Estimating potential cardiovascular health benefits of improved population level control of LDL cholesterol through a twice-yearly siRNA-based approach: A simulation study of a health-system level intervention.

BACKGROUND AND AIMS: Inclisiran, an siRNA therapy, consistently reduces low-density lipoprotein cholesterol (LDL-C) with twice-yearly dosing. Potential cardiovascular benefits of implementing inclisiran at a population level, added to statins, were evaluated through simulation. METHODS: For each participant in the ORION-10 and ORION-11 trials comparing inclisiran with placebo, baseline 10-year cardiovascular risk was estimated using the SMART equation. The time-adjusted LDL-C difference from baseline observed 90-540 days after baseline was assumed to persist and used to estimate potential reduction in 10-year cardiovascular risk. Impact on 500,000 ORION-like individuals was simulated with Monte-Carlo. RESULTS: Mean baseline LDL-C and predicted 10-year major vascular risk among patients randomized to inclisiran (n = 1288) versus placebo (n = 1264) were 2.66 mmol/L versus 2.60 mmol/L and 24.9% versus 24.6%, respectively. Placebo-corrected time-adjusted absolute reduction in LDL-C with inclisiran was -1.32 mmol/L (95% CI -1.37 to -1.26; p < 0.001), which predicted a 10-year cardiovascular risk of 18.1% with inclisiran versus 24.7% with placebo (absolute difference [95% CI], -6.99% [-7.33 to -6.66]; p < 0.001) NNT 15. Extrapolating to 500,000 inclisiran-treated individuals, the model predicted large population shifts towards lower quintiles of risk with fewer remaining in high-risk categories; 3350 to 471 (≥80% risk), 11,793 to 3332 (60-<80% risk), 52,142 to 22,665 (40-<60% risk), 197,752 to 141,014 (20-<40% risk), and more moving into the lowest risk category (<20%) from 234,963 to 332,518. CONCLUSIONS: Meaningful gains in population health might be achieved over 10 years by implementing at-scale approaches capable of providing substantial and sustained reductions in LDL-C beyond those achievable with statins.

Music interventions with children, adolescents and emerging adults in mental health settings: a scoping review.

BACKGROUND: Music is increasingly used with youths in health and psychosocial interventions. We conducted a scoping review with the aim to provide an overview of the current available evidence on music intervention for youth in mental health settings, to inform practice and further research. METHODS: Three databases (PsycINFO, PubMed and CINAHL) were surveyed. Using the PRISMA review method, 23 studies met inclusion criteria. RESULTS: Young people aged from 4 to 25 years old with various mental health conditions participated in music interventions. Music therapy was the most investigated (71%). Improving social skills was the most frequent therapeutic aim addressed. Music interventions are mostly appreciated by the participants, but it is difficult to make conclusions about their effectiveness because of the heterogeneity of research designs and the limited current state of research. CONCLUSION: Music interventions appear to represent a promising complementary approach to usual psychiatric care, but further standardised research is necessary to continue investigating their therapeutic effects.

Translational Population-Pharmacodynamic Modeling of a Novel Long-Acting siRNA Therapy, Inclisiran, for the Treatment of Hypercholesterolemia.

Inclisiran is a novel N-acetylgalactosamine (GalNAc) conjugated small-interfering ribonucleic acid (siRNA) therapy designed to specifically target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment results in a rapid uptake into the liver, and thus a short plasma half-life, but long duration of effects on PCSK9 inhibition and low-density lipoprotein cholesterol (LDL-C) lowering. The effects on PCSK9 inhibition and consequent LDL-C reduction are sustained for more than 6 months following a single subcutaneous (s.c.) dose, despite inclisiran being detectable in the plasma only for up to 48 hours. A kinetic-pharmacodynamic (K-PD) model was developed to characterize inclisiran's dose-related LDL-C lowering effects and to evaluate the impact of intrinsic and extrinsic factors on LDL-C lowering. To accommodate the long duration of action, the K-PD model incorporated an effect compartment which represents the liver. Inclisiran concentration in the liver leads to decreased production of the PCSK9 protein and allow recycling of more LDL-C receptors on the hepatocyte cell surface, which results in a reduction of circulating LDL-C. The analysis of covariates identified PCSK9 and LDL-C baseline levels as important factors for the effects of LDL-C lowering. Observations and modeling and simulation results demonstrated that PCSK9 and LDL-C reductions are achieved rapidly after dosing and sustained when patients are treated with a 300 mg s.c. dose once every 6 months.

