Intrasubject Coefficient Of Variation Research Articles

Integrating Clinical Variability into PBPK Models for Virtual Bioequivalence of Single and Multiple Doses of Tofacitinib Modified-Release Dosage Form.

Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate-release (IR) tablets, modified-release (MR) tablets, and IR solution. A once daily MR microsphere formulation was developed for use in pediatric patients. Demonstration of bioequivalence (BE) between the 10 mg once daily (q.d.) MR microsphere formulation and 5 mg twice daily (b.i.d.) IR solution is needed to enable the exposure-response analyses-based bridging to support regulatory approval. To assess BE between MR microsphere and IR solution, an innovative approach was utilized with physiologically-based pharmacokinetic (PBPK) virtual BE trials (VBE) in lieu of a clinical BE trial. A PBPK model was developed to characterize the absorption of different formulations of tofacitinib using Simcyp ADAM module. VBE trials were conducted by simulating PK profiles using the verified PBPK model and integrating the clinically observed intrasubject coefficient of variation (ICV) where BE was assessed with a predetermined sample size and prespecified criteria. The VBE trials demonstrated BE between IR solution 5 mg b.i.d. and MR microsphere 10 mg q.d. after a single dose on day 1 and after multiple doses on day 5. This research presents an innovative approach that incorporates clinically observed ICV in PBPK model-based VBE trials, which could reduce unnecessary drug exposure to healthy volunteers and streamline new formulation development strategies.

Reciprocal Impact of Molnupiravir and Favipiravir Monocomponents of the Combination Drug on Each Other's Pharmacokinetics in a Phase I Clinical Trial

Introduction. COVID-19 (Coronavirus disease 2019) almost 4 years after he start of the pandemic is still a significant public health problem. SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) that causes COVID-19 continues to mutate and spread throughout the world. Molnupiravir and favipiravir have been shown to be efficacious against variety of RNA viruses including the SARS-CoV-2. The Ministry of Health of the Russian Federation approved the use of these drugs as a treatment of COVID-19. The developed drug contains the combination of two antiviral agents with different mechanisms of suppressing viral RNA replication, which suggests efficacy against the vast majority of ARVI pathogens found in the human population including SARS-CoV-2 and influenza.Aim. The aim of the pharmacokinetics study is comparison between JTBC00301 (INN: molnupiravir + favipiravir), film-coated tablets (LLC "PROMOMED RUS", Russia), Esperavir® (INN: molnupiravir), capsules (LLC "PROMOMED RUS", Russia) and Areplivir® (INN: favipiravir), film-coated tablets (LLC "PROMOMED RUS", Russia) to evaluate the impact of monocomponents on each other's pharmacokinetics.Materials and methods. The clinical and analytical phases as well as pharmacokinetic analyses have been performed as a part of a phase I, randomized, open-label, 3-period crossover study of drug JTBC00301 (INN: molnupiravir + favipiravir), film-coated tablets, 400 + 400 mg (LLC "PROMOMED RUS", Russia). The plasma concentration of β-D-N4-hydroxycytidine (NHC), the active metabolite of molnupiravir and favipiravir were determined in 42 healthy volunteers after taking the test drug JTBC00301 (1 tablet of 400 + 400 mg), the reference drug Esperavir® (2 capsules of 200 mg) and the reference drug Areplivir® (2 tablets of 200 mg). The descriptive statistics were calculated using Microsoft Excel (Microsoft Corporation, USA). The pharmacokinetic parameters, analysis of variance (ANOVA), the intra-subject coefficient of variation (CVintra) and 90 % confidence intervals (90 % CI) were calculated by R Project 3.5.1 software (package «bear», version 2.8.3-2), originally created by Hsin-ya Lee and Yung-jin Lee, Taiwan.Results and discussion. Pharmacokinetic parameters of NHC and favipiravir were determined, averaged pharmacokinetic profiles in linear and log-linear scales were plotted, analysis of variance was carried out. The 90% CIs for geometric mean ratios of Сmax and AUC(0–t) for NHC and favipiravir were all within the acceptance range of 80–125 % which means there is no effect of monocomponents on each other’s pharmacokinetics.Conclusion. The development of the fixed-dose drug combination of molnupiravir and favipiravir has great potential as it may allow to increase the safety profile and improve the tolerability of therapy as well as increase the effectiveness of antiviral therapy. The results justified the study of the subsequent phases of clinical trials of JTBC00301 (INN: molnupiravir + favipiravir), film-coated tablets, 400 + 400 mg (LLC "PROMOMED RUS", Russia).

