Publications by authors named "Stephen J Balevic"

18 Publications

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Delivering clinical trials at home: protocol, design and implementation of a direct-to-family paediatric lupus trial.

Lupus Sci Med 2021 May;8(1)

Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA

Introduction: Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.

Methods: Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.

Discussion And Dissemination: Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.

Trial Registration Number: ClinicalTrials.gov Registry (NCT04358302).
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http://dx.doi.org/10.1136/lupus-2021-000494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108689PMC
May 2021

The importance of pregnancy planning in lupus pregnancies.

Lupus 2021 Apr 28;30(5):741-751. Epub 2021 Jan 28.

Duke University Medical Center, Durham, NC, USA.

Objective: In seeking new approaches to improve lupus pregnancy outcomes, we study the association between pregnancy planning, behaviors recommended by American College of Rheumatology's Reproductive Health Guideline 2020, and pregnancy and infant outcomes.

Methods: Lupus pregnancies in a prospective registry (1/1/2018 to 4/1/2020) were classified as planned or not-planned using the patient-reported London Measure of Unplanned Pregnancy. These groups were compared for demographics, pre-pregnancy disease activity, pregnancy planning behaviors, and delivery outcomes.

Results: Among 43 women with 43 singleton pregnancies the average age was 29.4 years and 42% were Black. Overall, 60% were planned pregnancies and 40% were not-planned (16 ambivalent, 1 unplanned). Women with not-planned pregnancies had lower age, income, and education, and more required Medicaid. Women with not-planned pregnancies were more likely to conceive when lupus activity was higher (p = 0.001), less likely to receive pre-pregnancy counseling with a rheumatologist (p = 0.02), and less likely to continue pregnancy-compatible medications (p = 0.03). Severe PROMISSE adverse pregnancy outcomes (APOs) and severe neonatal outcomes were higher among women with not-planned than planned pregnancies (43% vs 0% p = 0.003; 70% vs 30% p = 0.06).

Conclusion: This study identifies pregnancy intention as a potentially modifiable risk factor for poor outcomes in women with lupus. It highlights a unique population of women with lupus at high risk for pregnancy and infant complications: those ambivalent about pregnancy. These women may not be effectively engaging in health behaviors that prevent pregnancy nor those that will prepare for a safe pregnancy. With effective pregnancy planning and contraception guidance, we may decrease their risk for maternal-fetal morbidity and mortality.
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http://dx.doi.org/10.1177/0961203321989803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026487PMC
April 2021

Hydroxychloroquine and COVID-19: a Rheumatologist's Take on the Lessons Learned.

Curr Allergy Asthma Rep 2021 01 21;21(1). Epub 2021 Jan 21.

Duke University Medical Center, Box 2978, Durham, NC, 27710, USA.

Purpose Of Review: Told from the viewpoint of rheumatologists, this review tells the story of hydroxychloroquine and its swift ascent to become a household name as a therapeutic strategy against the novel SARS-CoV-2 virus. This review describes the history, mechanisms, pharmacokinetics, therapeutic applications, and safety profile of hydroxychloroquine as an immunomodulatory and antiviral agent. It also summarizes the major studies that launched and assessed the use of hydroxychloroquine against COVID-19 infection.

Recent Findings: More recent literature calls into question the long-held dogma that endolysosomal alkalinization is the primary mode of action of hydroxychloroquine. Ongoing uncertainty about the multiple potential mechanisms contributing to the therapeutic effect of hydroxychloroquine in rheumatic and viral disease led to a natural avenue for exploration in the treatment of COVID-19. Taken as a whole, the literature does not support utilizing hydroxychloroquine to treat or prevent infection from the SARS-CoV-2 virus. This is, at least in part, due to the wide variability in hydroxychloroquine pharmacokinetics between patients and difficulty achieving adequate target tissue concentrations of hydroxychloroquine without encountering unacceptable toxicities. Hydroxychloroquine continues to be a routinely prescribed, well-tolerated, effective, and low-cost treatment for rheumatic disease. Its therapeutic versatility has led to frequent repurposing for other conditions, most recently as an investigative treatment against the SARS-CoV-2 virus. Despite overall negative findings, the intense study of hydroxychloroquine against COVID-19 infection has enhanced our overall understanding of how hydroxychloroquine operates in autoimmune disease and beyond.
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http://dx.doi.org/10.1007/s11882-020-00983-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818062PMC
January 2021

Bringing research directly to families in the era of COVID-19.