Population Pharmacokinetics of Heptanoate in Healthy Subjects and Patients With Long-Chain Fatty Acid Oxidation Disorders Treated With Triheptanoin.

Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of three fatty acids with seven carbons each on a glycerol backbone, indicated for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD). A total of 562 plasma concentrations of heptanoate, the most abundant and pharmacologically active metabolite of triheptanoin, from 13 healthy adult subjects and 30 adult and pediatric subjects with LC-FAOD were included in the population pharmacokinetic (PK) analyses. Multiple peaks of heptanoate observed in several subjects were characterized by dual first-order absorption with a lag time in the second absorption compartment. The disposition of heptanoate in human plasma was adequately described by one-compartmental distribution with a linear elimination. The apparent clearance (CL/F) and apparent volume of distribution were allometrically scaled with body weight to describe PK data across a wide range of age groups in subjects with LC-FAOD. The typical CL/F in adult subjects with LC-FAOD was ≈19% lower than that in healthy subjects. Model-estimated elimination half-life for LC-FAOD patients was ∼1.7 hours, supporting a recommended dosing frequency of ≥4 times per day. Covariate analyses indicate that age, race, and sex did not lead to clinically meaningful changes in the exposure of heptanoate.

Effect of personalized musical intervention on burden of care in dental implant surgery: A pilot randomized controlled trial.

OBJECTIVE: To explore a personalized musical intervention's effect on burden of care during dental implants placement. METHODS: Randomized Controlled Trial in 24 dental implant surgery patients. A personalized music intervention (Music Care© application) or an audiobook control condition was administered. Burden of care (a composite outcome including self-reported anxiety, pain, and dissatisfaction felt during surgery), expected pain prior to surgery, pre- and post-surgery affect, memory of pain felt during surgery, and participants' emotional judgments of the music and audiobook listening were assessed. RESULTS: The personalized music intervention significantly reduced the burden of care for dental implant surgery (p = 0.02; d = 1.07). Both groups reported positive affect after surgery, but the music group felt better. The pain remembered after seven postoperative days was significantly lower in the music group (p = 0.02). Participants judged the music listened to during surgery as more relaxing and pleasant than the audiobook (p = 0.002 and p = 0.001, respectively). CONCLUSIONS: Personalized music intervention could be effective in decreasing patients' burden of care during dental implant surgery. These results need to be confirmed by a rigorous randomized control trial. CLINICAL SIGNIFICANCE: The burden of care associated with the pain and anxiety experienced during dental implant surgery can be reduced using a personalized and standardized music intervention. This approach may provide a simple complementary approach to improve surgical care in various settings.

Population Pharmacokinetics and Pharmacodynamics of Burosumab in Adult and Pediatric Patients With X-linked Hypophosphatemia.

Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X-linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK-PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first-order absorption, 1-compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK-PD parameters. No other intrinsic factors affected PK or PK-PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data.

Effects of Music Intervention on Stress in Concussed and Non-Concussed Athletes.

Sport-related concussion is a serious public health issue affecting millions of individuals each year. Among the many negative side effects, emotional symptoms, such as stress, are some of the most common. Stress management is repeatedly cited by expert groups as an important intervention for this population. It was shown that music has relaxing effects, reducing stress through the activation of brain areas involved in emotions and pleasure. The objective of this study was to explore the effects of a music-listening intervention compared with silence on experimentally induced stress in concussed and non-concussed athletes. To this aim, four groups of athletes (non-concussed music, non-concussed silence, concussed music, and concussed silence) performed the Trier Social Stress Test, for which both physiological (skin conductance level) and self-reported stress measurements were taken. No significant difference was found in the pattern of stress recovery for self-reported measurements. However, the skin conductance results showed greater and faster post-stress recovery after listening to music compared with silence for concussed athletes only. Taken together, these results suggest that music could be an efficient stress management tool to implement in the everyday life of concussed athletes to help them prevent stress accumulation.

The Emotional Effect of Background Music on Selective Attention of Adults.

Daily activities can often be performed while listening to music, which could influence the ability to select relevant stimuli while ignoring distractors. Previous studies have established that the level of arousal of music (e.g., relaxing/stimulating) has the ability to modulate mood and affect the performance of cognitive tasks. The aim of this research was to explore the effect of relaxing and stimulating background music on selective attention. To this aim, 46 healthy adults performed a Stroop-type task in five different sound environments: relaxing music, stimulating music, relaxing music-matched noise, stimulating music-matched noise, and silence. Results showed that response times for incongruent and congruent trials as well as the Stroop interference effect were similar across conditions. Interestingly, results revealed a decreased error rate for congruent trials in the relaxing music condition as compared to the relaxing music-matched noise condition, and a similar tendency between relaxing music and stimulating music-matched noise. Taken together, the absence of difference between background music and silence conditions suggest that they have similar effects on adult's selective attention capacities, while noise seems to have a detrimental impact, particularly when the task is easier cognitively. In conclusion, the type of sound stimulation in the environment seems to be a factor that can affect cognitive tasks performance.

