Low Etanercept Concentrations in Children With Obesity and Juvenile Idiopathic Arthritis

OBJECTIVE To evaluate the impact of obesity on etanercept (ETN) drug exposure in children with juvenile idiopathic arthritis (JIA). METHODS We conducted a pilot, cross-sectional, observational study in a real-world cohort of children with JIA receiving ETN as standard of care from a single center. We analyzed the relationship between body size and ETN plasma concentrations, adjusting for dosage. Body size was analyzed as a continuous measure using weight and body mass index (BMI) percentiles and categorically using BMI percentile classifications according to the CDC guidelines. RESULTS We enrolled a total of 29 children. Each child provided one plasma sample for ETN concentration measurement, and all participants were receiving subcutaneous ETN dosed weekly. We observed that the ETN concentration normalized for dose decreased significantly as a function of weight (p = 0.004) and BMI percentile (p = 0.04). Similarly, we observed a progressive decline in mean and median dose-normalized concentrations across higher body size categories. Because of reaching maximum ETN dosage (50 mg), 7 of 8 children (87.5%) with obesity received a weight-based dosage < 0.8 mg/kg/dose. CONCLUSIONS We found that higher body weight and BMI percentile are significantly and negatively associated with ETN drug serum concentration, accounting for differences in dosing. Our data suggest that children who are obese may be routinely under-dosed using current dosing strategies. Inadequate dosing may increase the risk for therapeutic failure and long-term morbidity in a developing child. As a result, characterizing adequate drug exposure in children of all sizes is an important step toward precision dosing.

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Evidence for Residual Immunity to Smallpox After Vaccination

Prehospital and Disaster Medicine ◽

10.1017/s1049023x19002802 ◽

2019 ◽

Vol 34 (s1) ◽

pp. s129-s129

Author(s):

Mohana Kunasekaran ◽

Xin Chen ◽

Valentina Costantino ◽

Abrar Chughtai ◽

Raina MacIntyre

Keyword(s):

Neutralizing Antibodies ◽

Immunological Memory ◽

Evidence Base ◽

Childhood Vaccination ◽

Smallpox Vaccination ◽

Cross Sectional ◽

Modeling Studies ◽

Cdc Guidelines ◽

Duration Of Protection ◽

The Impact

Introduction:Smallpox has been eradicated, but advances in synthetic biology have increased the risk of its re-emergence. Residual immunity in individuals who were previously vaccinated may mitigate the impact of an outbreak, but there is a high degree of uncertainty regarding the duration and degree of residual immunity.Methods:A systematic literature review using the PRISMA criteria was conducted to quantify the duration and extent of residual immunity to smallpox after vaccination. 29 papers related to quantifying residual immunity to smallpox after vaccination were identified.Results:Duration of protection of >20 years was consistently shown in the 16 retrospective cross-sectional studies, while the lowest estimated duration of protection was 11.7 years among the modeling studies. Childhood vaccination conferred longer duration of protection than vaccination in adulthood. Multiple vaccinations did not appear to improve immunity. Most studies suggest a longer duration of residual immunity (at least 20 years) than assumed in smallpox guidelines. Estimates from modeling studies were less but still greater than the 3-10 years suggested by the WHO Committee on International Quarantine or US CDC guidelines. These recommendations were probably based on observations and studies conducted while smallpox was endemic. The cut-off values for pre-existing antibody levels of >1:20 and >1:32 reported during the period of endemic smallpox circulation may not be relevant to the contemporary population but have been used as a threshold for identifying people with residual immunity in post-eradication era studies.Discussion:Of the total antibodies produced in response to smallpox vaccination, neutralizing antibodies have shown to contribute significantly to immunological memory. Although the mechanism of immunological memory and boosting is unclear, revaccination is likely to result in a more robust response. There is a need to improve the evidence base for estimates on residual immunity to better inform planning and preparedness for re-emergent smallpox.

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Medication Intake Is Associated with Lower Plasma Carotenoids and Higher Fat-Soluble Vitamins in the Cross-Sectional MARK-AGE Study in Older Individuals

Journal of Clinical Medicine ◽

10.3390/jcm9072072 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2072

Author(s):

Daniela Weber ◽

Bastian Kochlik ◽

Wolfgang Stuetz ◽

Martijn E. T. Dollé ◽

Eugène H. J. M. Jansen ◽

...

