Neural mechanism of non-adaptive cognitive emotion regulation in patients with non-suicidal self-injury.

BACKGROUND: The incidence of non-suicidal self-injury (NSSI) has been on the rise in recent years. Studies have shown that people with NSSI have difficulties in emotion regulation and cognitive control. In addition, some studies have investigated the cognitive emotion regulation of people with NSSI which found that they have difficulties in cognitive emotion regulation, but there was a lack of research on cognitive emotion regulation strategies and related neural mechanisms. METHODS: This study included 117 people with NSSI (age = 19.47 ± 5.13, male = 17) and 84 non-NSSI participants (age = 19.86 ± 4.14, male = 16). People with NSSI met the DSM-5 diagnostic criteria, and non-NSSI participants had no mental or physical disorders. The study collected all participants' data of Cognitive Emotion Regulation Questionnaire (CERQ) and functional magnetic resonance imaging (fMRI) to explore the differences in psychological performance and brain between two groups. Afterwards, Machine learning was used to select the found differential brain regions to obtain the highest correlation regions with NSSI. Then, Allen's Human Brain Atlas database was used to compare with the information on the abnormal brain regions of people with NSSI to find the genetic information related to NSSI. In addition, gene enrichment analysis was carried out to find the related pathways and specific cells that may have differences. RESULTS: The differences between NSSI participants and non-NSSI participants were as follows: positive refocusing (t = -4.74, p < 0.01); refocusing on plans (t = -4.11, p < 0.01); positive reappraisal (t = -9.22, p < 0.01); self-blame (t = 6.30, p < 0.01); rumination (t = 3.64, p < 0.01); catastrophizing (t = 9.10, p < 0.01), and blaming others (t = 2.52, p < 0.01), the precentral gyrus (t = 6.04, pFDR < 0.05) and the rolandic operculum (t = -4.57, pFDR < 0.05). Rolandic operculum activity was negatively correlated with blaming others (r = -0.20, p < 0.05). Epigenetic results showed that excitatory neurons (p < 0.01) and inhibitory neurons (p < 0.01) were significant differences in two pathways, "trans-synaptic signaling" (p < -log108) and "modulation of chemical synaptic transmission" (p < -log108) in both cells. CONCLUSIONS: People with NSSI are more inclined to adopt non-adaptive cognitive emotion regulation strategies. Rolandic operculum is also abnormally active. Abnormal changes in the rolandic operculum of them are associated with non-adaptive cognitive emotion regulation strategies. Changes in the excitatory and inhibitory neurons provide hints to explore the abnormalities of the neurological mechanisms at the cellular level of them. Trial registration number NCT04094623.

Psychometric properties of the Chinese version of the 15-item Need for Closure Scale: Scale validation and associations with mental health.

BACKGROUND: Need for closure (NFC) has been found to be implicated in different forms of psychopathology. The 15-item Need for Closure Scale (NFCS) is an efficient and easy tool for assessing individuals' NFC in Western contexts. However, the psychometric properties of the 15-item NFCS have not yet been validated in Chinese populations. METHODS: Two different samples of university students from China were recruited in this study. The first sample (N = 5080, 49.9% females) was used to conduct exploratory factor analysis and reliability analysis. The second sample (N = 3968, 64.2% females) was used to perform confirmatory factor analysis, exploratory structural equation modeling (ESEM), and bifactor models, followed by tests of measurement invariance and criterion validity. RESULTS: The full scale showed good internal consistency. The bifactor-ESEM result with a general factor and four specific factors was chosen as our final model. Strong measurement invariance across sex and ethnicity groups was supported. Evidence was obtained for the criterion validity of NFCS scores with respect to depression, anxiety, and psychological distress. CONCLUSION: The Chinese NFCS appears to be a valid and reliable instrument for measuring the NFC, which could promote both the assessment and research of the NFC in Chinese populations.

Psychometric properties of the Chinese version of the Gudjonsson compliance scale: scale validation and associations with mental health.

