rating Scale (NRS)-pruritus temporarily significantly increased after interval prolongation but remained low (median NRS-pruritus≤4). Median dupilumab levels remained stable in group A (standard dosage), but significantly decreased in groups B and C (24.1 mg/L (IQR=17.1-45.6); 12.5 mg/L (IQR=1.7-22.3)) compared with the levels during the standard dosage (88.2 mg/L [IQR=67.1-123.0, p < .001]). Disease severity biomarker levels (CCL17/CCL18) remained low in all study groups during the whole observation period. This study showed that dose reduction was successful in a subgroup of patients with controlled AD by using a patient-centered dosing regimen. These patients showed stable low disease activity and low severity biomarkers over time.

Ustekinumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum

BackgroundPatients with ulcerative colitis (UC) may be concerned about medication safety during preconception, pregnancy, and lactation, and they should be closely followed up to ensure that UC activity is controlled during the perinatal period. Reported information on the safety of ustekinumab during pregnancy and lactation is limited. In this case report, we examined the safety of ustekinumab in a fetus and breastfed infant with reference to drug concentrations in maternal serum, cord blood, breast milk, and infant serum.Case presentationA 36-year-old female who developed hematochezia and was diagnosed with ulcerative colitis at age 24 was pregnant with her first child. During pregnancy she was treated with subcutaneous bimonthly ustekinumab, at a dose of 90 mg, until 29 weeks of gestation. Her ulcerative colitis symptoms remained in remission. At 38 weeks of gestation she underwent cesarean section and delivered a healthy female infant weighing 3043 g and with no congenital malformations. The infant received routine vaccinations with no adverse events. Ustekinumab treatment was resumed at 7 weeks postpartum.The ustekinumab concentration in maternal serum at 12 days after injection (30.7 weeks of gestation) was 7968.5 ng/mL, and it decreased to 106.1 ng/mL at 114 days after the last dose. In cord blood, the ustekinumab concentration was 1131.2 ng/mL at 65 days after the last dose; this was 2.5 times higher than that in the maternal serum, which was consistent with a previous report. Ustekinumab was detected in infant serum collected at 71 days after the last maternal dose (299.0 ng/mL), with rapid elimination from the infant’s body. In breast milk, the maximum ustekinumab concentrations were 13.6 ng/mL at 9 days after the last maternal dose, respectively. The ratio of the calculated areas under the time-concentration curves of ustekinumab in breast milk and maternal serum was 0.0008 (257.1/327632.7), which was comparable with a previous human study.ConclusionThe placental transfer and breast milk secretion of ustekinumab in our case were comparable with previous reports. Use of ustekinumab during pregnancy and lactation was feasible in this case. Further research is needed to clarify the safety of ustekinumab during pregnancy and lactation.

A Review of Pharmacogenetics of Anticoagulant Therapy

Variances in the patients’ outcomes have been a well-documented challenge in anticoagulant therapy. A clinical encounter with a thromboembolic or a hemorrhagic event, due to subtherapeutic or adverse effects of an anticoagulant, is often managed by switching the anticoagulant agent into another, which is more specific and direct-acting. This management approach is usually associated with a financial burden. Additionally, the certainty of achieving better efficacy and safety profile is still questionable. Genetic variants affecting the protein sites that are involved in the anticoagulant pharmacokinetic and pharmacodynamics interactions have been suggested to contribute to the variability in the response to anticoagulant therapy. The current work reviewed the studies investigating the response variability associated with the anticoagulant therapy (heparins, rivaroxaban, apixaban, and dabigatran) and the potential pharmacogenes contributing to such response variability. Several genetic polymorphisms were reported as potential contributors to variances in response to anticoagulant therapy and were associated with adverse events. A link has been proposed for heparin resistance with single nucleotide polymorphisms (SNPs) of the anti-thrombin-encoding gene (SERPINC1) as well as heparin-induced thrombocytopenia with human leukocyte antigen (HLA) variant allele (HLA-DRB3*01:01). Several investigations also remarked variations in the serum drug level of direct oral anticoagulants (DOACs) that are associated with SNPs in the proteins contributing to the pharmacokinetics of the anticoagulant agent. Several studies discerned significant associations between SNPs in the ABCB1 gene and elevations in the serum levels of rivaroxaban, apixaban, and dabigatran. Moreover, carriers of the variant genotype of the SNP (rs776746) in the cytochrome P450 3A5 enzyme-encoding gene (CYP3A5) had significantly higher drug levels when compared with the non-carriers. In contrast, some SNPs were reported to impart a protective phenotype to the carrier. The SNP (rs2244613) in the carboxylesterase-encoding gene (CES1) has been significantly associated with a decline in dabigatran trough levels and a lower risk of hemorrhage. Further investigations are essential to elucidate the extent of pharmacogenetics-based alterations in the drug levels as well as the subsequent clinical outcomes of anticoagulant therapy.

Serum Levels of Infliximab Biosimilar in a Child Delivered From a Mother Treated for Ulcerative Colitis.

Lay Summary The infliximab biosimilar CT-P13 is used for the treatment of ulcerative colitis. We report for the first time the serum drug levels and long-term health status of the child of a patient treated with CT-P13 throughout her pregnancy.