Pitch and Rhythm Perception and Verbal Short-Term Memory in Acute Traumatic Brain Injury.

Music perception deficits are common following acquired brain injury due to stroke, epilepsy surgeries, and aneurysmal clipping. Few studies have examined these deficits following traumatic brain injury (TBI), resulting in an under-diagnosis in this population. We aimed to (1) compare TBI patients to controls on pitch and rhythm perception during the acute phase; (2) determine whether pitch and rhythm perception disorders co-occur; (3) examine lateralization of injury in the context of pitch and rhythm perception; and (4) determine the relationship between verbal short-term memory (STM) and pitch and rhythm perception. Music perception was examined using the Scale and Rhythm tests of the Montreal Battery of Evaluation of Amusia, in association with CT scans to identify lesion laterality. Verbal short-term memory was examined using Digit Span Forward. TBI patients had greater impairment than controls, with 43% demonstrating deficits in pitch perception, and 40% in rhythm perception. Deficits were greater with right hemisphere damage than left. Pitch and rhythm deficits co-occurred 31% of the time, suggesting partly dissociable networks. There was a dissociation between performance on verbal STM and pitch and rhythm perception 39 to 42% of the time (respectively), with most individuals (92%) demonstrating intact verbal STM, with impaired pitch or rhythm perception. The clinical implications of music perception deficits following TBI are discussed.

Neuropsychology supervision: A survey of practices in Quebec and a cross-cultural comparison.

OBJECTIVE: Supervisors in neuropsychology have an ethical responsibility to continuously improve their ability to supervise. Despite a growing interest in the field, there exist little data on the actual practice and few guidelines to help the practitioner through the process of neuropsychology supervision. This study aims to characterize neuropsychology supervisors and their practices in Quebec, Canada and compare these with supervisory practices of supervisors in the United States, with the ultimate aim of offering recommendations to supervisors. METHOD: Seventy-nine neuropsychology supervisors responded to the 20-question online survey of supervisory experience, education, practices, and familiarity with and use of supervision models that was inspired by Shultz and colleagues. RESULTS: Experience in clinical supervision ranged from 0.12 to 35 years and from having supervised 1-150 supervisees. About half of respondents reported having received continuing education in supervision and about two thirds were familiar with at least one type of supervision model. Some supervisory practices were associated with experience, but not with familiarity and utilization of supervision models. Supervisors from Quebec and the U.S. reported a similar frequency of addressing most of the various supervisory competencies with their supervisees. CONCLUSIONS: Based on the competency-based approach we offer a portrait of neuropsychology supervision in Quebec while highlighting some cultural differences with the U.S. Recommendations include focusing more on certain foundational (e.g. reflective practice) and functional competencies (supervision most notably). Neuropsychology supervisors are also encouraged to devote more time to continuing education opportunities in supervision in order to ensure supervisee development and quality care.

Effect of Background Music on Attentional Control in Older and Young Adults.

Healthy aging may be accompanied by cognitive decline that includes diminished attentional control, an executive function that allows us to focus our attention while inhibiting distractors. Previous studies have demonstrated that background music can enhance some executive functions in both young and older adults. According to the Arousal-Mood Theory, the beneficial influence of background music on cognitive performance would be related to its ability to increase the arousal level of the listeners and to improve their mood. Consequently, stimulating and pleasant music might enhance attentional control. Therefore, the aims of this study were (1) to determine if the influence of background music, and more specifically its arousal level, might improve attentional control in older adults and (2) whether this effect is similar across older and young adults. Older and young adults performed a visuo-spatial flanker task during three auditory conditions: stimulating music, relaxing music, and silence. Participants had to indicate as fast and as accurately as possible the direction of a central arrow, which was flanked by congruent or incongruent arrows. As expected, reaction times were slower for the incongruent compared to congruent trials. Interestingly, this difference was significantly greater under the relaxing music condition compared to other auditory conditions. This effect was the same across both age groups. In conclusion, relaxing music seems to interfere with visuo-spatial attentional control compared to stimulating music and silence, regardless of age.