BACKGROUND: Trait compliance involves people reacting favorably to demands made by others across different situations. This may lead to susceptibility to external pressures, exploitation, and manipulation. Moreover, trait compliance was found to correlate with various mental health outcomes, such as depression and anxiety. The Gudjonsson Compliance Scale (GCS) is an efficient tool for assessing trait compliance in Western contexts. To date, no study has validated the psychometric properties of the GCS in Chinese populations. METHODS: Two college student samples from China were recruited. The first sample (N = 4,276) was used to conduct exploratory factor analysis. The second (N = 4,356) was used to perform a confirmatory factor analysis. The reliability, measurement invariance, and correlational tests were conducted on the two combined samples. RESULTS: The Chinese GCS showed a 3-factor structure, with two items deleted. Reliability was supported by moderate-to-good internal consistency of the three-factor scales and good internal consistency on the full scale. Strong measurement invariance across sex, ethnicity, and group recruitment was supported. Scores of the total scale and factor scales were found to significantly associated with several mental health problems. CONCLUSIONS: The Chinese version of the GCS appears to be a valid and reliable instrument for measuring trait compliance and could promote both the assessment and research on compliance in Chinese population.

A mechanistic pharmacokinetic model for intrathecal administration of antisense oligonucleotides.

Intrathecal administration is an important mode for delivering biological agents targeting central nervous system (CNS) diseases. However, current clinical practices lack a sound theorical basis for a quantitative understanding of the variables and conditions that govern the delivery efficiency and specific tissue targeting especially in the brain. This work presents a distributed mechanistic pharmacokinetic model (DMPK) for predictive analysis of intrathecal drug delivery to CNS. The proposed DMPK model captures the spatiotemporal dispersion of antisense oligonucleotides (ASO) along the neuraxis over clinically relevant time scales of days and weeks as a function of infusion, physiological and molecular properties. We demonstrate its prediction capability using biodistribution data of antisense oligonucleotide (ASO) administration in non-human primates. The results are in close agreement with the observed ASO pharmacokinetics in all key compartments of the central nervous system. The model enables determination of optimal injection parameters such as intrathecal infusion volume and duration for maximum ASO delivery to the brain. Our quantitative model-guided analysis is suitable for identifying optimal parameter settings to target specific brain regions with therapeutic drugs such as ASOs.

Altered brain function in patients with acrophobia: A voxel-wise degree centrality analysis.

AIM: To explore the local spontaneous neural activity and whole-brain functional connectivity patterns in the resting brain of acrophobia patients. METHODS: 50 patients with acrophobia and 47 healthy controls were selected for this study. All participants underwent resting-state MRI scans after enrollment. The imaging data were then analyzed using a voxel-based degree centrality (DC) method, and seed-based functional connectivity (FC) correlation analysis was used to explore the correlation between abnormal functional connectivity and clinical symptom scales in acrophobia. The severity of symptoms was evaluated using self-report and behavioral measures. RESULTS: Compared to controls, acrophobia patients showed higher DC in the right cuneus and left middle occipital gyrus and significantly lower DC in the right cerebellum and left orbitofrontal cortex (p < 0.01, GRF corrected). Additionally, there were negative correlations between the acrophobia questionnaire avoidance (AQ- Avoidance) scores and right cerebellum-left perirhinal cortex FC (r = -0.317, p = 0.025) and between scores of the 7-item generalized anxiety disorder scale and left middle occipital gyrus-right cuneus FC (r = -0.379, p = 0.007). In the acrophobia group, there was a positive correlation between behavioral avoidance scale and right cerebellum-right cuneus FC (r = 0.377, p = 0.007). CONCLUSIONS: The findings indicated that there are local abnormalities in spontaneous neural activity and functional connectivity in the visual cortex, cerebellum, and orbitofrontal cortex in patients with acrophobia.

Orexin 2 receptor-selective agonist danavorexton (TAK-925) promotes wakefulness in non-human primates and healthy individuals.

The orexin 2 receptor-selective agonist danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1 mg kg-1 , and p < 0.001 at 1 mg kg-1 and 10 mg kg-1 ) and cynomolgus monkeys (p ≤ 0.05 at 1 mg kg-1 and 3 mg kg-1 ). In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n = 18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of danavorexton 44 mg, danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least-squares mean difference from placebo in average sleep latency was 16.8 min with danavorexton 44 mg and 30.2 min with danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p = 0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase.

Opportunities and Challenges of Disease Progression Modeling in Drug Development - An IQ Perspective.

