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Article ; Online: Cardiometabolic Effects of Denosumab in Premenopausal Women with Breast Cancer Receiving Estradiol Suppression: RCT.

Ramchand, Sabashini K / Hoermann, Rudolf / White, Shane / Yeo, Belinda / Francis, Prudence A / Xu, Cecilia L H / Zajac, Jeffrey D / Seeman, Ego / Grossmann, Mathis

The Journal of clinical endocrinology and metabolism

2024

Abstract: Context: Menopause is associated with changes in musculoskeletal, body composition, and metabolic parameters that may be amplified in premenopausal women receiving estradiol suppression for breast cancer. Denosumab offsets deleterious skeletal effects ... ...

Abstract	Context: Menopause is associated with changes in musculoskeletal, body composition, and metabolic parameters that may be amplified in premenopausal women receiving estradiol suppression for breast cancer. Denosumab offsets deleterious skeletal effects of estradiol suppression and has been reported to have effects on body composition and metabolic parameters in pre-clinical and observational studies, though evidence from double-blind randomized controlled trials is limited. Objective: To assess the effect of denosumab on body composition and metabolic parameters. Methods: In a pre-specified secondary analysis of a 12-month randomized, double-blind, placebo-controlled trial, 68 premenopausal women with breast cancer initiating ovarian function suppression and aromatase inhibition were randomized to denosumab 60-mg or placebo administered at baseline and 6 months. Outcome measures were total and regional fat and lean mass (DXA), body mass index (BMI), waist and hip circumference, fasting glucose, HOMA-IR, and lipid profile. Using a mixed model, between-group mean adjusted differences, MAD, [95% confidence interval], over time are reported. Results: Over 12 months, relative to placebo, android and gynoid fat mass decreased in the denosumab group (-266 g [95%CI -453 to -79], P = 0.02, and -452 g [95%CI -783 to -122], P = 0.03, respectively). Total fat mass and waist circumference were lower in the denosumab group but not significantly so (-1792g [95% CI -3346 to -240], P = 0.08 and (- 3.77 cm [95% CI -6.76 to -0.79], P = 0.06, respectively). No significant treatment effects were detected in lean mass, BMI, hip circumference, fasting glucose, HOMA-IR, or lipid profile. Conclusions: In premenopausal women receiving estradiol suppression, denosumab decreases some measures of fat mass with no detectable effects on other measures of body composition or metabolic parameters.
Language	English
Publishing date	2024-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgae003
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Article ; Online: Vitamin D supplementation and exercise for improving physical function, body composition and metabolic health in overweight or obese older adults with vitamin D deficiency: a pilot randomized, double-blind, placebo-controlled trial

Mesinovic, Jakub / Rodriguez, Alexander J. / Cervo, Mavil May / Gandham, Anoohya / Xu, Cecilia L.H. / Glavas, Costas / de Courten, Barbora / Zengin, Ayse / Ebeling, Peter R. / Scott, David

Eur J Nutr. 2023 Mar., v. 62, no. 2 p.951-964

2023

Abstract: ... D deficiency (25-hydroxyvitamin D [25(OH)D] < 50 nmol/L) were recruited. Participants were ... increased serum 25(OH)D levels (placebo: 2.5 ± 14.7 nmol/L; treatment: 43.4 ± 18.4 nmol/L; P < 0.001) and ...

Abstract	PURPOSE: Vitamin D supplementation may have non-skeletal health benefits and enhance exercise responsiveness, particularly in those with low vitamin D levels. We determined whether, compared with placebo, vitamin D supplementation taken prior to and during a 12-week exercise program improves physical function, body composition or metabolic health, in overweight and obese older adults with vitamin D deficiency. METHODS: Fifty overweight or obese older adults (mean ± SD age: 60 ± 6 years; BMI 30.6 ± 5.7 kg/m²) with vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] < 50 nmol/L) were recruited. Participants were randomly allocated to receive either vitamin D₃ (4000 IU/day) or matching placebo for 24 weeks. Between weeks 12 and 24, all participants completed multi-modal exercise three days per week while continuing with vitamin D/placebo. Mean changes in physical function (primary outcome: gait speed), body composition and biochemical parameters at weeks 12 and 24 were compared between groups. RESULTS: Vitamin D supplementation, with or without exercise, had no effect on gait speed. From baseline to week 12, vitamin D supplementation increased serum 25(OH)D levels (placebo: 2.5 ± 14.7 nmol/L; treatment: 43.4 ± 18.4 nmol/L; P < 0.001) and reduced stair climb times (placebo: 0.3 ± 1.0 s; treatment: − 0.2 ± 1.0 s; P = 0.046). From 12 to 24 weeks, vitamin D supplementation combined with exercise decreased waist circumference (placebo: 1.3 ± 7.3 cm; treatment: − 3.0 ± 6.1 cm; P = 0.02) and waist-to-hip ratio (placebo: 0.01 ± 0.05; treatment: − 0.03 ± 0.05; P = 0.01) relative to placebo. Vitamin D supplementation, with or without exercise, had no effect on other physical function, body composition or metabolic health outcomes. CONCLUSION: Vitamin D supplementation had no effect on most physical function, body composition or metabolic health parameters when taken alone, or during exercise, in overweight or obese older adults with vitamin D deficiency. Vitamin D-related improvements in stair climb times and waist circumference suggest that future trials should explore the effects of vitamin D on muscle power, and its effects on body composition when combined with exercise, in populations with moderate or severe vitamin D deficiency.
Keywords	blood serum ; body composition ; exercise ; gait ; muscles ; overweight ; placebos ; waist circumference ; waist-to-hip ratio
Language	English
Dates of publication	2023-03
Size	p. 951-964.
Publishing place	Springer Berlin Heidelberg
Document type	Article ; Online
ZDB-ID	1466536-0
ISSN	1436-6215 ; 1436-6207
ISSN (online)	1436-6215
ISSN	1436-6207
DOI	10.1007/s00394-022-03038-z
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Duration of Respiratory and Gastrointestinal Viral Shedding in Children With SARS-CoV-2: A Systematic Review and Synthesis of Data.