Chassis-based fiber-coupled opticalprobe design for reproducible quantitative diffuse optical spectroscopy measurements.

Advanced optical neuromonitoring of cerebral hemodynamics with hybrid diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) methods holds promise for non-invasive characterization of brain health in critically ill patients. However, the methods' fiber-coupled patient interfaces (probes) are challenging to apply in emergent clinical scenarios that require rapid and reproducible attachment to the head. To address this challenge, we developed a novel chassis-based optical probe design for DOS/DCS measurements and validated its measurement accuracy and reproducibility against conventional, manually held measurements of cerebral hemodynamics in pediatric swine (n = 20). The chassis-based probe design comprises a detachable fiber housing which snaps into a 3D-printed, circumferential chassis piece that is secured to the skin. To validate its reproducibility, eight measurement repetitions of cerebral tissue blood flow index (BFI), oxygen saturation (StO2), and oxy-, deoxy- and total hemoglobin concentration were acquired at the same demarcated measurement location for each pig. The probe was detached after each measurement. Of the eight measurements, four were acquired by placing the probe into a secured chassis, and four were visually aligned and manually held. We compared the absolute value and intra-subject coefficient of variation (CV) of chassis versus manual measurements. No significant differences were observed in either absolute value or CV between chassis and manual measurements (p > 0.05). However, the CV for BFI (mean ± SD: manual, 19.5% ± 9.6; chassis, 19.0% ± 10.8) was significantly higher than StO2 (manual, 5.8% ± 6.7; chassis, 6.6% ± 7.1) regardless of measurement methodology (p<0.001). The chassis-based DOS/DCS probe design facilitated rapid probe attachment/re-attachment and demonstrated comparable accuracy and reproducibility to conventional, manual alignment. In the future, this design may be adapted for clinical applications to allow for non-invasive monitoring of cerebral health during pediatric critical care.

CEST and nuclear Overhauser enhancement imaging withdeep learning-extrapolated semisolid magnetization transfer reference: Scan-rescan reproducibility andreliability studies.

To develop a novel MR physics-driven, deep-learning, extrapolated semisolid magnetization transfer reference (DeepEMR) framework to provide fast, reliable magnetization transfer contrast (MTC) and CEST signal estimations, and to determine the reproducibility and reliability of the estimates from the DeepEMR. A neural network was designed to predict a direct water saturation and MTC-dominated signal at a certain CEST frequency offset using a few high-frequency offset features in the Z-spectrum. The accuracy, scan-rescan reproducibility, and reliability of MTC, CEST, and relayed nuclear Overhauser enhancement (rNOE) signals estimated from the DeepEMR were evaluated on numerical phantoms and in heathy volunteers at 3 T. In addition, we applied the DeepEMR method to brain tumor patients and compared tissue contrast with other CEST calculation metrics. The DeepEMR method demonstrated a high degree of accuracy in the estimation of reference MTC signals at ±3.5 ppm for APT and rNOE imaging, and computational efficiency (˜190-fold) compared with a conventional fitting approach. In addition, the DeepEMR method achieved high reproducibility and reliability (intraclass correlation coefficient = 0.97, intersubject coefficient of variation = 3.5%, and intrasubject coefficient of variation = 1.3%) of the estimation of MTC signals at ±3.5 ppm. In tumor patients, DeepEMR-based amide proton transfer images provided higher tumor contrast than a conventional MT ratio asymmetry image, particularly at higher B1 strengths (>1.5 μT), with a distinct delineation of the tumor core from normal tissue or peritumoral edema. The DeepEMR approach is feasible for measuring clean APT and rNOE effects in longitudinal and cross-sectional studies with low scan-rescan variability.

Comparison of Various Smoothness Metrics for Upper Limb Movements in Middle-Aged Healthy Subjects.

Metrics for movement smoothness include the number of zero-crossings on the acceleration profile (N0C), the log dimensionless jerk (LDLJ), the normalized averaged rectified jerk (NARJ) and the spectral arc length (SPARC). Sensitivity to the handedness and movement type of these four metrics was compared and correlations with other kinematic parameters were explored in healthy subjects. Thirty-two healthy participants underwent 3D upper limb motion analysis during two sets of pointing movements on each side. They performed forward- and backward-pointing movements at a self-selected speed to a target located ahead at shoulder height and at 90% arm length, with and without a three-second pause between forward and backward movements. Kinematics were collected, and smoothness metrics were computed. LDLJ, NARJ and N0C found backward movements to be smoother, while SPARC found the opposite. Inter- and intra-subject coefficients of variation were lowest for SPARC. LDLJ, NARJ and N0C were correlated with each other and with movement time, unlike SPARC. There are major differences between smoothness metrics measured in the temporal domain (N0C, LDLJ, NARJ), which depend on movement time, and those measured in the frequency domain, the SPARC, which gave results opposite to the other metrics when comparing backward and forward movements.

