Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Sotrovimab 500 mg administered by a single intravenous (IV) infusion has been granted special approval for emergency use in Japan for treatment of SARS-CoV-2 infection in adults and children aged ≥ 12 years weighing ≥ 40 kg. This Phase 1, single-dose study investigated the pharmacokinetics, safety, and tolerability of IV or intramuscular (IM) sotrovimab 500 mg doses versus placebo in healthy Japanese and Caucasian volunteers. METHODS: This was a two-part, Phase 1, randomized, placebo-controlled, single-blind study. In Part 1, participants received a single sotrovimab 500 mg IV infusion or matching placebo on Day 1. In Part 2, participants received a single sotrovimab 500 mg IM dose or matching placebo on Day 1, administered as two 4 mL injections. RESULTS: There was no effect of ethnicity on the peak or total serum exposure of IV sotrovimab through Week 18; after adjusting for body weight, the point estimate and 90 % confidence interval for the ratio of total exposure between Japanese and Caucasian participants fell within conventional bioavailability bounds (80-125%). Geometric mean Cmax and AUClast following a single IM administration of sotrovimab were higher in Japanese participants compared with Caucasian participants, even after adjustment for body weight. Overall, a single IV or IM dose of sotrovimab was well tolerated by both Japanese and Caucasian participants. CONCLUSIONS: After adjusting for body weight, exposures following a single IV dose of sotrovimab 500 mg were similar between Japanese and Caucasian participants, and higher in Japanese participants following IM administration. Higher exposures were not associated with any safety signals. TRIAL REGISTRATION: ClinicalTrials.Gov: NCT04988152.

Formulary coverage for lipid-lowering drugs recommended for children.

OBJECTIVE/METHODS: A cross-sectional assessment to describe availability, coverage, and pediatric labeling status of lipid-lowering drugs offered by 1 private and 1 public insurance plan formularies. RESULTS: Both insurance plans had equal medication availability of bile acid sequestrants (7), statins (10), and cholesterol-absorption blockers (CAB; 1). The private plan had 3 bile acid sequestrants and 3 statins listed as preferred drugs; the CAB was not preferred. In contrast, the public plan had 5 bile acid sequestrants, 7 statins, and the CAB as preferred drugs. For medications with pediatric labeling, the private plan covered 50% as preferred drugs whereas the public plan covered 70% as preferred drugs. CONCLUSIONS: If new recommendations of the American Academy of Pediatrics for treatment of dyslipidemia in children were implemented today, children with the public plan would have equal choice but better coverage of lipid-lowering drugs as preferred drugs, including those with FDA approval, compared with children with the private plan.

Off-label utilization of antihypertensive medications in children.

OBJECTIVE: To examine off-label use and costs of antihypertensive drugs in children by using a national sample of prescription claims. METHODS: We conducted a cross-sectional study using the 2002 Medstat MarketScan Database, a national sample of outpatient prescription claims of children or=12 years were more likely to be prescribed off-label antihypertensives (53%) compared with children aged

Variation in pediatric asthma quality improvement programs by managed care plans.

Although asthma quality improvement (QI) programs are common, little is known about the scope and content of QI initiatives in managed care arrangements. The authors conducted a cross-sectional survey of all managed care plans in Michigan serving the pediatric Medicaid population. Using semi-structured interviews, they assessed the comprehensiveness of the asthma QI program regarding provider, allied health professional, pharmacy, and member services. Although all QI initiatives included some type of physician-directed component and patient-directed components, only half included allied health professionals and one quarter included pharmacy-directed components. Interactive physician continuing medical education was associated with plans whose members were concentrated in only 1 or 2 counties. The authors noted wide variation in content, format, inclusion of incentives, inclusion of other health professionals, and outcome goals. The variation in QI approaches by each of the managed care organizations suggests that there is a dearth of information on appropriate and cost-effective methods to improve pediatric asthma quality at the plan level.

Use of antihypertensive medications and diagnostic tests among privately insured adolescents and young adults with primary versus secondary hypertension.