Disease progression modeling (DPM) represents an important model-informed drug development framework. The scientific communities support the use of DPM to accelerate and increase efficiency in drug development. This article summarizes International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development mediated survey conducted across multiple biopharmaceutical companies on challenges and opportunities for DPM. Additionally, this summary highlights the viewpoints of IQ from the 2021 workshop hosted by the US Food and Drug Administration (FDA). Sixteen pharmaceutical companies participated in the IQ survey with 36 main questions. The types of questions included single/multiple choice, dichotomous, rank questions, and open-ended or free text. The key results show that DPM has different representation, it encompasses natural disease history, placebo response, standard of care as background therapy, and can even be interpreted as pharmacokinetic/pharmacodynamic modeling. The most common reasons for not implementing DPM as frequently seem to be difficulties in internal cross-functional alignment, lack of knowledge of disease/data, and time constraints. If successfully implemented, DPM can have an impact on dose selection, reduction of sample size, trial read-out support, patient selection/stratification, and supportive evidence for regulatory interactions. The key success factors and key challenges of disease progression models were highlighted in the survey and about 24 case studies across different therapeutic areas were submitted from various survey sponsors. Although DPM is still evolving, its current impact is limited but promising. The success of such models in the future will depend on collaboration, advanced analytics, availability of and access to relevant and adequate-quality data, collaborative regulatory guidance, and published examples of impact.

Altered spontaneous neural activity in frontal and visual regions in patients with acrophobia.

BACKGROUND: Acrophobia is a prevalent type of specific phobia, which frequently leads to functional impairments and occupational limitations. However, the neural pathology of acrophobia is still largely unknown. METHODS: 26 acrophobic patients and 30 healthy controls were enrolled in this study. All participants underwent a resting-state fMRI scan. Severity of symptoms was evaluated using self-report and behavioral measures. The regional homogeneity (ReHo) and seed-based functional connectivity (FC) were then examined. RESULTS: Compared to controls, acrophobic patients demonstrated higher ReHo in the right fusiform gyrus and lower ReHo in the bilateral superior frontal gyrus. Lower FC of right fusiform gyrus-bilateral caudate, right fusiform gyrus-right parahippocampal gyrus, and left medial superior frontal gyrus-left cuneus was also found in the acrophobia group. Additionally, there were negative correlations between behavior avoidance scores and FC of right fusiform gyrus- right parahippocampal gyrus (r = -0.42, p = 0.04) and between scores of the 7-item generalized anxiety disorder scale and FC of left medial superior frontal gyrus- left cuneus (r = -0.40, p = 0.049) in the acrophobia group. LIMITATIONS: Owing to the cross-sectional design, it was unclear whether the functional abnormalities found in the acrophobic patients were related to state or trait effects. CONCLUSIONS: Preliminary results indicated that acrophobic patients revealed abnormal brain function in orbitofrontal cortex, medial prefrontal cortex, and visual regions. These abnormalities may be helpful in understanding the possible neurobiological mechanism of acrophobia and may serve as potential intervention and prevention targets.

A Disease Progression Model to Quantify the Nonmotor Symptoms of Parkinson's Disease in Participants With Leucine-Rich Repeat Kinase 2 Mutation.

Leucine-rich repeat kinase 2 (LRRK2) inhibitors are currently in clinical development as interventions to slow progression of Parkinson's disease (PD). Understanding the rate of progression in PD as measured by both motor and nonmotor features is particularly important in assessing the potential therapeutic effect of LRRK2 inhibitors in clinical development. Using standardized data from the Critical Path for Parkinson's Unified Clinical Database, we quantified the rate of progression of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I (nonmotor aspects of experiences of daily living) in 158 participants with PD who were carriers and 598 participants with PD who were noncarriers of at least one of three different LRRK2 gene mutations (G2019S, R1441C/G, or R1628P). Age and disease duration were found to predict baseline disease severity, while presence of at least one of these three LRRK2 mutations was a predictor of the rate of MDS-UPDRS Part I progression. The estimated progression rate in MDS-UPDRS Part I was 0.648 (95% confidence interval: 0.544, 0.739) points per year in noncarriers of a LRRK2 mutation and 0.259 (95% confidence interval: 0.217, 0.295) points per year in carriers of a LRRK2 mutation. This analysis demonstrates that the rate of progression based on MDS-UPDRS Part I is ~ 60% lower in carriers as compared with noncarriers of LRRK2 gene mutations.

Can attention bias modification augment the effect of CBT for anxiety disorders? A systematic review and meta-analysis.