Semen parameter variability among users of at-home sperm testing kits

BackgroundDespite the generally accepted World Health Organization guidelines on semen analysis, an individual’s results can display significant variation when performed across time or in different laboratories. Semen parameters are in fact highly variable measures that can differ significantly between various analyses. Numerous researchers have discovered a wide range of semen parameters within each individual male, but only a few studies included the analysis of semen parameters variability in patients with infertility. The aim of this study was to evaluate the inter- and intra-individual variability of semen parameters in men of reproductive age with normozoospermia and those with oligozoospermia.MethodsFive hundred and thirteen who provided ≥ 2 semen samples (798 samples in total) using an at-home mail-in kit over a period of about 2 years were enrolled in the study. Semen samples collection using Give Legacy at-home mail-in semen collection kit; semen analysis at a CLIA-certified laboratory.ResultsThe degree of intra-subject variation across all semen parameters was lower in men with normozoospermia compared to men with oligozoospermia. Men with normozoospermia furthermore demonstrated a level of intra-subject variation that was lower than inter-subject variation across all measured parameters. No association was observed between intra-subject coefficients of variation in any of the semen parameters, including sperm concentration, sperm count, motile sperm count, total motility, progressive motility, the percentage of sperm with normal morphology, and the age, duration of abstinence, and BMI of the men.ConclusionThe results of this observational study confirm the significant variability in semen parameters in men with normozoospermia and oligozoospermia, as measured from at-home semen collection kit samples. This further underscore the importance of securing multiple samples for analysis to provide a robust assessment of male fertility.

Kinematic Evaluation of the Sagittal Posture during Walking in Healthy Subjects by 3D Motion Analysis Using DB-Total Protocol.

Posture can be evaluated by clinical and instrumental methods. Three-dimensional motion analysis is the gold standard for the static and dynamic postural assessment. Conventional stereophotogrammetric protocols are used to assess the posture of pelvis, hip, knee, ankle, trunk (considered as a single segment) and rarely head and upper limbs during walking. A few studies also analyzed the multi-segmental trunk and whole-body kinematics. Aim of our study was to evaluate the sagittal spine and the whole-body during walking in healthy subjects by 3D motion analysis using a new marker set. Fourteen healthy subjects were assessed by 3D-Stereophotogrammetry using the DB-Total protocol. Excursion Range, Absolute Excursion Range, Average, intra-subject Coefficient of Variation (CV) and inter-subject Standard Deviation Average (SD Average) of eighteen new kinematic parameters related to sagittal spine and whole-body posture were calculated. The analysis of the DB-Total parameters showed a high intra-subject (CV < 50%) and a high inter-subject (SD Average < 1) repeatability for the most of them. Kinematic curves and new additional values were reported. The present study introduced new postural values characterizing the sagittal spinal and whole-body alignment of healthy subjects during walking. DB-Total parameters may be useful for understanding multi-segmental body biomechanics and as a benchmark for pathological patterns.

Reproducibility of rapid multi-parameter mapping at 3T and 7T with highly segmented and accelerated 3D-EPI.

Quantitative multi-parameter mapping (MPM) has been shown to provide good longitudinal and cross-sectional reproducibility for clinical research. Unfortunately, acquisition times (TAs) are typically infeasible for routine scanning at high resolutions. A fast whole-brain MPM protocol based on interleaved multi-shot 3D-EPI with controlled aliasing (SC-EPI) at 3T and 7T is proposed and compared with MPM using a standard spoiled gradient echo (FLASH) sequence. Four parameters (R1 , PD, , and MTsat) were measured in less than 3min at 1 mm isotropic resolution. Five subjects went through the same scanning sessions twice at each scanner. The intra-subject coefficient of variation (scan-rescan) (CoV) was estimated for each protocol and scanner to assess the longitudinal reproducibility. At 3T, the CoV of SC-EPI ranged between 1.2%-4.8% for PD and R1 , 2.8%-10.6% for and MTsat, which was comparable with FLASH (0.6%-4.9% for PD and R1 , 2.6%-11.3% for and MTsat). At 7T, where the SC-EPI TA was reduced to ∼2min, the CoV of SC-EPI (1.4%-10.6% for PD, R1 , and ) was 1.2-2.4 times larger than the CoV of FLASH (1.0%-15%) and MTsat showed much higher variability across subjects. The SC-EPI-MPM protocol at 3T showed high reproducibility and yielded stable quantitative maps at a clinically feasible resolution and scan time, whereas at 7T, MT saturation homogeneity needs to be improved. SC-EPI-based MPM is feasible as an additional MRI modality in clinical or population studies where the parameters offer great potential as biomarkers.