Xu, Cecilia L H / Raval, Manjri / Schnall, Jesse A / Kwong, Jason C / Holmes, Natasha E

The Pediatric infectious disease journal

2020 Volume 39, Issue 9, Page(s) e249–e256

Abstract: Background: Children with coronavirus disease 2019 (COVID-19) are more likely to have mild or no symptoms compared with adults and may represent important vectors for transmitting the virus. Little is known about the duration of respiratory and ... ...

Abstract	Background: Children with coronavirus disease 2019 (COVID-19) are more likely to have mild or no symptoms compared with adults and may represent important vectors for transmitting the virus. Little is known about the duration of respiratory and gastrointestinal viral shedding in children with COVID-19. Objective: To determine the average shedding times of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the respiratory and gastrointestinal tracts in children. Methods: We performed a systematic search of Ovid MEDLINE, Embase and Cochrane CENTRAL databases for studies reporting real-time reverse transcriptase polymerase chain reaction (rt-PCR) results in children with COVID-19, then extracted and synthesized data on duration of viral shedding from symptom onset in respiratory and gastrointestinal samples. Results: Based on data compiled from 69 pediatric cases, the duration of viral shedding through the respiratory tract is up to 24 days from symptom onset with a mean of 11.1 ± 5.8 days. Of the children who underwent testing with stool PCR, rectal swab or anal swab, 86% returned a positive result. The mean duration of viral shedding via the gastrointestinal tract was 23.6 ± 8.8 days from symptom onset. In 89% of cases, viral shedding via the gastrointestinal tract persisted after nasopharyngeal or throat swabs became negative, for as long as 4 weeks. Conclusions: To our knowledge, this is the first attempt to systematically review the duration of respiratory and gastrointestinal viral shedding of SARS-CoV-2 in pediatric patients. These findings may have important implications for infection control strategies during the COVID-19 pandemic.
MeSH term(s)	Adolescent ; Betacoronavirus/genetics ; Betacoronavirus/isolation & purification ; Betacoronavirus/physiology ; COVID-19 ; Child ; Child, Preschool ; Coronavirus Infections/epidemiology ; Coronavirus Infections/virology ; Databases, Factual ; Feces/virology ; Gastrointestinal Tract/virology ; Humans ; Infant ; Infant, Newborn ; Nasopharynx/virology ; Pandemics ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/virology ; RNA, Viral/analysis ; Real-Time Polymerase Chain Reaction ; Respiratory System/virology ; SARS-CoV-2 ; Virus Shedding
Chemical Substances	RNA, Viral
Keywords	covid19
Language	English
Publishing date	2020-07-01
Publishing country	United States
Document type	Journal Article ; Systematic Review
ZDB-ID	392481-6
ISSN	1532-0987 ; 0891-3668
ISSN (online)	1532-0987
ISSN	0891-3668
DOI	10.1097/INF.0000000000002814
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Article ; Online: Duration of Respiratory and Gastrointestinal Viral Shedding in Children With SARS-CoV-2 ; A Systematic Review and Synthesis of Data

Xu, Cecilia L. H. / Raval, Manjri / Schnall, Jesse A. / Kwong, Jason C. / Holmes, Natasha E.

Pediatric Infectious Disease Journal

2020 Volume Publish Ahead of Print

Keywords	Pediatrics, Perinatology, and Child Health ; Microbiology (medical) ; Infectious Diseases ; covid19
Language	English
Publisher	Ovid Technologies (Wolters Kluwer Health)
Publishing country	us
Document type	Article ; Online
ZDB-ID	392481-6
ISSN	1532-0987 ; 0891-3668
ISSN (online)	1532-0987
ISSN	0891-3668
DOI	10.1097/inf.0000000000002814
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Vitamin D supplementation and exercise for improving physical function, body composition and metabolic health in overweight or obese older adults with vitamin D deficiency: a pilot randomized, double-blind, placebo-controlled trial.