Pediatr Res 2021 02 11;89(3):404-406. Epub 2020 Nov 11.

Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.

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http://dx.doi.org/10.1038/s41390-020-01260-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656893PMC
February 2021

Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019.

JAMA Pediatr 2020 10 5;174(10):e202422. Epub 2020 Oct 5.

Duke Clinical Research Institute, Durham, North Carolina.

Importance: Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required.

Objective: To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment.

Design, Setting, And Participants: Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population.

Interventions: Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies.

Main Outcomes And Measures: The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration.

Results: For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL).

Conclusions And Relevance: This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.
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http://dx.doi.org/10.1001/jamapediatrics.2020.2422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275264PMC
October 2020

Dr. Balevic, reply.

J Rheumatol 2020 10 25;47(10):1587. Epub 2020 May 25.

Duke Clinical Research Institute, Durham, North Carolina.

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http://dx.doi.org/10.3899/jrheum.200681DOI Listing
October 2020

Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials.

J Rheumatol 2020 May 11. Epub 2020 May 11.

From the Department of Rheumatology and Immunology, Duke University School of Medicine, Durham, North Carolina, USA; Duke Clinical Research Institute, Durham, North Carolina, USA; Department of Pediatrics, and the Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Evanston, Illinois, USA; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. This study was supported by the Rheumatology Research Foundation's Scientist Development Award, the Thrasher Research Fund, the Childhood Arthritis and Rheumatology Research Alliance/Arthritis Foundation, the Derfner Foundation, NIGMS/NICHD (2T32GM086330-06), NICHD (5R01-HD076676-04, HHSN275201000003I), and a Duke Health/Private Diagnostic Clinic ENABLE grant. The Atherosclerosis Prevention in Pediatric Lupus Erythematosus [APPLE (ClinicalTrials. gov: NCT00065806)] trial is supported by the US National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) contract N01-AR-2-2265, the Edna and Fred L. Mandel Jr. Center for Hypertension and Atherosclerosis, and Pfizer, which provided atorvastatin and matching placebo. S.J.B. receives support from the NIH (5R01-HD076676-04, 1R01HD083003-01, HHSN275201000003I, HHSN275201800003I, HHSN272201500006I 5U24-TR001608-03), the US Food and Drug Administration (5U18FD006298-03), the Patient-Centered Outcomes Research Institute (PCORI), the Rheumatology Research Foundation's Scientist Development Award, the Thrasher Research Fund, and the Childhood Arthritis and Rheumatology Research Alliance/Arthritis Foundation. C.P.H. receives salary support for research from the National Institute for Child Health and Human Development (NICHD; 1K23HD090239; R13HD102136), National Heart Lung and Blood Institute (R61/R33HL147833), FDA (1R01-FD006099, PI: Laughon; and 5U18-FD006298, PI: Benjamin), the US government for his work in pediatric clinical pharmacology (Government Contract HHSN275201800003I, PI: Benjamin under the Best Pharmaceuticals for Children Act), the nonprofit Burrhoughs Wellcome Fund, and other sponsors for drug development in adults and children (dcri.org/about-us/ conflict-of-interest). D.G. receives support for research from the Eunice Kennedy Shriver NICHD (5R01HD096435). A.M. receives research support from the Thrasher Research Fund (www.thrasherresearch.org). L.E.S. receives support for research from the NIH (U19AR069522), PCORI (8177), and the Childhood Arthritis and Rheumatology Research Alliance. She is on the Data Safety Monitoring Board for investigational product trials for UCB (Cimzia) and Sanofi (sarilumab). Sanofi is a maker of hydroxychloroquine. Samples used in this publication were collected as part of NIH/NIAMS (N01-AR-2-2265). A.M.E. receives support from the NIH National Center for Advancing Translational Sciences. G.K.S. receives support for research from the NIH (UG1 HD068258‑06, HHSN272201300017I, 1UL1TR002553-01, R21AI132677) and the Centers for Disease Control and Prevention (200-2012-53663). She chairs an Independent Data Monitoring Committee for GlaxoSmithKline (RSV vaccine trials). M.C.W. receives support for research from the NIH (1R01-HD076676‑01A1 and 1K24-AI143971), National Institute of Allergy and Infectious Diseases (HHSN272201500006I and HHSN272201300017I), NICHD (HHSN275201000003I), FDA (5U18-FD006298), and the industry for drug development in adults and children. S.J. Balevic, MD, MHS, Department of Rheumatology and Immunology, and Department of Pediatrics, Duke University School of Medicine, and Duke Clinical Research Institute; C.P. Hornik, MD, PhD, Duke Clinical Research Institute, and Department of Pediatrics, Duke University School of Medicine; T.P. Green, MD, MS, Department of Pediatrics, Northwestern University, Feinberg School of Medicine; M.E. Clowse, MD, MPH, Department of Rheumatology and Immunology, Duke University School of Medicine; D. Gonzalez, PharmD, PhD, Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill; A.R. Maharaj, PhD, Duke Clinical Research Institute; L.E. Schanberg, MD, Duke Clinical Research Institute, and Department of Pediatrics, Duke University School of Medicine; A.M. Eudy, PhD, Department of Rheumatology and Immunology, Duke University School of Medicine; G.K. Swamy, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Duke University School of Medicine; B.L. Hughes, MD, MSc, Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Duke University School of Medicine; M. Cohen-Wolkowiez, MD, PhD, Duke Clinical Research Institute, and Department of Pediatrics, Duke University School of Medicine. Address correspondence to Dr. S.J. Balevic, Department of Rheumatology and Immunology, Duke University School of Medicine, 2301 Erwin Road, CHC, T-Level, Durham, North Carolina 27710, USA. E-mail: Full Release Article. For details see Reprints and Permissions at jrheum. org. Accepted for publication May 14, 2019.