Reproducibility of 7-T brain spectroscopy using an ultrashort echo time STimulated Echo Acquisition Mode sequence and automated voxel repositioning.

Establishing the reproducibility of brain MRS is important for clinical studies so that researchers can evaluate changes in metabolites due to treatment or the course of a disease and better understand the brain in healthy and disordered states. Prior 7-T MRS reproducibility studies using the stimulated echo acquisition mode (STEAM) sequence have focused on the anterior cingulate cortex or posterior cingulate cortex and precuneus. The purpose of this study was to evaluate the reproducibility of metabolite measurements in the dorsolateral prefrontal cortex (DLPFC) using an ultrashort echo time (TE) STEAM sequence and automated voxel repositioning. Spectra were acquired during two scan sessions from nine subjects using the AutoAlign method for voxel repositioning. Reproducibility was evaluated with coefficients of variation (CVs) and percentage differences. The mean intrasubject CVs were less than 6% for the major metabolites glutamate, N-acetylaspartate, total creatine, total choline, and myo-inositol. The mean CVs were less than 20% for the smaller signals of GABA, glutamine, glutathione, and taurine. These results indicate that 7-T MRS using a STEAM sequence with ultrashort TE and automated voxel repositioning provides excellent reproducibility of metabolites in the DLPFC.

Fast in vivo 23 Na imaging and mapping using accelerated 2D-FID UTE magnetic resonance spectroscopic imaging at 3 T: Proof of concept and reliability study.

To implement an accelerated MR-acquisition method allowing to map relaxation and absolute concentration of sodium within skeletal muscles at 3T. A fast-UTE-2D density-weighted concentric-ring-trajectory 23 Na-MRSI technique was used to acquire 64 time points of FID with a spectral bandwidth of 312.5 Hz with an in-plane resolution of 2.5 × 2.5 mm2 in ~15 min. The fast-relaxing 23 Na signal was localized with a single-shot, inversion-recovery-based, non-echo (SIRENE) outer volume suppression (OVS) method. The sequence was verified using simulation and phantom studies before implementing it in human calf muscles. To evaluate the 2D-SIRENE-MRSI (UTE = 0.55 ms) imaging performance, it was compared to a 3D-MRI (UTE = 0.3 ms) sequence. Both data sets were acquired within 2 same-day sessions to assess repeatability. The values were fitted voxel-by-voxel using a biexponential model for the 2D-MRSI data. Finally, intra-subject coefficients of variation (CV) were estimated. The MRSI-FID data allowed us to map the fast and slow components of in the calf muscles. The spatial distributions of 23 Na concentration for both MRSI and 3D-MRI acquisitions were significantly correlated (P < .001). The test-retest analysis rendered high repeatability for MRSI with a CV of 5%. The mean in muscles was 0.7 ± 0.1 ms (contribution fraction = 37%), whereas was 13.2 ± 0.2 ms (63%). The mean absolute muscle 23 Na concentration calculated from the -corrected data was 28.6 ± 3.3 mM. The proposed MRSI technique is a reliable technique to map sodium's absolute concentration and within a clinically acceptable scan time at 3T.

Reproducibility of whole-brain temperature mapping and metabolite quantification using proton magnetic resonance spectroscopy.

