BACKGROUND Twenty-four-hour ambulatory blood pressure monitoring (ABPM) is an essential tool in the diagnosis and therapeutic monitoring of arterial hypertension in children. The statistical use of ...pediatric ABPM reference values has been compromised by the non-Gaussian distribution of 24-h blood pressure (BP) in children.
OBJECTIVE To develop distribution-adjusted pediatric ABPM reference tables.
METHODS From cross-sectional ABPM data obtained in 949 healthy children and adolescents aged 5–20 years, a set of reference tables was developed for 24-h, daytime and night-time mean values of systolic, diastolic, mean arterial BP and heart rate, utilizing the LMS method to account for the variably skewed distribution of ABPM data. Age- and gender-specific estimates of the distribution median (M), coefficient of variation (S) and degree of skewness (L) were obtained by a maximum-likelihood curve-fitting technique. The estimates of L, M and S can be used to normalize ABPM data to gender and age or height.
RESULTS Re-application of the established L, M and S values in the reference population confirmed appropriate normalization of ABPM values. Height standard deviation scores (SDS), body mass index (BMI) SDS and heart rate SDS were independent positive predictors of 24-h systolic BP SDS. Diastolic 24-h mean BP SDS showed a weak correlation with BMI SDS only.
CONCLUSIONS The use of LMS reference tables permits calculation of appropriate SDS values for ABPM in children. Whereas systolic 24-h BP is independently correlated with age, relative height and obesity, diastolic values are almost independent of age and relative height, and weakly associated with relative obesity.
Ambulatory blood pressure (ABP) monitoring is increasingly used to evaluate the blood pressure of children and adolescents. The upper normal ABP values in the pediatric age group are still unknown, ...because reference values based on a sufficiently high number of healthy children have not yet been published. In this multicenter trial, we pooled ABP records of 1141 healthy children and adolescents with a body height between 115 and 185 cm. The study was carried out by seven centers according to a common protocol. The 50th percentile for 24-hour systolic ABP increased moderately with height, from 103 to 113 mm Hg in girls and from 105 to 120 mm Hg in boys. The 50th percentile for diastolic 24-hour means was 66 ± 1 mm Hg, irrespective of height or gender. Diastolic daytime means were 73 ± 1 mm Hg, which is remarkably high compared with reference values for casual blood pressure. The mean nocturnal systolic and diastolic ABP (midnight to 6
am ) was 13% ± 6% and 23% ± 9% lower compared with the daytime means (8
am to 8
pm ), respectively. This multicenter study provides well-based limits of normal ABP in mid-European children. (J Pediatr 1997;130:178-84)
Aims
This study aimed to assess safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of ensovibep, a designed ankyrin repeat protein antiviral being evaluated as a COVID‐19 ...treatment, in healthy volunteers in a first‐in‐human ascending single‐dose study.
Methods
Subjects were dosed intravenously, in a randomized double‐blinded manner, with either ensovibep at 3, 9 or 20 mg/kg or with placebo, and followed until Day 100. PK and safety were assessed throughout the study duration. Immunogenicity and PD via viral neutralization in serum were also assessed.
Results
All adverse events were of mild to moderate severity, and no serious adverse events were observed. One subject who received the 20‐mg/kg dose presented with moderate hypersensitivity vasculitis 3 weeks after infusion, which fully resolved using standard procedures. In most subjects ensovibep showed expected mono‐exponential decline with a half‐life of around 2 weeks. Anti‐drug antibodies were detected in 15 of 17 subjects, with the earliest onset detected on Day 29. Viral neutralization assays on subject serum showed effective viral neutralization over the first 3 weeks following dosing with titre values in a dose dependent manner.
Conclusion
Ensovibep proved safe in this first‐in‐human safety study and exhibited PK and PD parameters consistent with the expected treatment period required for acute COVID‐19 infection.
Aim
To assess viral clearance, pharmacokinetics, tolerability and symptom evolution following ensovibep administration in symptomatic COVID‐19 outpatients.