Objective: To characterize hydroxychloroquine (HCQ) exposure in patients with rheumatic disease receiving longterm HCQ compared to target concentrations with reported antiviral activity against the coronavirus disease 2019 caused by SARS-CoV-2 (COVID-19).

Methods: We evaluated total HCQ concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric systemic lupus erythematosus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted HCQ concentrations to target concentrations with reported antiviral activity against SARS-CoV-2.

Results: The average total serum/plasma HCQ concentrations were below the lowest SARS-CoV-2 target of 0.48 mg/l in all studies. Assuming the highest antiviral target exposure (total plasma concentration of 4.1 mg/l), all studies had about one-tenth the necessary concentration for viral inhibition. Pharmacokinetic model simulations confirmed that pregnant adults receiving common dosing for rheumatic diseases did not achieve target exposures; however, the models predict that a dosage of 600 mg once a day during pregnancy would obtain the lowest median target exposure for most patients after the first dose.

Conclusion: We found that the average patient receiving treatment with HCQ for rheumatic diseases, including children and non-pregnant/pregnant adults, are unlikely to achieve total serum or plasma concentrations shown to inhibit SARS-CoV-2 . Nevertheless, patients receiving HCQ long term may have tissue concentrations far exceeding that of serum/plasma. Because the therapeutic window for HCQ in the setting of SARS-CoV-2 is unknown, well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for HCQ.
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http://dx.doi.org/10.3899/jrheum.200493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655510PMC
May 2020

Cefazolin pharmacokinetics in premature infants.

J Perinatol 2019 09 3;39(9):1213-1218. Epub 2019 Apr 3.

Duke Clinical Research Institute, Durham, NC, USA.

Objective: Pharmacokinetic (PK) data to guide cefazolin dosing in premature infants are virtually non-existent. Therefore, we aimed to characterize cefazolin PK in infants aged ≤32 weeks of gestation at birth.