Assessing brain temperature can provide important information about disease processes (e.g., stroke, trauma) and therapeutic effects (e.g., cerebral hypothermia treatment). Whole-brain magnetic resonance spectroscopic imaging (WB-MRSI) is increasingly used to quantify brain metabolites across the entire brain. However, its feasibility and reliability for estimating brain temperature needs further validation. Therefore, the present study evaluates the reproducibility of WB-MRSI for temperature mapping as well as metabolite quantification across the whole brain in healthy volunteers. Ten healthy adults were scanned on three occasions 1 week apart. Brain temperature, along with four commonly assessed brain metabolites-total N-acetyl-aspartate (tNAA), total creatine (tCr), total choline (tCho) and myo-inositol (mI)-were measured from WB-MRSI data. Reproducibility was evaluated using the coefficient of variation (CV). The measured mean (range) of the intra-subject CVs was 0.9% (0.6%-1.6%) for brain temperature mapping, and 4.7% (2.5%-15.7%), 6.4% (2.4%-18.9%) and 14.2% (4.4%-52.6%) for tNAA, tCho and mI, respectively, with reference to tCr. Consistently larger variability was found when using H2 O as the reference for metabolite quantifications: 7.8% (3.3%-17.8%), 7.8% (3.1%-18.0%), 9.8% (3.7%-31.0%) and 17.0% (5.9%-54.0%) for tNAA, tCr, tCho and mI, respectively. Further, the larger the brain region (indicated by a greater number of voxels within that region), the better the reproducibility for both temperature and metabolite estimates. Our results demonstrate good reproducibility of whole-brain temperature and metabolite measurements using the WB-MRSI technique.

Planning and Evaluation of Bioequivalence Studies of Lopinavir/Ritonavir Preparations

Issues with planning bioequivalence studies of lopinavir/ritonavir (LPV/RTV) preparations are discussed. LPV is an antiviral (HIV) medicine and HIV protease inhibitor that was developed in a fixed-dose combination with RTV. According to existing RF legislation, results from bioequivalence studies with a reference drug must be submitted to register generics. Protocols and reports of bioequivalence studies of LPV/RTV film-coated tablet dosage forms that were submitted for review to the SCEEMP, MHRF, are analyzed. The number of administered tablets and duration of sample collection differed slightly in the study designs. The number of volunteers included in the study differed more substantially and was calculated based on the intra-subject coefficient of variation of LPV/RTV. A search of the internet for data on the variability of LPV/RTV found several results indicating that LPV/RTV was highly variable (30%). Recommendations for planning bioequivalence studies of LPV/RTV preparations are formulated based on the analysis.

Планирование и оценка исследований биоэквивалентности препаратов лопинавира/ритонавира

Рассмотрены вопросы планирования исследований биоэквивалентности препаратов лопинавира/ритонавира (LPV/RTV). LPV — противовирусное (ВИЧ) средство, ингибитор протеазы ВИЧ, который разрабатывался в фиксированной комбинации с RTV. Согласно действующему в РФ законодательству, при регистрации воспроизведенных лекарственных препаратов необходимо представление результатов исследований биоэквивалентности с референтным препаратом. Проведен анализ протоколов и отчетов исследований биоэквивалентности препаратов LPV/RTV в таблетированной лекарственной форме, поступивших на экспертизу в ФГБУ «НЦЭСМП» Минздрава России. Выявлены незначительные различия в дизайне исследований, включающие количество принимаемых таблеток и длительность отбора проб. Более существенные отличия наблюдались в количестве добровольцев, включенных в исследование, расчет которого основывается на значении коэффициента внутрииндивидуальной вариабельности LPV/RTV. Проведен поиск данных о вариабельности LPV/RTV в сети Интернет, некоторые результаты которого указывают на высокую вариабельность (&gt; 30 %) LPV/RTV. На основании проведенного анализа сформулированы рекомендации по планированию исследований биоэквивалентности препаратов LPV/RTV.

FEV1 recovery following methacholine challenge in asthma: Variability and comparison of methods

BackgroundMethacholine challenges have been used in clinical trials to assess therapeutic effects and potential adverse reactions of interventions on pulmonary function in a sensitive population, such as in subjects with asthma. Here, we evaluate the variability of the methacholine challenge recovery model, and compare the results obtained for both incremental and bolus challenge methods. MethodsThe extent, time course and variability of change in forced expiratory volume in 1 s (FEV1) following repeated methacholine challenges in subjects with mild asthma were investigated in an open-label, four-period, fixed-sequence, two-method, replicate crossover study. At Visits 1 and 2, subjects underwent an incremental challenge using doubling doses of methacholine until a ≥20% decrease in FEV1 was observed; at Visits 3 and 4, subjects underwent a bolus challenge, inhaling a single dose of methacholine calculated from the cumulative dose established during Visit 1. ResultsA total of 19 subjects were included in the study. Both the mean FEV1 area under the curve (FEV1 AUC0–tz) and mean maximum reductions in FEV1 (absolute and relative) 120 min post-challenge values were higher for the incremental challenges than the bolus challenges, with no reported difference between repetitions of the same methodology. FEV1 AUC0–tz decrease 120 min post challenge demonstrated an intra-subject coefficient of variation (CV) of 47.2% (incremental) and 78.3% (bolus), suggesting considerable between-visit variability. The mean absolute, and similarly relative, maximum reductions in FEV1 compared with post-diluent baseline values demonstrated lower intra-subject variability (incremental 21.16%, bolus 40.67%) than the FEV1 AUC0–tz-based endpoint.There was a trend towards faster recovery following the bolus challenge than with the incremental challenge. The provocative dose of methacholine inducing a ≥20% decrease in FEV1 resulted in a between-group mean difference of 27.20% in the incremental challenge periods, with a high intra-subject CV of 80.64%, demonstrating considerable variability. ConclusionMaximum reduction in FEV1 had the lowest variability. There was little difference between repetitions of the same methodology, as indicated by overlapping confidence intervals. There was a trend towards faster recovery following bolus challenge than with the incremental challenge. The results of this trial could be of value when designing future clinical trials using the methacholine challenge methodology.