Methods
In this open‐label, ...first‐in‐patient study a single dose of either 225 mg (n = 6) or 600 mg (n = 6) of ensovibep was administered intravenously in outpatients with mild‐to‐moderate COVID‐19 symptoms. Pharmacokinetic profiles were determined (90‐day period). Pharmacodynamic assessments consisted of viral load (qPCR and cultures) and symptom questionnaires. Immunogenicity against ensovibep and SARS‐CoV‐2‐neutralizing activity were determined. Safety and tolerability were assessed throughout a 13‐week follow‐up.
Results
Both doses showed similar pharmacokinetics (first‐order) with mean half‐lives of 14 (SD 5.0) and 13 days (SD 5.7) for the 225‐ and 600‐mg groups, respectively. Pharmacologically relevant serum concentrations were maintained in all subjects for at least 2 weeks postdose, regardless of possible immunogenicity against ensovibep. Viral load changes from baseline at day 15 were 5.1 (SD 0.86) and 5.3 (SD 2.2) log10 copies/mL for the 225‐ and 600‐mg doses, respectively. COVID‐19 symptom scores decreased from 10.0 (SD 4.1) and 11.3 (SD 4.0) to 1.6 (SD 3.1) and 3.3 (SD 2.4) in the first week for the 225‐ and 600‐mg groups, respectively. No anti‐SARS‐CoV‐2 neutralizing activity was present predose and all patients had SARS‐CoV‐2 antibodies at day 91. Adverse events were of mild‐to‐moderate severity, transient and self‐limiting.
Conclusion
Single‐dose intravenous administration of 225 or 600 mg of ensovibep appeared safe and well tolerated in patients with mild‐to‐moderate COVID‐19. Ensovibep showed favourable pharmacokinetics in patients and the pharmacodynamic results warrant further research in a larger phase 2/3 randomized‐controlled trail.
Background
Macitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that ...it is important to recognize potential drug–drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH.
Objective
Two Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan.
Methods
Healthy male subjects received a single oral dose of rosuvastatin 10 mg (
n
= 20) or riociguat 1 mg (
n
= 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (
C
max
), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC
0–
t
), the AUC from zero to infinity (AUC
0–∞
) and the terminal elimination half-life (
t
½
) of rosuvastatin, riociguat and riociguat’s metabolite, M1. The difference in the time to reach maximum plasma concentration (
t
max
) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout.
Results
Ninety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80–1.25. There was no significant difference between test and reference
t
max
. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs.
Conclusions
Macitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects.
EudraCT numbers
: 2017–003095–31 and 2017–003502–41.
Abstract Background The coronavirus disease 2019 (COVID-19) pandemic was characterized by rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, affecting viral ...transmissibility, virulence, and response to vaccines/therapeutics. EMPATHY (NCT04828161), a phase 2 study, investigated the safety/efficacy of ensovibep, a multispecific designed ankyrin repeat protein (DARPin) with multivariant in vitro activity, in ambulatory patients with mild to moderate COVID-19. Methods Nonhospitalized, symptomatic patients (N = 407) with COVID-19 were randomized to receive single-dose intravenous ensovibep (75, 225, or 600 mg) or placebo and followed until day 91. The primary endpoint was time-weighted change from baseline in log10 SARS-CoV-2 viral load through day 8. Secondary endpoints included proportion of patients with COVID-19–related hospitalizations, emergency room (ER) visits, and/or all-cause mortality to day 29; time to sustained clinical recovery to day 29; and safety to day 91. Results Ensovibep showed superiority versus placebo in reducing log10 SARS-CoV-2 viral load; treatment differences versus placebo in time-weighted change from baseline were −0.42 (P = .002), −0.33 (P = .014), and −0.59 (P < .001) for 75, 225, and 600 mg, respectively. Ensovibep-treated patients had fewer COVID-19–related hospitalizations, ER visits, and all-cause mortality (relative risk reduction: 78% 95% confidence interval, 16%–95%) and a shorter median time to sustained clinical recovery than placebo. Treatment-emergent adverse events occurred in 44.3% versus 54.0% of patients in the ensovibep and placebo arms; grade 3 events were consistent with COVID-19 morbidity. Two deaths were reported with placebo and none with ensovibep. Conclusions All 3 doses of ensovibep showed antiviral efficacy and clinical benefits versus placebo and an acceptable safety profile in nonhospitalized patients with COVID-19.