Study Design: We conducted a prospective, open-label PK and safety study of cefazolin in infants ≤32 weeks gestation from a University Medical Center. We administered intravenous cefazolin and collected both timed and scavenged blood samples. We analyzed data using non-linear mixed effect modeling and simulated several dosage regimens to achieve target concentrations against methicillin-susceptible Staphylococcus aureus.

Results: We analyzed 40 samples from nine infants and observed that premature infants had lower clearance and greater volume of distribution for cefazolin compared to older children. The median (range) individual Bayesian estimates were 0.03 L/h/kg (0.01-0.08) for clearance and 0.39 L/kg (0.31-0.52) for volume.

Conclusion: Simulations suggested reduced cefazolin dosing based on postmenstrual age achieve target concentrations and potentially reduce unnecessary exposure.
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http://dx.doi.org/10.1038/s41372-019-0368-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713589PMC
September 2019

Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children.

Clin Pharmacokinet 2019 07;58(7):887-898

Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.

Objective: The aims of this study were to (1) determine whether opportunistically collected data can be used to develop physiologically based pharmacokinetic (PBPK) models in pediatric patients; and (2) characterize age-related maturational changes in drug disposition for the renally eliminated and hepatically metabolized antibiotic trimethoprim (TMP)-sulfamethoxazole (SMX).

Methods: We developed separate population PBPK models for TMP and SMX in children after oral administration of the combined TMP-SMX product and used sparse and opportunistically collected plasma concentration samples to validate our pediatric model. We evaluated predictability of the pediatric PBPK model based on the number of observed pediatric data out of the 90% prediction interval. We performed dosing simulations to target organ and tissue (skin) concentrations greater than the methicillin-resistant Staphylococcus aureus (MRSA) minimum inhibitory concentration (TMP 2 mg/L; SMX 9.5 mg/L) for at least 50% of the dosing interval.

Results: We found 67-87% and 71-91% of the observed data for TMP and SMX, respectively, were captured within the 90% prediction interval across five age groups, suggesting adequate fit of our model. Our model-rederived optimal dosing of TMP at the target tissue was in the range of recommended dosing for TMP-SMX in children in all age groups by current guidelines for the treatment of MRSA.

Conclusion: We successfully developed a pediatric PBPK model of the combination antibiotic TMP-SMX using sparse and opportunistic pediatric pharmacokinetic samples. This novel and efficient approach has the potential to expand the use of PBPK modeling in pediatric drug development.
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http://dx.doi.org/10.1007/s40262-018-00733-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586496PMC
July 2019

Pharmacokinetics of ticarcillin-clavulanate in premature infants.

Br J Clin Pharmacol 2019 05 6;85(5):1021-1027. Epub 2019 Mar 6.

Duke University Medical Center, Durham, NC, USA.

Ticarcillin-clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants <30 weeks gestational age, pharmacokinetic data to guide ticarcillin-clavulanate dosing are lacking. We enrolled 15 premature infants <30 weeks gestational age, determined pharmacokinetic parameters, and performed dosing simulations to determine optimal dosing for ticarcillin-clavulanate. The infants had a median (range) postnatal age (PNA) of 18 days (6-44 days) and gestational age of 25 weeks (23-28 weeks). Clearance was lower in infants with a PNA <14 days (0.050 L/kg/h [range 0.043-0.075]) compared with a PNA ≥14-45 days (0.078 L/kg/h [0.047-0.100]), consistent with maturation of renal function. Dosing simulations determined that ticarcillin 75 mg/kg q12h (PNA <14 days) or q8h (PNA ≥ 14-45 days) achieved the target exposure for organisms with a minimum inhibitory concentration ≤16 μ/mL in >90% of simulated infants. For highly resistant organisms (minimum inhibitory concentration 32 μg/mL), increased dosing frequency or extended infusion are necessary.
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http://dx.doi.org/10.1111/bcp.13882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475694PMC
May 2019

Hydroxychloroquine Levels throughout Pregnancies Complicated by Rheumatic Disease: Implications for Maternal and Neonatal Outcomes.

J Rheumatol 2019 01 1;46(1):57-63. Epub 2018 Oct 1.