Attention Bias Modification (ABM) is a novel computerized therapy for anxiety disorders and is thought to augment the effect of Cognitive Behavior Therapy (CBT) as it may target different mechanisms. Recently, a growing number of studies have examined the combined effects of ABM and CBT on clinically anxious patients, with mixed results. This review examined the combined efficacy of ABM and CBT. A literature search was conducted in four main databases: PsycINFO, Embase, Pubmed and the Cochrane library, resulting in 11 randomized studies. The combination of ABM and CBT had small but significant effects on clinician-rated anxiety symptoms and attention bias towards threat compared to the control group, while ESs for anxiety (all measures), self-reported or parent-reported anxiety measures and depression symptoms were non-significant. Studies in which ABM was conducted as an integral part of each CBT session yielded greater reduction in anxiety symptoms than those conducting ABM and CBT at separate time points. Older participants and patients with social anxiety disorder tended to benefit less from the combination of ABM and CBT based on bias scores. This study may provide preliminary evidence that ABM and CBT have the potential to complement each other, especially when they are conducted integrally.

Attention bias modification for anxiety disorders in children and adolescents: A systematic review and meta-analysis.

Despite accumulating evidence suggesting the effectiveness of Attention Bias Modification (ABM) in adults, little is known about its efficacy in children and adolescents. As anxiety has been the chief target in most studies and research in this area has grown rapidly in recent years, we conducted the first meta-analysis to establish the effects of ABM alone for anxiety disorders in children and adolescents. Studies were identified through a systematic search in three main databases: PubMed, EMBASE and PsycInfo, resulting in 17 randomized studies. The quality of these studies, possible publication bias and moderators were then examined. ABM had small but significant effects on clinician-rated anxiety symptoms and attention bias towards threat, while the effect on self or parent-reported anxiety measures was non-significant. Evidence quality ranged from moderate to very low. ABM was more effective when conducted as a stand-alone treatment than as an adjunct to other treatments. In addition, younger age and larger number of training sessions were associated with a greater reduction in clinician-rated anxiety symptoms. Results indicate that ABM may have significant effects on anxiety and attention bias in children and adolescents. Overall, the effects of ABM are mainly evident when clinical outcome is assessed by a clinician.

Characterizing Effects of Antidiabetic Drugs on Heart Rate, Systolic and Diastolic Blood Pressure.

A model-based meta-analysis was performed with reported data from obese subjects and patients with type 2 diabetes (T2DM) to characterize the effects of dipeptidyl peptidase 4 (DPP4) inhibitors, gastric inhibitory polypeptides (GIPs), glucagon-like peptide-1 (GLP1), and dual GIP/GLP1 agonists, or a combination of these antidiabetic drugs (ADs) on heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP). A systematic literature search and review after the Cochrane method identified sources for investigational and approved ADs resulted in a comprehensive database with data from 178 clinical studies in obese subjects and patients with T2DM. Results indicated that there were AD class-dependent effects on HR and SBP, whereas no clear AD-related effects on DBP were found. All AD classes, except for DPP4 inhibitors, increased HR. The largest increase of 12 bpm was seen with GLP1 receptor agonists. All AD classes appeared to decrease SBP. DPP4 inhibitors were associated with a marginal decrease of ~ 1 mmHg, whereas GLP1 and GIP/GLP1 dual agonists exhibited the largest decrease of ~ 3 mmHg in SBP. AD-related effects were similar in obese subjects and patients with T2DM. In conclusion, there are clinically relevant AD-related effects on both HR and SBP, but not on DBP. DPP4 inhibitors are associated with the smallest (if at all) effects on HR and SBP, whereas GLP1 inhibitors exhibited the largest effects on these two cardiovascular end points. Additional studies are warranted to further investigate how AD-related SBP decreases combined with HR increases affect long-term cardiovascular mortality.

Addendum: The antibody aducanumab reduces Aß plaques in Alzheimer's disease.

This corrects the article DOI: 10.1038/nature21361.

Population-Based Pharmacokinetic and Exposure-Efficacy Analyses of Peginterferon Beta-1a in Patients With Relapsing Multiple Sclerosis.

Peginterferon beta-1a reduced annualized relapse rate as compared with placebo and was approved to treat multiple sclerosis patients. A population pharmacokinetic and an exposure-efficacy model were developed to establish the quantitative relationship between pharmacokinetics and annualized relapse rate. The pharmacokinetics was well described by a 1-compartment model with first-order absorption and linear elimination kinetics. Body mass index was the most significant covariate that impacted both clearance and volume of distribution, which in turn impacted area under the curve and maximum serum concentration. Cumulative monthly area under the curve and annualized relapse rate were best described by a Poisson-gamma (negative binomial) model, demonstrating that the improved efficacy of every-2-weeks dosing was driven by greater drug exposure. The results supported the superior efficacy of the every-2-week dosing regimen compared with the every-4-weeks dosing regimen.