Clinical Characteristics of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): A Retrospective Chart Review Study

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease that manifests with complement-mediated chronic intravascular hemolysis resulting in hemolytic anemia, tendency to thrombosis, and peripheral blood cytopenias. Eculizumab is a recombinant humanized IgG2/4 chimeric monoclonal antibody that is approved for the treatment of PNH, generalized myasthenia gravis (gMG), atypical hemolytic uremic syndrome (aHUS), and neuromyelitis optica spectrum disorder (NMOSD). Eculizumab specifically binds to the human C5 complement protein (C5), thereby inhibiting the complement cascade. To obtain a better understanding of PNH biology and provide insight toward improving the clinical management of patients with this disease, a retrospective chart review was performed from pre-existing medical records of patients with PNH treated with eculizumab. This analysis is expected to inform eculizumab biosimilar development; data collected on clinical characteristics of this patient population are presented here. Methods: This is a multicenter retrospective chart review study of pre-existing medical records of patients ≥18 years old with PNH who were treated with eculizumab between 01 January 2008 and 31 January 2016. Anonymized data from eligible patients were recorded by sites onto an electronic case report form (eCRF) and collected into an electronic data capture (EDC) system. The primary objective of the study was to assess the lactate dehydrogenase (LDH) concentration over time in eculizumab-treated patients with PNH, including during clinical events and after discontinuation of therapy. Secondary objectives included assessment of coexisting disease, vital signs, laboratory results, and clinical findings. Subjects' LDH time profiles and mean change from baseline of LDH in the maintenance phase were assessed. Maintenance phase was defined as the time period from the first of every 2 weeks (Q2W) eculizumab dose to the data cutoff date, or from the first Q2W eculizumab dose date to the last Q2W dose date for patients who discontinued prior to data cutoff. Baseline of the maintenance phase was defined as the last non-missing assessment taken prior to or on the same day of the first Q2W eculizumab dose. The inter- and intra-subject coefficient of variation (CV) of the 12-week area under effective curve (AUEC) of LDH was based on patients who had at least 2 LDH measurements during the maintenance treatment phase within 12 weeks of each other. Results: The medical records of 47 patients with PNH who were treated with eculizumab during the study period were reviewed; of these, 27 (57.4%) were female. At the time of the diagnosis, the mean age of all patients was 35.0 years and LDH values were reported for 5 of the 47 patients, 3 of which were ≥1.5 times the upper limit of normal. LDH values for most subjects during the study were within the expected ranges for the PNH population with stabilized hemoglobin levels on eculizumab. The mean change from baseline of LDH in the maintenance phase showed a decrease or no change for most time points. For the 26 patients who had ≥2 LDH measurements that were ≤ 12 weeks of each other, inter- and intra-subject CVs for the 12-week AUEC of LDH were 74.70% (95% confidence interval [CI] of 58.23%, 88.15%) and 34.05% (95% CI of 30.65%, 38.34%), respectively. The most commonly reported disease-related symptoms were hemoglobinuria (25 patients [53.2%]), abdominal pain (14 patients [29.8%]), thrombosis (11 patients [23.4%]), and infection (8 patients [17.0%]). Disease-related symptoms listed as 'Other' were reported in 14 (29.8%) patients and included dyspnea, fatigue, exertional dyspnea, aplastic anemia, kidney failure, and dysphagia. All reported concurrent medical conditions and symptoms have been previously well-documented in PNH patients. Ninety-two transfusions were administered to 15 (31.91%) patients within 6 weeks of the first eculizumab dose. Vital signs data did not demonstrate any clinically significant findings. Conclusions: The LDH levels for the majority of PNH patients with stabilized hemoglobin levels on eculizumab were well controlled and within the expected range; the inter- and intra-subject variability of 12-week AUEC of LDH were 74.70% and 34.05%, respectively. There were no unexpected or remarkable findings with respect to disease-related symptoms, vital signs, clinical findings, or laboratory data. Disclosures Hanes: Amgen Inc.: Employment. Pan:Amgen Inc.: Employment. Chow:Amgen Inc.: Employment.