Impact of Music on Working Memory in Rwanda.

Previous research shows that listening to pleasant, stimulating and familiar music is likely to improve working memory performance. The benefits of music on cognition have been widely studied in Western populations, but not in other cultures. The purpose of this study was to explore the impact of music on working memory in a non-Western sociocultural context: Rwanda. One hundred and nineteen participants were randomly assigned to a control group (short story) or one of four different musical conditions varying on two dimensions: arousal (relaxing, stimulating) and cultural origin (Western, Rwandan). Working memory was measured using a behavioral task, the n-back paradigm, before and after listening to music (or the short story in the control condition). Unlike in previous studies with Western samples, our results with this Rwandan sample did not show any positive effect of familiar, pleasant and stimulating music on working memory. Performance on the n-back task generally improved from pre to post, in all conditions, but this improvement was less important in participants who listened to familiar Rwandan music compared to those who listened to unfamiliar Western music or to a short story. The study highlights the importance of considering the sociocultural context in research examining the impact of music on cognition. Although different aspects of music are considered universal, there may be cultural differences that limit the generalization of certain effects of music on cognition or that modulate the characteristics that favor its beneficial impact.

Population Pharmacokinetic-Pharmacodynamic Model of Serum Transthyretin Following Patisiran Administration.

Hereditary transthyretin-mediated amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by mutated transthyretin (TTR) protein. Patisiran is a small interfering RNA (siRNA) formulated in a lipid nanoparticle that inhibits hepatic TTR protein synthesis by RNA interference. We have developed an indirect-response pharmacokinetic-pharmacodynamic model relating plasma siRNA (ALN-18328) levels to serum TTR reduction across five clinical studies. A sigmoidal function described this relationship, with estimated Hill coefficient of 0.548, and half maximal inhibitory concentration (IC50), IC80, and IC90 values of 9.45, 118.5, and 520.5 ng/mL, respectively. Following patisiran 0.3 mg/kg every 3 weeks (q3w), steady-state plasma ALN-18328 exposures were between IC80 and IC90, yielding average serum TTR reductions of 80%-90% from baseline. Covariate analysis indicated similar TTR reduction across evaluated intrinsic and extrinsic factors, obviating the need for dose adjustment. Modeling results support the recommended patisiran dosing schedule of 0.3 mg/kg q3w, with a maximum dose of 30 mg for patients weighing ≥100 kg.

Influence of Background Musical Emotions on Attention in Congenital Amusia.

Congenital amusia in its most common form is a disorder characterized by a musical pitch processing deficit. Although pitch is involved in conveying emotion in music, the implications for pitch deficits on musical emotion judgements is still under debate. Relatedly, both limited and spared musical emotion recognition was reported in amusia in conditions where emotion cues were not determined by musical mode or dissonance. Additionally, assumed links between musical abilities and visuo-spatial attention processes need further investigation in congenital amusics. Hence, we here test to what extent musical emotions can influence attentional performance. Fifteen congenital amusic adults and fifteen healthy controls matched for age and education were assessed in three attentional conditions: executive control (distractor inhibition), alerting, and orienting (spatial shift) while music expressing either joy, tenderness, sadness, or tension was presented. Visual target detection was in the normal range for both accuracy and response times in the amusic relative to the control participants. Moreover, in both groups, music exposure produced facilitating effects on selective attention that appeared to be driven by the arousal dimension of musical emotional content, with faster correct target detection during joyful compared to sad music. These findings corroborate the idea that pitch processing deficits related to congenital amusia do not impede other cognitive domains, particularly visual attention. Furthermore, our study uncovers an intact influence of music and its emotional content on the attentional abilities of amusic individuals. The results highlight the domain-selectivity of the pitch disorder in congenital amusia, which largely spares the development of visual attention and affective systems.

Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants.

Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo-controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted-versus-observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration-versus-time profiles in the active and placebo groups. Terminal elimination half-life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment-emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.

A randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of a fixed-dose combination of phentermine/topiramate in adolescents with obesity.