Keyword(s):

Regression Models ◽

Plasma Concentrations ◽

Older Individuals ◽

Linear Regression Models ◽

Cross Sectional ◽

Medication Intake ◽

The One ◽

Fat Soluble Vitamins ◽

The Impact ◽

Β Carotene

The regular use of medication may interfere with micronutrient metabolism on several levels, such as absorption, turnover rate, and tissue distribution, and this might be amplified during aging. This study evaluates the impact of self-reported medication intake on plasma micronutrients in the MARK-AGE Project, a cross-sectional observational study in 2217 subjects (age- and sex-stratified) aged 35–75 years from six European countries that were grouped according to age. Polypharmacy as possible determinant of micronutrient concentrations was assessed using multiple linear regression models adjusted for age-group, dietary fruit, vegetables, and juice intake, and other confounders. Younger participants reported taking fewer drugs than older participants. Inverse associations between medication intake and lutein (−3.31% difference per increase in medication group), β-carotene (−11.44%), α-carotene (−8.50%) and positive associations with retinol (+2.26%), α-tocopherol/cholesterol (+2.89%) and γ-tocopherol/cholesterol (+1.36%) occurred in multiple adjusted regression models. Combined usage of a higher number of medical drugs was associated with poorer status of carotenoids on the one hand and higher plasma concentrations of retinol, α- and γ-tocopherol on the other hand. Our results raise concerns regarding the safety of drug combinations via the significant and surprisingly multifaceted disturbance of the concentrations of relevant micronutrients.

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Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure

10.21203/rs.2.13120/v2 ◽

2019 ◽

Author(s):

Christian Siebel ◽

Gudrun Würthwein ◽

Claudia Lanvers-Kaminsky ◽

Nicolas André ◽

Frank Berthold ◽

...

Keyword(s):

Young Children ◽

Drug Exposure ◽

Plasma Concentrations ◽

Treatment Strategies ◽

Population Pharmacokinetic ◽

Delphi Consensus ◽

Treatment Regimens ◽

Consensus Procedure ◽

Dosing Strategies ◽

Pharmacokinetic Simulations

Abstract Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects. Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process. Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended. Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.

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Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure

10.21203/rs.2.13120/v3 ◽

2020 ◽

Author(s):

Christian Siebel ◽

Gudrun Würthwein ◽

Claudia Lanvers-Kaminsky ◽

Nicolas André ◽

Frank Berthold ◽

...

Keyword(s):

Young Children ◽

Drug Exposure ◽

Plasma Concentrations ◽

Treatment Strategies ◽

Population Pharmacokinetic ◽

Delphi Consensus ◽

Treatment Regimens ◽

Consensus Procedure ◽

Dosing Strategies ◽

Pharmacokinetic Simulations

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Quality of Life Impact and Special Issues in Women with Inflammatory Bowel Diseases

10.21203/rs.3.rs-223640/v1 ◽

2021 ◽

Author(s):

Gabriel Constantinescu ◽

Gina Gheorghe ◽

Ecaterina Rinja ◽

Oana Plotogea ◽

Vasile Sandru ◽

...

Keyword(s):

Quality Of Life ◽

Inflammatory Bowel Diseases ◽

Standard Of Care ◽

Cross Sectional ◽

Men And Women ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

The Impact ◽

Gender Specific

Abstract Background: The impact of inflammatory bowel diseases (IBD) on quality of life (QoL) of patients is significant and has important social and professional consequences. Methods: We aimed to describe the patients’ perspective regarding the impact of IBD on their overall QoL and to evaluate the differences between men and women. An observational cross-sectional study, that included 180 patients with IBD in clinical remission, was conducted. All the patients completed a number of 3 questionnaires in order to evaluate the general aspects of their QoL. A separate questionnaire was created regarding gender-specific issues in women with IBD encounter. Also, particular features such as the incidence of anemia and osteoporosis among IBD patients were documented. The data obtained were analyzed and compared between the two gender-classified groups. Results: According to the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), patients had a general perception of a good QoL, but the impact was higher in women. Fatigue and tiredness were severely perceived almost to the same degree regardless of gender, whereas anxiety and unemployment were more present in men. No significant differences in women with IBD during active disease and during disease remission were found. Conclusions: The overall quality of life of IBD patients is affected in many aspects, leading to the deterioration of their social and professional lives, for both men and women, but some aspects remain gender-specific and require a personalized standard of care.