PURPOSE: To compare the use of antihypertensive medications and diagnostic tests among adolescents and young adults with primary versus secondary hypertension. METHODS: We conducted retrospective cohort analysis of claims data for adolescents and young adults (12-21 years of age) with ≥3 years of insurance coverage (≥11 months/year) in a large private managed care plan during 2003-2009 with diagnosis of primary hypertension or secondary hypertension. We examined their use of antihypertensive medications and identified demographic characteristics and the presence of obesity-related comorbidities. For the subset receiving antihypertensive medications, we examined their diagnostic test use (echocardiograms, renal ultrasounds, and electrocardiograms). RESULTS: The study sample included 1,232 adolescents and young adults; 84% had primary hypertension and 16% had secondary hypertension. The overall prevalence rate of hypertension was 2.6%. One quarter (28%) with primary hypertension had one or more antihypertensive medications, whereas 65% with secondary hypertension had one or more antihypertensive medications. Leading prescribers of antihypertensives for subjects with primary hypertension were primary care physicians (80%), whereas antihypertensive medications were equally prescribed by primary care physicians (43%) and sub-specialists (37%) for subjects with secondary hypertension. CONCLUSIONS: The predominant hypertension diagnosis among adolescents and young adults is primary hypertension. Antihypertensive medication use was higher among those with secondary hypertension compared with those with primary hypertension. Further study is needed to determine treatment effectiveness and patient outcomes associated with differential treatment patterns used for adolescents and young adults with primary versus secondary hypertension.

Underlying Rationale and Approach to Treat Hypertension in Adolescents by Physicians of Different Specialty.

OBJECTIVE: To describe the underlying clinical decision-making rationale among general pediatricians, family physicians, pediatric cardiologists and pediatric nephrologists in their approach to an adolescent with hypertension. METHODS: We conducted semi-structured phone interviews with a convenience sample of physicians from the above-mentioned 4 specialties. Each participant was asked to "think aloud" regarding their approach to a hypothetical patient - 12 year old boy with persistent hypertension for 6 months. Standardized open-ended questions about potential factors that could affect physicians' diagnosis and treatment strategies (e.g., patient age) were used. Interviews were audio-recorded; transcribed verbatim; transcripts were independently coded by 2 investigators; emergent themes identified and inter-coder agreement achieved. Thematic analysis was performed based on grounded theory. RESULTS: Nineteen participants included 5 general pediatricians, 5 pediatric cardiologists, 5 pediatric nephrologists and 4 family physicians. Five themes emerged: 1) Accuracy of blood pressure measurement and hypertension diagnosis, 2) Shift in the epidemiology of pediatric hypertension from secondary to primary hypertension, 3) Patient characteristics considered in the decision to initiate workup, 4) Obesity-centered choice of diagnostic tests and lifestyle modifications, and 5) Variable threshold for initiating antihypertensive pharmacotherapy vs. referral to hypertension specialists. CONCLUSIONS: There is variation across primary care and specialty physicians who provide care for children and adolescents with hypertension. Key areas of variability include the willingness to initiate antihypertensive medications, the use of diagnostic tests (e.g., ambulatory blood pressure monitoring), and the perceived need for specialty referral. Further study is needed to assess whether different treatment paradigms result in differential patient outcomes.

Clonidine utilization trends for Medicaid children.

OBJECTIVE: To characterize clonidine utilization trends among children. DESIGN/METHODS: Serial cross-sectional analysis of Michigan Medicaid claims data for children aged 6 to 18 years. The authors identified children with ≥1 clonidine prescription; the authors examined their ICD-9 diagnoses categorized as simple and complex attention deficit hyperactivity disorder (ADHD), non-ADHD mental health disorder, hypertension, or others. Also identified were child demographics and prescribing physician specialty. RESULTS: From 2003 to 2008, the proportion of children receiving clonidine prescription nearly doubled in all demographics. Across years, the majority of clonidine prescription was for simple and complex ADHD and other mental health disorders. Leading prescribers were psychiatrists followed by general pediatricians and adult primary care physicians. CONCLUSIONS: Clonidine was used extensively to treat simple and complex ADHD in children although FDA approval for this indication did not occur until 2010. Further study is warranted to better understand clinical outcomes and costs associated with clonidine use for the treatment of children with ADHD.

Antihypertensive prescribing patterns for adolescents with primary hypertension.