The antibody aducanumab reduces Aß plaques in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aß to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aß. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aß, and reduce soluble and insoluble Aß in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aß in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Population PK-PD analyses of CD25 occupancy, CD56bright NK cell expansion, and regulatory T cell reduction by daclizumab HYP in subjects with multiple sclerosis.

AIM: Daclizumab high yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit of the interleukin-2 receptor and is being developed for treatment of multiple sclerosis (MS). This manuscript characterized the pharmacokinetic-pharmacodynamic (PK-PD) relationships of daclizumab HYP in subjects with MS. METHODS: Approximately 1400 subjects and 7000 PD measurements for each of three biomarkers [CD25 occupancy, CD56bright natural killer (NK) cell count, regulatory T cell (Treg) count] from four clinical trials were analyzed using non-linear mixed effects modelling. Evaluated regimens included 150 or 300 mg subcutaneous (s.c.) every 4 weeks. RESULTS: CD25 occupancy was characterized using a sigmoidal maximum response (Emax ) model. Upon daclizumab HYP treatment, CD25 saturation was rapid with complete saturation occurring after approximately 7 h and maintained when daclizumab HYP serum concentration was ≥5 mg l-1 . After the last 150 mg s.c. dose, unoccupied CD25 returned to baseline levels in approximately 24 weeks, with daclizumab HYP serum concentration approximately ≤1 mgl-1 1L. CD56bright NK cell expansion was characterized using an indirect response model. Following daclizumab HYP 150 mg s.c. every 4 weeks, expansion plateaus approximately at week 36, at which the average maximum expansion ratio is 5.2. After the last dose, CD56bright NK cells gradually declined to baseline levels within 24 weeks. Treg reduction was characterized by a sigmoidal Emax model. Average maximum reduction of 60% occurred approximately 4 days post 150 mg s.c. dose. After the last dose, Tregs were projected to return to baseline levels in approximately 20 weeks. CONCLUSIONS: Robust PK-PD models of CD25 occupancy, CD56bright NK cell expansion and Treg reduction by daclizumab HYP were developed to characterize its key pharmacodynamic effects in the target patient population.

Analysis of peginterferon ß-1a exposure and Gd-enhanced lesion or T2 lesion response in relapsing-remitting multiple sclerosis patients.

The effect of subcutaneous (SC) peginterferon ß-1a exposure on reduction of gadolinium-enhanced (Gd+) lesion count over time was evaluated in patients with relapsing-remitting multiple sclerosis (RRMS) in a Phase 3 study (ADVANCE). Patients were randomized to receive SC injections of placebo (n = 500), 125 mcg every-2-weeks (n = 512), or 125 mcg every-4-weeks (n = 500) for 1 year, and then active treatment in the second year. Steady state 4-week AUC (AUCss) was derived for each individual based on sparse pharmacokinetic (PK) sample and a population PK model. Several longitudinal count models, including marginal, mixed effect, and mixture models, were compared to explore the relationship between AUCss and Gd+ lesion count (or T2 lesion count). A mixture model which divided subjects into two subpopulations by low and high baseline lesion activity was found to yield best goodness-of-fit for the data. In this model, the point estimate and 95 % CI for drug effect slope on log(λ) are -0.0256 (-0.0304, -0.0216) for Gd+ lesion and -0.0147 (-0.0170, -0.0124) for T2 lesion. This suggested that reduction of Gd+ lesion (or T2 lesion) count over time is significantly related to SC peginterferon ß-1a exposure, and that the increased reduction lesion count with the every-2-week regimen versus the every-4-week regimen was driven by the higher exposure achieved in that treatment arm (mean Gd+ lesion count 0.2 and 0.7 at Year 2, respectively). The every-2-week regimen produced an exposure range that was close to the plateau range of the exposure-response curve, supporting its selection as the regulatory approved dosage.

Population Pharmacokinetics of Daclizumab High-Yield Process in Healthy Volunteers and Subjects with Multiple Sclerosis: Analysis of Phase I-III Clinical Trials.