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Single Bout Exercise in Children with Juvenile Idiopathic Arthritis: Impact on Inflammatory Markers

Mediators of Inflammation ◽

10.1155/2018/9365745 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Rochette Emmanuelle ◽

Duché Pascale ◽

Hourdé Christophe ◽

Evrard Bertrand ◽

Pereira Bruno ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Inflammatory Markers ◽

Acute Exercise ◽

Venous Blood ◽

Plasma Concentrations ◽

Exercise Bout ◽

Fold Increase ◽

Leg Pain ◽

Single Bout ◽

The Impact

Objective. In a context of inflammatory disease such as juvenile idiopathic arthritis (JIA), we do not know what impact physical activity may have on a deregulated immune system. The objective is to measure the impact of a single bout of exercise on plasma inflammatory markers such as calprotectin, IL-6, sIL-6R, sgp130, and the hypothalamic-pituitary-adrenal axis in children with juvenile idiopathic arthritis. Methods. Twelve children with JIA performed a nonexercise control day and a consecutive day that included a 20 min exercise bout at 70% of max-HR at 08:30 am. Venous blood samples were taken at 08:30, 08:50, 09:30, 10:30 am, and 12:00 pm to measure plasma concentrations of calprotectin, IL-6, sIL-6R, sgp130, cortisol, and ACTH. Pain was evaluated at 08:30, 08:50 am, and 06:00 pm. Results. There was a transient twofold increase in postexercise self-evaluated pain (p=0.03) that disappeared in the evening. A single bout of exercise resulted in a 1.7-fold increase in plasma calprotectin (p<0.001) but not IL-6 and its soluble receptors. Calprotectin levels returned to baseline within 3 hours after cessation of exercise. Conclusion. Acute exercise in children with JIA induced slightly musculoskeletal leg pain and transient increased plasma calprotectin levels but not IL-6 levels. Trial registration in ClinicalTrials.gov, reference number NCT 02502539, registered on 29 May 2015.

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Using PBPK Modeling to Predict Drug Exposure and Support Dosage Adjustments in Patients With Renal Impairment: An Example with Lamivudine

Current Drug Discovery Technologies ◽

10.2174/1570163816666190214164916 ◽

2020 ◽

Vol 17 (3) ◽

pp. 387-396 ◽

Cited By ~ 1

Author(s):

Kushal Shah ◽

Briann Fischetti ◽

Agnes Cha ◽

David R. Taft

Keyword(s):

Renal Impairment ◽

Drug Exposure ◽

Plasma Concentrations ◽

Systemic Exposure ◽

Transcriptase Inhibitor ◽

Pbpk Modeling ◽

Published Data ◽

Post Dose ◽

Model Simulations ◽

The Impact

Background: Lamivudine is a nucleoside reverse transcriptase inhibitor used to treat HIV and hepatitis B. It is primarily cleared by the kidney with renal secretion mediated by OCT2 and MATE. Objective: To use PBPK modeling to assess the impact of renal impairment on lamivudine pharmacokinetics using the Simcyp® Simulator. Methods: The model incorporated the Simcyp® Mechanistic Kidney Model option to predict renal disposition. The model was initially verified using the Simcyp® Healthy Volunteer population. Two discrete patient populations were then created for moderate (GFR 10-40 mL/min) and severe (GFR < 10 mL/min) renal failure (RF), and model simulations were compared to published data. The developed model was then utilized in a clinical study evaluating the clinical experience and plasma exposure of lamivudine when administered at higher than recommended doses to HIV-infected patients with varying degrees of renal impairment. Results: Predicted systemic exposure metrics (Cmax, AUC) compared favorably to published clinical data for each population, with the following fold errors (FE, ratio of predicted and observed data) for Cmax/AUC: Healthy Volunteers 1.04/1.04, Moderate RF 1.03/0.78, Severe RF 0.89/0.79. The model captured lamivudine plasma concentrations measured pre- and post-dose (0.5-1.5hr) in study participants (n = 34). Model simulations demonstrated comparable systemic profiles across patient cohorts, supporting the proposed dosage adjustment scheme. Conclusion: This study illustrates how PBPK modeling can help verify dosing guidelines for patients with varying levels of renal impairment. This approach may also be useful for predicting potential changes in exposure during renal insufficiency for compounds undergoing clinical development.