BACKGROUND: Hypertension is an increasingly common problem in adolescents yet current medical management of primary hypertension in adolescents has not been well-described. METHODS: We identified adolescents with primary hypertension by International Classification of Diseases, Ninth Revision codes and looked at prescription patterns chronologically for antihypertensive drug class prescribed and the specialty of prescribing physician. We also examined patient demographics and presence of obesity-related comorbidities. RESULTS: During 2003-2008, there were 4296 adolescents with primary hypertension (HTN); 66% were boys; 73% were aged 11 to 14 years; 53% were black, 41% white, and 4% Hispanic; and 48% had obesity-related comorbidity. Twenty-three percent (977) received antihypertensive prescription. White subjects (odds ratio [OR]: 1.61; confidence interval [CI]: 1.39-1.88), older adolescents (≥15 years, OR: 2.11; CI: 1.79-2.48), and those with comorbidity (OR: 1.57; CI: 1.36-1.82) were more likely to receive antihypertensive prescriptions controlling for gender and years of Medicaid eligibility in logistic regression. Angiotensin converting enzyme inhibitors were the most frequently prescribed monotherapy. Nearly two-thirds of adolescents received prescriptions from adult primary care physicians (PCPs) only. More than one-quarter of adolescents who received a prescription received combination therapy, which was most often prescribed by adult PCPs. CONCLUSIONS: Adult PCPs were the leading prescribers of antihypertensives for adolescents with primary HTN. Race differences exist in physicians' prescribing of antihypertensives to adolescents with primary HTN. The choice of antihypertensives by physicians of different specialties warrants additional study to understand the underlying rationale for treatment decisions and to determine treatment effectiveness.

Use of diagnostic tests in adolescents with essential hypertension.

OBJECTIVE: To describe the use of diagnostic tests in adolescents with essential hypertension. DESIGN: Longitudinal analysis of administrative claims data. SETTING: Michigan Medicaid program during 2003 to 2008. PARTICIPANTS: Adolescents with 3 or more years of Medicaid eligibility (≥ 11 months/y) who had a diagnosis of essential hypertension and 1 or more antihypertensive medication pharmacy claims. MAIN OUTCOME MEASURES: We examined adolescents' echocardiogram use and compared it with electrocardiogram (EKG) and renal ultrasonography use. We examined timing of the 3 diagnostic tests in relation to the first pharmacy claim. We examined patient demographics and presence of obesity-related comorbidities. RESULTS: During 2003 to 2008, there were 951 adolescents with essential hypertension who had antihypertensive pharmacy claims; 24% (226) had echocardiograms; 22% (207) had renal ultrasonography; and 50% (478) had EKGs. Males (odds ratio [OR], 1.53; 95% CI, 1.06-2.21), younger adolescents (OR, 1.69; 95% CI, 1.17-2.44), those who had EKGs (OR, 5.79; 95% CI, 4.02-8.36), and those who had renal ultrasonography (OR, 2.22; 95% CI, 1.54-3.20) were more likely to obtain echocardiograms compared with females, older adolescents, and adolescents who did not have EKGs or renal ultrasonography. CONCLUSIONS: Guideline-recommended diagnostic tests-echocardiograms and renal ultrasonography-were equally poorly used by adolescents with essential hypertension. Sex and age differences exist in the use of echocardiograms by adolescents with essential hypertension. The decision and choice of diagnostic tests to evaluate adolescents with essential hypertension warrant further study to understand the underlying rationale for those decisions and to determine treatment effectiveness.

Parental preferences for FDA-approved medications prescribed for their children.

OBJECTIVE: To describe parental preferences for FDA-approved prescription medications for their children. STUDY DESIGN: Cross-sectional Web-enabled survey of a national sample of 1562 parents. RESULTS: Response rate was 61%. Most parents (77%) preferred prescription of only FDA-approved medications for their child. However, one half of parents preferred that their child's doctor prescribe medication that is safest and works best, even if not FDA approved for children. One third of parents (34%) preferred nothing but FDA-approved medications for their child, regardless of drug safety, effectiveness, or cost. Controlling for parent race and education, mothers (odds ratio = 1.52; P = .004) and older parents (odds ratio = 1.60; P = .025) were more likely to prefer nothing but FDA-approved medications for their children compared with fathers and younger parents. CONCLUSIONS: Although most parents initially indicate preference for FDA-approved medications, one half of parents will accept a non-FDA-approved medication for their children with the understanding that it is safer or more effective than the FDA-approved alternative.