Abstract
Background
Ensovibep is a multi-specific DARPin (designed ankyrin repeat protein) antiviral in clinical development for treatment of COVID-19. In the Phase 2 EMPATHY study, ensovibep ...demonstrated greater viral load decline versus placebo. Here we report (1) the efficacy of ensovibep in patients with and without anti-SARS-CoV-2 antibodies at baseline and (2) SARS-CoV-2 mutation emergence data with treatment.
Methods
Eligible ambulatory patients with ≥2 COVID-19 symptoms (onset within 7 days) and positive SARS-CoV-2 rapid antigen test on day of dosing, were randomized (1:1:1:1) to ensovibep (600, 225 or 75 mg) or placebo as single, IV infusion. Chemiluminescent immunoassays were used for antibody detection (SARS-CoV-2 S1/S2 IgG and SARS-CoV-2 IgM). A pre-specified subgroup analysis was performed based on baseline anti-SARS-CoV-2 antibody status. Analysis of changes in viral genome from baseline to post baseline was performed to evaluate treatment-emergent mutations.
Results
Of the patients analyzed, 48.5% had anti-SARS-CoV-2 antibodies at baseline. Baseline log10 SARS-CoV-2 viral load (mean ±SD) was similar across groups ensovibep (all doses) 6.5 ±1.5, placebo 6.2 ±1.5; > 90% were infected with the Delta (B.1.617.2) variant. SARS-CoV-2 viral load reduction up to Day 8 showed similar effects in favor of ensovibep compared with placebo regardless of the presence of anti-SARS-CoV-2 antibodies (Figure 1). Patients in ensovibep 75 mg, 600 mg, and placebo groups had comparable incidences of emergent mutations, with a higher incidence in the 225 mg group. Based on analysis of 70% of the expected viral sequencing data, two mutations in the key binding residues of ensovibep were observed (Y489H and F486L) in a total of three patients treated with ensovibep. These patients either cleared virus by Day 8 or mutations were transient (occurred at a single time point but not later in the course of infection). Figure 1Forest plot of estimated treatment differences and associated 95% confidence intervals in time-weighted change from baseline in log10 SARS-CoV-2 viral load through Day 8 by subgroups for the presence of anti-SARS-CoV-2 antibodies (SARS-CoV-2 S1/S2 IgG and/or SARS-CoV-2 IgM) at baseline.
Conclusion
Ensovibep effectively reduces SARS-CoV-2 viral load regardless of the presence of anti-SARS-CoV-2 antibodies at baseline. Furthermore, there were no emerging mutations of concern, indicating that a single dose administration of ensovibep is associated with minimal selective pressure.
Disclosures
Marc Bonten, MD, PhD, Astra-Zeneca: Advisor/Consultant|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|Novartis: Advisor/Consultant Richa Chandra, MD, Novartis Pharmaceuticals Corporation: Employee Damodaran Solai Elango, MD, Novartis Healthcare Pvt Ltd: Employee Pierre Fustier, PhD, Molecular Partners AG: Employee Kinfemichael Gedif, PhD, Novartis Pharmaceuticals Corporation: Employee Susana Goncalves, MD, Novartis Pharma AG: Employee Awawu Igbinadolor, MD, Novartis: Awawu Igbinadolor reports financial support from different pharmaceutical companies and organizations Jeff Kingsley, DO, MBA, CPI, FACRP, Centricity Research: Other Charles G. Knutson, PhD, Novartis Institutes for BioMedical Research: Employee Petra Kukkaro, PhD, Novartis Pharma AG: Employee Nagalingeswaran Kumarasamy, MD, Novartis: Nagalingeswaran Kumarasamy reports financial support from different pharmaceutical companies and organizations Philippe Legenne, MD, Molecular Partners AG: Employee Martha Mekebeb-Reuter, MD, Novartis: Martha Mekebeb-Reuter reports financial support from different pharmaceutical companies and organizations Krishnan Ramanathan, MD, Novartis Pharma AG: Employee Evgeniya Reshetnyak, PhD, Novartis Pharmaceuticals Corporation: Employee Michael Robinson, PhD, Novartis Institute for Tropical Disease: Employee Jennifer Rosa, MD, Novartis: Jennifer Rosa reports financial support from different pharmaceutical companies and organizations Marianne Soergel, MD, Molecular Partners AG: Employee Vaia Stavropoulou, PhD, Molecular Partners AG: Employee Nina Stojcheva, PhD, Molecular Partners AG: Employee Michael T. Stumpp, PhD, Molecular Partners AG: Employee Andreas Tietz, MD, Novartis Pharma AG: Employee Xiaojun Zhao, PhD, Novartis Institutes for BioMedical Research: Employee Zhaojie Zhang, PhD, 8. Novartis Institutes for BioMedical Research: Employee.