Three-dimensional high-resolution simultaneous quantitative mapping of the whole brain with 3D-QALAS: An accuracy and repeatability study

BackgroundPrevious methods for the quantification of brain tissue properties by magnetic resonance imaging were mainly based on two-dimensional acquisitions and were thus limited to a relatively low resolution in the slice direction compared to three-dimensional (3D) acquisitions. The 3D-quantification using an interleaved Look–Locker acquisition sequence with a T2 preparation pulse (3D-QALAS) sequence may allow for simultaneous acquisition of relaxometry parameters in high spatial resolution. PurposeTo evaluate bias, linearity, and day-to-day repeatability of relaxometry parameters, as well as tissue fraction maps, acquired with 3D-QALAS. Materials and methodsScan–rescan test of the 3D-QALAS sequence was performed on a 1.5-T scanner with the International Society for Magnetic Resonance in Medicine/National institute of Standards and Technology system phantom and 10 healthy volunteers (7 male, 3 female; mean age, 23.2 ± 3.6 years). Simple linear regression analysis, Bland–Altman plots, and intrasubject coefficients of variation (CV) were used to assess the reliability of 3D-QALAS sequence-derived parameters. The T1, T2, proton density (PD), and myelin volume fraction (MVF) of in vivo brain regions were compared with values obtained using the multidynamic multi-echo sequence. ResultsIn the phantom study, the T1, T2, and PD values measured by 3D-QALAS showed strong linearity with the reference values (R2 = 0.998, 0.998, and 0.960 for T1, T2, and PD, respectively) and high repeatability (mean CV of 1.2%, 2.8%, and 2.9% for T1, T2, and PD, respectively). The T1, T2, PD, and MVF values of in vivo brain regions obtained with 3D-QALAS were highly consistent within subjects, with mean intrasubject CVs of 0.5%, 0.5%, 0.4%, and 1.6% for the T1, T2, PD, and MVF values, respectively. Conclusion3D-QALAS enables reliable measurement of T1, T2, PD, and MVF values of the whole brain in high spatial resolution across a clinically-relevant dynamic range.

Cerebral oxygenation and blood flow in normal term infants at rest measured by a hybrid near-infrared device (BabyLux).

The BabyLux device is a prototype optical neuro-monitor of cerebral oxygenation and blood flow for neonatology integrating time-resolved reflectance spectroscopy and diffuse correlation spectroscopy. Here we report the variability of six consecutive 30 s measurements performed in 27 healthy term infants at rest. Poor data quality excluded four infants. Mean cerebral oxygenation was 59.6 ± 8.0%, with intra-subject standard deviation of 3.4%, that is, coefficient of variation (CV) of 5.7%. The inter-subject CV was 13.5%. Mean blood flow index was 2.7 × 10-8 ± 1.56 × 10-8 (cm2/s), with intra-subject CV of 27% and inter-subject CV of 56%. The variability in blood flow index was not reduced by the use of individual measures of tissue scattering, nor accompanied by a parallel variability in cerebral oxygenation. The intra-subject variability for cerebral oxygenation variability was improved compared to spatially resolved spectroscopy devices, while for the blood flow index it was comparable to that of other modalities for estimating cerebral blood flow in newborn infants. Most importantly, the simultaneous measurement of oxygenation and flow allows for interpretation of the high inter-subject variability of cerebral blood flow as being due to error of measurement rather than to physiological instability.