Differences in pediatric drug information sources used by general versus subspecialist pediatricians.

OBJECTIVE: To describe pediatric labeling information needs and sources of general and subspecialist pediatricians. Study design. Self-administered questionnaire of Fellows of the American Academy of Pediatrics (AAP). RESULTS: The response rate was 48%. Top sources used by pediatricians to obtain pediatric labeling information were journals (86%), pediatric dosage books (84%), AAP News (77%), drug representatives (65%), and PDA-based databases (35%). Generalists were more likely than subspecialists to use AAP News (82% vs 60%; P < .001) and drug representatives (72% vs 41%; P < .001) to obtain prescribing information. Both groups reported that it was most important to have additional prescribing information for mental health and cardiovascular medications. CONCLUSIONS: Despite differences in the methods used to obtain pediatric labeling information, generalist and subspecialist pediatricians both prioritized mental health and cardiovascular medications as needing additional prescribing information. Interventions to effectively disseminate new or revised pediatric labeling information to pediatricians should consider using methods identified in this study.

Medical management of children with primary hypertension by pediatric subspecialists.

Our aim was to characterize medical management of children with primary hypertension (HTN) by pediatric subspecialists. We performed a medical-record review of children < or = 18 years with primary HTN seen at pediatric cardiology or pediatric nephrology clinics at an academic center. Main outcomes were whether treatment decision was in agreement with national guidelines, whether an antihypertensive medication was prescribed, and medication choice. One hundred and eighty children had > or = 1 visit to a pediatric cardiology or nephrology clinic. The majority (83%) of children were pharmacologically managed according to national guidelines. However, only 1/3 children with stage 2 HTN received appropriate antihypertensive therapy from either subspecialty. Only 26 children were prescribed an antihypertensive drug. Children evaluated by pediatric nephrologists were fourfold more likely to receive an antihypertensive than children seen by pediatric cardiologists (29% vs. 7%; p < 0.001). However, all antihypertensive prescriptions were prescribed according to guidelines by both subspecialties. Medical management of children with primary HTN by pediatric cardiologists and pediatric nephrologists is largely consistent with guidelines. However, initiation of appropriate antihypertensive drugs for children with highest severity of HTN is equally poor for both subspecialties. Future studies should explore the factors underlying physicians' reluctance to initiate recommended chronic pharmacologic therapy in children and its associated outcomes.

Factors associated with non-attendance at pediatric subspecialty asthma clinics.

BACKGROUND: Children with Medicaid insurance are less likely to receive subspecialty asthma care than non-Medicaid patients. However, it is not clear if such disparities are due to non-attendance at scheduled visits by patients. OBJECTIVE: To determine factors associated with non-attendance at scheduled visits for pediatric subspecialty asthma care. DESIGN/METHODS: We conducted a cross-sectional study of children with scheduled visits at three asthma clinics during a 12-month period. Our outcome of interest was patient non-attendance for a scheduled visit, controlling for age, gender, new patient status, type of insurance, severity of illness, distance to clinic, clinic site, month, and weekday of scheduled visit. We used logistic regression for multivariate comparisons and controlled for clustering effects for children with multiple scheduled visits. RESULTS: There were 1236 scheduled visits for 857 unique patients. Median age: 7 years (IQR 3-11); median distance traveled: 24 miles (IQR 13-41); 20% had Medicaid insurance. The non-attendance rate was 8%. In multivariate analysis, Medicaid insurance (OR 2.33, 95% CI 1.45-3.74) and visits scheduled in September-December (3.26, 2.08-5.11) were associated with non-attendance. CONCLUSIONS: Children with Medicaid insurance are less likely to attend scheduled visits for subspecialty asthma care, controlling for seasonal variation. Programs designed to address disparities in pediatric asthma outcomes regarding subspecialist care may improve their effectiveness by addressing barriers to attendance and anticipating poor attendance in the fall season.