: When ambulatory blood pressure monitoring (ABPM) is performed in populations with a high risk for secondary hypertension, such as solid organ transplant recipients, hypertension or abnormalities ...in circadian blood pressure variability are often discovered even in patients with normal office blood pressure (BP). To discuss whether ABPM should be routinely assessed in pediatric solid organ recipients, the available information on pathological findings, association of ABPM abnormalities with outcome parameters, and treatment options is reviewed. ABPM is a useful tool to optimize therapy in the large proportion of transplant recipients with confirmed hypertension. Whether the use of ABPM on a routine basis should be recommended for pediatric transplantation patients without office hypertension remains to be determined.
This article reviews the current state of knowledge concerning the vicious cycle of hypertension and progressive loss of renal function in renal disease, as well as the renoprotective potential of ...antihypertensive treatment, with a specific focus on children and adolescents. Deficient arteriolar autoregulation renders damaged kidneys particularly sensitive to systemic high blood pressure (BP). Intraglomerular hypertension promotes proteinuria, which further activates the renin-angiotensin system (RAS). Angiotensin II, apart from its vasoconstrictor effects, induces local proinflammatory and profibrotic signaling molecules resulting in renal scarring. The activity of the scarring process with the resultant loss of functional renal mass appears to be modulated, in part, by a polymorphism in the angiotensin converting enzyme (ACE) gene. Clinical studies in adults have demonstrated convincingly the high risk of progression of chronic renal failure (CRF) associated with high BP, the benefit of lowering BP to even the low normal range, and the specific benefit of drugs that inhibit the RAS on the progression of CRF. In children, even moderately elevated BP and moderate proteinuria have been shown to be significant risk factors for progression and CRF. The optimal target BP for children with CRF is currently being determined in a multinational, randomized, prospective trial.
ABSTRACT—To assess the prevalence and characteristics of physiological circadian (24-hour) and ultradian (12-, 8-, and 6-hour) rhythms of mean arterial blood pressure (BP) and heart rate (HR), we ...analyzed 24-hour ambulatory BP profiles from 938 healthy school children aged 5 to 18 years. Cosine harmonics were fitted by Fourier analysis, and an amplitude and acrophase (time of peak) were calculated for each rhythm. Ninety percent of children displayed circadian rhythmicity of BP, independent of age, whereas circadian HR rhythmicity decreased with puberty from 96% to 87% (P <0.0001). Puberty had marked effects on the prevalence of ultradian rhythmicity12- and 6-hour rhythms increased for BP (27% to 47%, P <0.0001; 18% to 25%, P =0.01) and HR (36% to 47%, 17% to 31%, both P =0.001), whereas 8-hour BP rhythms decreased (34% to 23%, P =0.002). Median amplitudes were 10.1, 5.9, 5.6, and 5.2 mm Hg for the 24-, 12-, 8-, and 6-hour BP rhythms, respectively, and 13.4, 7.7, 6.8, and 6.4 bpm for HR. The acrophase occurred at approximately 14:00 hours, 8:00 hours, 5:30 hours, and 2:00 hours (military time) for the four BP rhythms, and at 13:30 hours, 08:30 hours, 01:50 hours, and 02:00 hours for HR. For the combined curve, the peak–trough difference was 25.9 mm Hg and 35 bpm for BP and HR, respectively, with the peaks occurring at 13:50 hours and 13:10 hours. There was marked association between BP and HR rhythms, both for prevalence (P <0.0001 for coupling of BP and HR rhythms of the same period length) and timing, with a median time lag of BP after HR acrophase of only 21, 16, 13, and 5 minutes for the four rhythms, respectively.
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