From the departments of Internal Medicine and Pediatrics, Duke University, and Duke Clinical Research Institute, Durham, North Carolina; Department of Pediatrics, Children's Hospital of Chicago, Chicago, Illinois, USA.

Objective: Pregnancies in women with active rheumatic disease often result in poor neonatal outcomes. Hydroxychloroquine (HCQ) reduces disease activity and flares; however, pregnancy causes significant physiologic changes that may alter HCQ levels and lead to therapeutic failure. Therefore, our objective was to evaluate HCQ concentrations during pregnancy and relate levels to outcomes.

Methods: We performed an observational study of pregnant patients with rheumatic disease who were taking HCQ from a single center during 2013-2016. Serum samples were analyzed using high-performance liquid chromatography/mass spectrometry. Primary HCQ exposure was categorized as nontherapeutic (≤ 100 ng/ml) or therapeutic (> 100 ng/ml). Categorical outcomes were analyzed using Fisher's exact test and continuous outcomes using linear regression models, Wilcoxon signed-rank test, Kruskal-Wallis test, t test, and ANOVA.

Results: We analyzed 145 samples from 50 patients with rheumatic disease, 56% of whom had systemic lupus erythematosus (SLE). HCQ concentration varied widely among individuals at each trimester. Mean physician's global assessment scores in patients with SLE were significantly higher in those with average drug levels ≤ 100 ng/ml compared to > 100 ng/ml (0.93 vs 0.32, p = 0.01). Of patients with SLE, 83% with average drug levels ≤ 100 ng/ml delivered prematurely (n = 6), compared to only 21% with average levels > 100 ng/ml (n = 19; p = 0.01). HCQ levels were not associated with prematurity or disease activity in non-SLE patients.

Conclusion: With both high and low HCQ levels associated with preterm birth and disease activity in SLE, further study is necessary to understand HCQ disposition throughout pregnancy and to clarify the relationship between drug levels and outcomes.
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http://dx.doi.org/10.3899/jrheum.180158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314916PMC
January 2019

Pharmacokinetics of Hydroxychloroquine in Pregnancies with Rheumatic Diseases.

Clin Pharmacokinet 2019 04;58(4):525-533

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.

Background: Hydroxychloroquine is an oral drug prescribed to pregnant women with rheumatic disease to reduce disease activity and prevent flares. Physiologic changes during pregnancy may substantially alter drug pharmacokinetics. However, the effect of pregnancy on hydroxychloroquine disposition and the potential need for dose adjustment remains virtually unknown.

Methods: We performed a population-pharmacokinetic analysis using samples from the Duke Autoimmunity in Pregnancy Registry from 2013 to 2016. We measured hydroxychloroquine concentration using high-performance liquid chromatography/tandem mass spectrometry and analyzed data using non-linear mixed-effect modeling. We calculated differences between pregnancy and postpartum empirical Bayesian estimates using paired t tests. We computed steady-state concentration profiles for hydroxychloroquine during pregnancy and postpartum using individual clinical data and empirical Bayesian estimates developed from the final pharmacokinetic model.

Results: We obtained 145 serum samples from 50 patients, 25 of whom had paired pregnancy and postpartum specimens. Five subjects had average concentrations (pregnancy and postpartum) < 100 ng/mL, consistent with medication non-adherence, and were excluded. The population estimated apparent volume of distribution was 1850 L/70 kg and estimated apparent clearance was 51 L/h. Compared with postpartum, median apparent volume of distribution increased significantly during pregnancy (p < 0.001), whereas apparent clearance and 24-h area under the curve did not change.

Conclusions: We developed a one-compartment population-pharmacokinetic model for hydroxychloroquine in pregnant women with rheumatic disease. Estimates for serum CL were within the expected range for plasma in non-pregnant adults. Because CL and 24-h area under the curve did not change during pregnancy compared with postpartum, our modeling in this small cohort does not support adjusting hydroxychloroquine dose during pregnancy.
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http://dx.doi.org/10.1007/s40262-018-0712-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397666PMC
April 2019

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children.

J Clin Pharmacol 2018 10;58 Suppl 10:S58-S72

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.