BACKGROUND AND OBJECTIVES: Daclizumab high-yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit (CD25) of the interleukin-2 receptor. The present work characterized the population pharmacokinetics of daclizumab HYP in healthy volunteers (HVs) and subjects with relapsing-remitting multiple sclerosis (RRMS) and evaluated the effects of covariates on daclizumab HYP exposure. METHODS: Measurable serum concentrations (n = 17,139) from 1670 subjects in seven clinical studies (three phase I, one immunogenicity, one phase II with extension, and one phase III) were included in this pharmacokinetic analysis using non-linear mixed-effects modeling. The three phase I studies evaluated single or multiple doses that ranged from 50 to 400 mg with either intravenous or subcutaneous (SC) administration in HVs (n = 71). The phase II with extension studies evaluated doses of 150 or 300 mg SC every 4 weeks (n = 567), and the immunogenicity (n = 113) and the phase III (n = 919) studies evaluated 150 mg SC every 4 weeks, all in RRMS patients. RESULTS: A two-compartment model with first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Clearance (CL) was 0.212 L/day and the central volume of distribution was 3.92 L, scaled by [body weight (kg)/68] with exponents of 0.87 and 1.12, respectively. The peripheral volume of distribution was 2.42 L. Absorption lag time, mean absorption time, and absolute bioavailability (100-300 mg SC) were 1.61 h, 7.2 days, and 88 %, respectively. The daclizumab HYP terminal half-life was 21 days. Baseline CD25, age, and sex did not influence daclizumab HYP pharmacokinetics. Body weight explained 37 and 27 % of the inter-individual variability for CL and central volume of distribution, respectively. Neutralizing antibody (NAb)-positive status (included as a time-varying covariate) increased daclizumab HYP CL by 19 %. CONCLUSIONS: Consistent with previous findings in HVs, this analysis including extensive data from RRMS patients demonstrates that daclizumab HYP is characterized by slow CL, linear pharmacokinetics at doses above 100 mg, and high SC bioavailability. The pharmacokinetics of daclizumab HYP were not influenced by age (range 18-66 years), the sex of adult subjects, or the baseline CD4+CD25+ T cells (target level). The impact of covariates (body weight, NAb) on daclizumab HYP pharmacokinetics is unlikely to be clinically relevant.

Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naive HIV-infected patients.

QDMRK was a phase III clinical trial of raltegravir given once daily (QD) (800-mg dose) versus twice daily (BID) (400 mg per dose), each in combination with once-daily coformulated tenofovir-emtricitabine, in treatment-naive HIV-infected patients. Pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses were conducted using a 2-step approach: individual non-model-based PK parameters from observed sparse concentration data were determined, followed by statistical analysis of potential relationships between PK and efficacy response parameters after 48 weeks of treatment. Sparse PK sampling was performed for all patients (QD, n = 380; BID, n = 384); selected sites performed an intensive PK evaluation at week 4 (QD, n = 22; BID, n = 20). In the intensive PK subgroup, daily exposures (area under the concentration-time curve from 0 to 24 h [AUC(0-24)]) were similar between the two regimens, but patients on 800 mg QD experienced ~4-fold-higher maximum drug concentration in plasma (C(max)) values and ~6-fold-lower trough drug concentration (C(trough)) values than those on 400 mg BID. Geometric mean (GM) C(trough) values were similarly lower in the sparse PK analysis. With BID dosing, there was no indication of any significant PK/PD association over the range of tested PK parameters. With QD dosing, C(trough) values correlated with the likelihood of virologic response. Failure to achieve an HIV RNA level of <50 copies/ml appeared predominantly at high baseline HIV RNA levels in both treatment arms and was associated with lower values of GM C(trough) in the 800-mg-QD arm, though other possible drivers of efficacy, such as time above a threshold concentration, could not be evaluated due to the sparse sampling scheme. Together, these findings emphasize the importance of the shape of the plasma concentration-versus-time curve for long-term efficacy.

Protein image alignment via piecewise affine transformations.

We present a new approach for aligning families of 2D gels. Instead of choosing one of the gels as reference and performing a pairwise alignment, we construct an ideal gel that is representative of the entire family and obtain a set of piecewise affine transformations that optimally align each gel of the family to the ideal gel. The coefficients defining the transformations as well as the ideal landmarks are obtained as the solution of a large-scale quadratic programming problem that can be solved efficiently by interior-point methods.