AIMS: To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI-0521, a fixed-dose combination of immediate-release phentermine (PHEN) and extended-release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination. MATERIALS AND METHODS: This was a multicentre, randomized, double-blind, parallel-design, placebo-controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid-dose (PHEN/TPM 7.5 mg/46 mg), or a top-dose (PHEN/TPM 15 mg/92 mg) of VI-0521. A total of 26 adolescents were included in the PK analysis (14 from the mid-dose group and 12 from the top-dose group). RESULTS: On day 56, arithmetic means of terminal elimination half-life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid- and top-dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was -5.2 mmHg for the placebo group, -2.5 mmHg for the mid-dose group, and - 5.5 mmHg for the top-dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was -2.4 mmHg for the placebo group, +3.8 mmHg for the mid-dose group, and + 2.0 mmHg for the top-dose group. Participants in the top-dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid-dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated. CONCLUSIONS: Treatment of adolescents with obesity using a fixed-dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid- and top-dose levels are appropriate for longer-term safety and efficacy studies in adolescents.

Electrophysiological Responses to Emotional Facial Expressions Following a Mild Traumatic Brain Injury.

The present study aimed to measure neural information processing underlying emotional recognition from facial expressions in adults having sustained a mild traumatic brain injury (mTBI) as compared to healthy individuals. We thus measured early (N1, N170) and later (N2) event-related potential (ERP) components during presentation of fearful, neutral, and happy facial expressions in 10 adults with mTBI and 11 control participants. Findings indicated significant differences between groups, irrespective of emotional expression, in the early attentional stage (N1), which was altered in mTBI. The two groups showed similar perceptual integration of facial features (N170), with greater amplitude for fearful facial expressions in the right hemisphere. At a higher-level emotional discrimination stage (N2), both groups demonstrated preferential processing for fear as compared to happiness and neutrality. These findings suggest a reduced early selective attentional processing following mTBI, but no impact on the perceptual and higher-level cognitive processes stages. This study contributes to further improving our comprehension of attentional versus emotional recognition following a mild TBI.

Emotional recognition from dynamic facial, vocal and musical expressions following traumatic brain injury.

OBJECTIVES: To assess emotion recognition from dynamic facial, vocal and musical expressions in sub-groups of adults with traumatic brain injuries (TBI) of different severities and identify possible common underlying mechanisms across domains. METHODS: Forty-one adults participated in this study: 10 with moderate-severe TBI, nine with complicated mild TBI, 11 with uncomplicated mild TBI and 11 healthy controls, who were administered experimental (emotional recognition, valence-arousal) and control tasks (emotional and structural discrimination) for each domain. RESULTS: Recognition of fearful faces was significantly impaired in moderate-severe and in complicated mild TBI sub-groups, as compared to those with uncomplicated mild TBI and controls. Effect sizes were medium-large. Participants with lower GCS scores performed more poorly when recognizing fearful dynamic facial expressions. Emotion recognition from auditory domains was preserved following TBI, irrespective of severity. All groups performed equally on control tasks, indicating no perceptual disorders. Although emotional recognition from vocal and musical expressions was preserved, no correlation was found across auditory domains. CONCLUSIONS: This preliminary study may contribute to improving comprehension of emotional recognition following TBI. Future studies of larger samples could usefully include measures of functional impacts of recognition deficits for fearful facial expressions. These could help refine interventions for emotional recognition following a brain injury.

Population pharmacokinetics of bevacizumab in cancer patients with external validation.

BACKGROUND: Bevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics. METHODS: Rich and sparse bevacizumab serum concentrations were collected from Phase I through IV studies in early and metastatic cancers. Bevacizumab was given intravenously as single agent or in combination with chemotherapy for single- and multiple-dose schedules. RESULTS: Model-building used 8943 bevacizumab concentrations from 1792 patients with colon/colorectal, non-small cell lung, kidney, pancreatic, breast, prostate and brain cancer. Bevacizumab doses ranged from 1 to 20 mg/kg given once every 1, 2 or 3 weeks. A two-compartment model best described the data. The population estimates of clearance (CL), central volume of distribution (V1) and half-life for a typical 70-kg patient were 9.01 mL/h, 2.88 L and 19.6 days. CL and V1 increased with body weight and were higher in males than females by 14 and 18 %, respectively. CL decreased with increasing albumin and decreasing alkaline phosphatase. The final model was externally validated using 1670 concentrations from 146 Japanese patients that were not used for model-building. Mean prediction errors were -2.1, 3.1 and 1.0 % for concentrations, CL and V1, respectively, confirming adequate predictive performance. CONCLUSIONS: A robust bevacizumab pharmacokinetic model was developed and externally validated, which may be used to simulate bevacizumab exposure to optimize dosing strategies. Asian and non-Asian patients exhibited similar bevacizumab pharmacokinetics. Given the similarity in pharmacokinetics among monoclonal antibodies, this may inform pharmacokinetic studies in different ethnic groups for other therapeutic antibodies.