Measurement Reliability of Laryngeal Resistance and Mean Flow Rate in Pediatric Subjects

Mean flow rate (MFR) and laryngeal resistance (RL) are sensitive to changes in glottal configuration and biomechanics. There is little reported on aerodynamic parameters in children. We conducted a pilot study to evaluate MFR and RL measurement reliability in a pediatric population using labial and mechanical interruption methods. Thirty-nine subjects aged 4-17 performed 10 trials per method. For labial interruptions, subjects produced five labial plosives at a comfortable amplitude. For mechanical interruptions, subjects maintained a steady /α/ while a balloon valve interrupted their airflow five times for 250 milliseconds each. MFR was measured as the flow through the interruption device between interruptions. RL was calculated by dividing subglottal pressure (Ps) by MFR. The primary outcome measures of this study were the coefficients of variation of MFR and RL. Paired t tests were used to compare each variable between the two methods. Pearson's correlation was used to analyze the relationship between each parameter and subject age. Mean PS (t(38) = 2.966, P < 0.01) and RL (t(38)=3.563, P < 0.01) were higher for labial interruptions while mean MFR (t(38) = -2.036, P < 0.05) was lower. Intrasubject coefficients of variation were higher for the labial technique for both MFR (t(38) = 4.939, P < 0.001) and RL (t(38) = 3.439, P < 0.01) while there was no difference in PS variability (P = 0.260). Mean MFR and RL were related to age for both the labial (MFR: r = 0.588, P < 0.001; RL: r = -0.468, p = 0.003) and mechanical trials (MFR: r = 0.534, P < 0.001; RL: r = -0.496, P = 0.001). The coefficients of variation for RL were negatively correlated with age for both labial (r = -0.415, P = 0.009) and mechanical trials (r = -0.471, P = 0.002). MFR was only correlated in the labial trials (r = -0.514, P = 0.001) and PS was only correlated in the mechanical trials (r = -0.519, P = 0.001). Differences in means and intrasubject variation are likely due to differences in task and measurement timing. Precision of MFR and RL measurement in pediatric subjects was higher for mechanical interruption; further exploration of this method and its clinical utility is warranted. Measurement of aerodynamic parameters may be a useful addition to pediatric voice assessment.

PLANNING AND EVALUATION OF BIOEQUIVALENCE STUDIES OF ATAZANAVIR PRODUCTS

The Government of the Russian Federation approved the State strategy of combating the spread of HIV aimed at prevention of HIV epidemic. One of the goals of the Strategy is to increase the coverage of antiretroviral therapy for people infected with HIV, which includes extensive use of generic drugs. In order for a generic drug to be authorised, the applicant has to submit a report on the results of the bioequivalence studies in which the generic product was compared to the reference product. Atazanavir is an antiretroviral drug, which is also the drug of choice for the treatment and prevention of mother-to-child transmission of HIV. The aim of this study was to analyze the protocols and reports of atazanavir products bioequivalence studies, which were submitted for expert examination to the FSBI “SCEEMP” of the Ministry of Health of the Russian Federation, and to prepare recommendations for planning of bioequivalence studies of atazanavir products. The analysis of a number of studies revealed significant differences in the study design and number of subjects. The main reason for these differences is the conflicting data on the intrasubject coefficient of variation of atazanavir, which means that atazanavir may be considered a highly variable drug. The analysis helped to formulate recommendations for the design of bioequivalence studies of atazanavir products, including studies of the maximum dose, studies under fed conditions, and consideration of atazanavir variation when planning the study design.

How many squat\u2013stand manoeuvres to assess dynamic cerebral autoregulation?

PurposeSquat–stand manoeuvres (SSMs) have been used to induce blood pressure (BP) changes for the reliable assessment of dynamic cerebral autoregulation. However, they are physically demanding and thus multiple manoeuvres can be challenging for older subjects. This study aimed to determine the minimum number of SSMs required to obtain satisfactory coherence, thus minimising the subjects’ workload.Method20 subjects performed SSMs at a frequency of 0.05 Hz. End-tidal CO2, cerebral blood flow velocity, heart rate, continuous BP and the depth of the squat were measured. 11 subjects returned for a repeat visit. The time points at which subjects had performed 3, 6, 9, 12 and 15 SSMs were determined. Transfer function analysis was performed on files altered to the required length to obtain estimates of coherence and the autoregulation index (ARI).ResultsAfter three SSMs, coherence (0.05 Hz) was 0.93 ± 0.05, and peaked at 0.95 ± 0.02 after 12 manoeuvres. ARI decreased consecutively with more manoeuvres. ARI was comparable across the two visits (p = 0.92), but coherence was significantly enhanced during the second visit (p < 0.01). The intra-subject coefficients of variation (CoV) for ARI remained comparable as the number of manoeuvres varied.ConclusionsThis analysis can aid those designing SSM protocols, especially where participants are unable to tolerate a standard 5-min protocol or when a shorter protocol is needed to accommodate additional tests. We emphasise that fewer manoeuvres should only be used in exceptional circumstances, and where possible a full set of manoeuvres should be performed. Furthermore, these results need replicating at 0.10 Hz to ensure their applicability to different protocols.