Almost half of recent pediatric trials failed to achieve labeling indications, in large part because of inadequate study design. Therefore, innovative study methods are crucial to optimizing trial design while also reducing the potential harms inherent with drug investigation. Several methods exist to optimize the amount of pharmacokinetic data collected from the smallest possible volume and with the fewest number of procedures, including the use of opportunistic and sparse sampling, alternative and noninvasive matrices, and microvolume assays. In addition, large research networks using master protocols promote collaboration, reduce regulatory burden, and increase trial efficiency for both early- and late-phase trials. Large pragmatic trials that leverage electronic health records can capitalize on central management strategies to reduce costs, enroll patients with rare diseases on a large scale, and augment study generalizability. Further, trial efficiency and safety can be optimized through Bayesian adaptive techniques that permit planned protocol changes based on analyses of prior and accumulated data. In addition to these trial design features, advances in modeling and simulation have paved the way for systems-based and physiologically based models that individualize pediatric dosing recommendations and support drug approval. Last, given the low prevalence of many pediatric diseases, collecting deidentified genetic and clinical data on a large scale is a potentially transformative way to augment clinical pharmacology research in children.
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http://dx.doi.org/10.1002/jcph.1053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310922PMC
October 2018

Increasing contraception use among women receiving teratogenic medications in a rheumatology clinic.

BMJ Open Qual 2018 25;7(3):e000269. Epub 2018 Jul 25.

Division of Geriatrics, Department of Medicine, Duke Health, Durham, North Carolina, USA.

Teratogenic medications are often prescribed to women of childbearing age with autoimmune diseases. Literature suggests that appropriate use of contraception among these women is low, potentially resulting in high-risk unintended pregnancies. Preliminary review in our clinic showed suboptimal documentation of women's contraceptive use. We therefore designed a quality improvement initiative to target three process measures: documentation of contraception usage and type, contraception counselling and provider action after counselling. We reviewed charts of rheumatology clinic female patients aged 18-45 over the course of 10 months; for those who were on teratogenic medications (methotrexate, leflunomide, mycophenolate and cyclophosphamide), we looked for evidence of documentation of contraception use. We executed multiple plan-do-study-act (PDSA) cycles to develop and evaluate interventions, which centred on interprofessional provider education, modification of electronic medical record (EMR) templates, periodic provider reminders, patient screening questionnaires and frequent feedback to providers on performance. Among eligible patients (n=181), the baseline rate of documentation of contraception type was 46%, the rate of counselling was 30% and interventions after counselling occurred in 33% of cases. Averaged intervention data demonstrated increased provider performance in all three domains: documentation of contraception type increased to 64%, counselling to 45% and provider action to 46%. Of the patients with documented contraceptives, 50% used highly effective, 27% used effective and 23% used ineffective contraception methods. During this project, one unintentional pregnancy occurred in a patient on methotrexate not on contraception. Our interventions improved three measures related to contraception counselling and documentation, but there remains a need for ongoing quality improvement efforts in our clinic. This high-risk population requires increased provider engagement to improve contraception compliance, coupled with system-wide EMR changes to increase sustainability.
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http://dx.doi.org/10.1136/bmjoq-2017-000269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069913PMC
July 2018

Clinical Trial Design in Juvenile Idiopathic Arthritis.

Paediatr Drugs 2017 Oct;19(5):379-389

Division of Pediatric Rheumatology, Duke University Medical Center, 2301 Erwin Road, CHC, T-Level, Durham, NC, 27710, USA.

Randomized clinical trials provide the gold standard evidence base to guide clinical practice. Despite major advances in trial design, pediatric clinical trials are still difficult to perform and pose unique challenges, including the need to consider the impact of developmental changes in trial design. Advances within pediatric rheumatology combined with the need to comply with legislative requirements have driven new approaches to performing pediatric clinical trials such as utilization of large research networks, incorporation of patient and family stakeholders in the planning and implementation of clinical trials, and the development of novel trial designs. The expansion of available biological therapeutics that now includes biosimilar drugs highlights the important and difficult balance of providing new and cost-effective drugs to children while ensuring safety in a vulnerable population. Future advances in juvenile idiopathic arthritis (JIA) clinical trials will likely be the application of precision medicine based on biologic, rather than phenotypic, classification of JIA, with improved understanding of pediatric clinical pharmacology. Clinical trial simulations and comparative effectiveness studies are important supplements to traditional clinical trials, permitting efficient studies and results that are more generalizable.
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http://dx.doi.org/10.1007/s40272-017-0244-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105333PMC
October 2017

Prescribing for Children With Rheumatic Disease: Perceived Treatment Approaches Between Pediatric and Adult Rheumatologists.