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P072 Evaluation of dosing strategies of anti-TNFα monoclonal antibodies using pharmacokinetic modelling and simulation

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.201 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S171-S172

Author(s):

A Démaris ◽

A M Grišić ◽

W Huisinga ◽

R Walter ◽

C Kloft

Keyword(s):

Monoclonal Antibodies ◽

Body Size ◽

Fixed Dose ◽

Dosing Regimen ◽

Target Concentration ◽

Concentration Time ◽

Dosing Strategies ◽

Dosing Strategy ◽

The Impact ◽

Size Descriptor

Abstract Background Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed. Methods A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy. Results For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing. Conclusion By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively). References

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Clearance of Sclerostin, Osteocalcin, Fibroblast Growth Factor 23, and Osteoprotegerin by Dialysis

Blood Purification ◽

10.1159/000465513 ◽

2017 ◽

Vol 44 (2) ◽

pp. 122-128 ◽

Cited By ~ 2

Author(s):

Nicholas Carlson ◽

Ole H. Mortensen ◽

Mette Axelsen ◽

Robert S. Pedersen ◽

James G. Heaf

Keyword(s):

Growth Factor ◽

Bone Metabolism ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Plasma Concentrations ◽

Fibroblast Growth ◽

Ultrafiltration Rate ◽

Cross Sectional ◽

Blood Concentrations ◽

The Impact

Introduction: Fibroblast growth factor (FGF23), sclerostin, osteocalcin, and osteoprotegerin are important factors that control mineral bone metabolism. End-stage renal disease is associated with the pronounced dysregulation of mineral bone metabolism; however, the impact and clearance of mineral bone metabolism factors during dialysis remain largely undescribed. Methods: In a cross-sectional study, 10 chronic hemodialysis patients were treated with hemodialysis for 8 h using a high-flux filter and a dialysate bath of 50% calculated total body water continuously recycled at a rate of 500 mL/min. Plasma and dialysate concentrations of FGF23, sclerostin, osteoprotegerin, and osteocalcin were measured at 1, 2, 4, 6, and 8 h permitting the estimation of dialysis clearance. Results: Clearance of FGF23 was 7.7 mL/min, of sclerostin was 7.6 mL/min, of osteoprotegerin was 1.2 mL/min, and of osteocalcin was 19.7 mL/min. Clearance of FGF23 was correlated to sclerostin and osteoprotegerin clearance and also to the ultrafiltration rate. Although, osteocalcin blood concentrations decreased during dialysis, they rebounded within 6 h. Overall, no significant changes in blood concentrations of the measure mineral bone metabolism factors were observed. Conclusions: The intradialytic clearance of osteocalcin, FGF23, sclerostin, and osteoprotegerin occurs; however, only clearance of FGF23 is directly correlated with the ultrafiltration rate. The effects of dialytic clearance on mineral bone metabolism are, however, uncertain and intradialytic plasma concentrations of the studied substrates remained largely unchanged.

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Inflammatory Response 24 h Post-Exercise in Youth with Juvenile Idiopathic Arthritis

International Journal of Sports Medicine ◽

10.1055/a-0640-9063 ◽

2018 ◽

Vol 39 (11) ◽

pp. 867-874 ◽

Cited By ~ 1

Author(s):

Emmanuelle Rochette ◽

Etienne Merlin ◽

Christophe Hourdé ◽

Bertrand Evrard ◽

Bruno Peraira ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Venous Blood ◽

Plasma Concentrations ◽

Exercise Bout ◽

Fold Increase ◽

Cycle Ergometer ◽

Short Term ◽

Post Exercise ◽

Post Exercise Recovery ◽

The Impact

AbstractThe aim of this study was to measure the impact, at 24 h post-exercise, of a single exercise bout on plasma inflammatory markers such as calprotectin, IL-6, sIL-6 R, sgp130 and the hypothalamic-pituitary-adrenal (HPA) axis in children with juvenile idiopathic arthritis (JIA).Twelve children with JIA attended the laboratory on three consecutive days (control day, exercise day and 24 h post-exercise), including a 20-min exercise bout on a cycle-ergometer at 70% of max. HR at 8:30 a.m. on day 2. Plasma concentrations of calprotectin, IL-6, sIL-6 R, sgp130, cortisol, ACTH and DHEA were measured on venous blood samples taken every day.at rest and at 8:30, 8:50, 9:30, 10:30 a.m. and 12:00, 3:00, 5:30 p.m.A single exercise bout increased plasma calprotectin 1.7-fold (p<0.001) but did not increase IL-6 and soluble IL-6 receptors in short-term post-exercise recovery. However, at 24 h post-exercise, calprotectin, IL-6 and its receptors had decreased compared to control-day levels. There was a transient 2-fold increase in post-exercise self-evaluated pain (p=0.03) that disappeared in the evening without repercussions the following day.Physical activity in children with JIA results in a slight transient systemic inflammation but seems to be followed by counter-regulation at 24 h post-exercise with a decrease in proinflammatory markers.

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