Arthritis Care Res (Hoboken) 2018 02;70(2):268-274

University of Michigan, Ann Arbor.

Objective: To compare practice patterns and prescribing differences for juvenile idiopathic arthritis (JIA) between adult rheumatologists (ARs) and pediatric rheumatologists (PRs), the perceived educational needs, and factors that enhance or impede co-management.

Methods: Two parallel, cross-sectional surveys focusing on JIA were administered in 2009 to a random sample of 193 PRs and 500 ARs using the American College of Rheumatology membership file. Bivariate analysis was conducted for common items.

Results: The response rate was 62.1% for ARs (n = 306) and 72.3% for PRs (n = 138). Only 23% of responding ARs (n = 69) reported caring for children with JIA. Of these, 94% strongly agreed/agreed feeling comfortable diagnosing JIA; however, only 76% felt comfortable treating JIA. Clinical vignettes highlighted several prescribing differences. Forty-eight percent of ARs and 31% of PRs felt medications to treat JIA did not have clear dosing guidelines. Though PRs initiated disease-modifying antirheumatic drugs and biologic agents earlier, treatments were similar after 3 months. To enhance co-management, 74% of pediatric respondents endorsed shared medical records.

Conclusion: Nearly one-quarter of surveyed ARs care for children with JIA, with most limiting their practice to older children. There was more discomfort in treating JIA than diagnosing it, and there were significant prescribing differences. Both provider types identified the need for better dosing and treatment resources. Updated management guidelines along with exposure to pediatric rheumatology in fellowship could reduce treatment differences and enhance the care of children with JIA. Shared medical records and improvement in reimbursement may optimize co-management.
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http://dx.doi.org/10.1002/acr.23273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668199PMC
February 2018

Islands of Inflammation: Neurosarcoidosis.

Am J Med 2017 Feb 11;130(2):157-160. Epub 2016 Oct 11.

Division of Rheumatology, Duke University School of Medicine, Durham, NC; Division of Immunology, Duke University School of Medicine, Durham, NC.

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http://dx.doi.org/10.1016/j.amjmed.2016.09.009DOI Listing
February 2017

Profile of adalimumab and its potential in the treatment of uveitis.

Drug Des Devel Ther 2016 19;10:2997-3003. Epub 2016 Sep 19.

Department of Pediatric Rheumatology, Duke University Medical Center, Durham, NC, USA.

Uveitis refers to the presence of intraocular inflammation, and as a strict definition compromises the iris and ciliary body anteriorly and the choroid posteriorly (the uvea). Untreated, uveitis can lead to visual loss or blindness. The etiology of uveitis can include both infectious and noninfectious (usually immune-mediated) causes, the latter of which are often mediated predominantly by Th1 CD4 T-cells that secrete proinflammatory cytokines. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine involved in the pathogenesis of uveitis, which at high concentrations can cause excess inflammation and tissue damage. Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF-α. Historically, corticosteroids and methotrexate were used to treat uveitis; however, newer biologic agents such as adalimumab have revolutionized therapy for noninfectious uveitis. Adalimumab has shown efficacy in treating refractory uveitis in multiple settings, including idiopathic disease, juvenile idiopathic arthritis, sarcoidosis, Behçets disease, and uveitis secondary to spondyloarthropathies, among several other noninfectious uveitis conditions. In this paper, we will review the profile of adalimumab, the role of TNF-α in uveitis, discuss safety data, and summarize key articles evaluating the efficacy of adalimumab in treating uveitis secondary to the most commonly associated autoimmune diseases.
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http://dx.doi.org/10.2147/DDDT.S94188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034916PMC
May 2017