Mesinovic, Jakub / Rodriguez, Alexander J / Cervo, Mavil May / Gandham, Anoohya / Xu, Cecilia L H / Glavas, Costas / de Courten, Barbora / Zengin, Ayse / Ebeling, Peter R / Scott, David

European journal of nutrition

2022 Volume 62, Issue 2, Page(s) 951–964

Abstract: ... vitamin D supplementation increased serum 25(OH)D levels (placebo: 2.5 ± 14.7 nmol/L; treatment: 43.4 ± 18 ... 4 nmol/L; P < 0.001) and reduced stair climb times (placebo: 0.3 ± 1.0 s; treatment: - 0.2 ± 1.0 s ...

Abstract	Purpose: Vitamin D supplementation may have non-skeletal health benefits and enhance exercise responsiveness, particularly in those with low vitamin D levels. We determined whether, compared with placebo, vitamin D supplementation taken prior to and during a 12-week exercise program improves physical function, body composition or metabolic health, in overweight and obese older adults with vitamin D deficiency. Methods: Fifty overweight or obese older adults (mean ± SD age: 60 ± 6 years; BMI 30.6 ± 5.7 kg/m Results: Vitamin D supplementation, with or without exercise, had no effect on gait speed. From baseline to week 12, vitamin D supplementation increased serum 25(OH)D levels (placebo: 2.5 ± 14.7 nmol/L; treatment: 43.4 ± 18.4 nmol/L; P < 0.001) and reduced stair climb times (placebo: 0.3 ± 1.0 s; treatment: - 0.2 ± 1.0 s; P = 0.046). From 12 to 24 weeks, vitamin D supplementation combined with exercise decreased waist circumference (placebo: 1.3 ± 7.3 cm; treatment: - 3.0 ± 6.1 cm; P = 0.02) and waist-to-hip ratio (placebo: 0.01 ± 0.05; treatment: - 0.03 ± 0.05; P = 0.01) relative to placebo. Vitamin D supplementation, with or without exercise, had no effect on other physical function, body composition or metabolic health outcomes. Conclusion: Vitamin D supplementation had no effect on most physical function, body composition or metabolic health parameters when taken alone, or during exercise, in overweight or obese older adults with vitamin D deficiency. Vitamin D-related improvements in stair climb times and waist circumference suggest that future trials should explore the effects of vitamin D on muscle power, and its effects on body composition when combined with exercise, in populations with moderate or severe vitamin D deficiency.
MeSH term(s)	Humans ; Aged ; Middle Aged ; Overweight ; Pilot Projects ; Dietary Supplements ; Obesity ; Vitamin D ; Vitamin D Deficiency ; Vitamins ; Cholecalciferol ; Body Composition ; Double-Blind Method
Chemical Substances	Vitamin D (1406-16-2) ; Vitamins ; Cholecalciferol (1C6V77QF41)
Language	English
Publishing date	2022-11-04
Publishing country	Germany
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	1466536-0
ISSN	1436-6215 ; 1436-6207
ISSN (online)	1436-6215
ISSN	1436-6207
DOI	10.1007/s00394-022-03038-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Duration of Respiratory and Gastrointestinal Viral Shedding in Children With SARS-CoV-2: A Systematic Review and Synthesis of Data

Xu, Cecilia L H / Raval, Manjri / Schnall, Jesse A / Kwong, Jason C / Holmes, Natasha E

Pediatr Infect Dis J

Abstract: BACKGROUND: Children with coronavirus disease 2019 (COVID-19) are more likely to have mild or no symptoms compared with adults and may represent important vectors for transmitting the virus. Little is known about the duration of respiratory and ... ...

Abstract	BACKGROUND: Children with coronavirus disease 2019 (COVID-19) are more likely to have mild or no symptoms compared with adults and may represent important vectors for transmitting the virus. Little is known about the duration of respiratory and gastrointestinal viral shedding in children with COVID-19. OBJECTIVE: To determine the average shedding times of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the respiratory and gastrointestinal tracts in children. METHODS: We performed a systematic search of Ovid MEDLINE, Embase and Cochrane CENTRAL databases for studies reporting real-time reverse transcriptase polymerase chain reaction (rt-PCR) results in children with COVID-19, then extracted and synthesized data on duration of viral shedding from symptom onset in respiratory and gastrointestinal samples. RESULTS: Based on data compiled from 69 pediatric cases, the duration of viral shedding through the respiratory tract is up to 24 days from symptom onset with a mean of 11.1 ± 5.8 days. Of the children who underwent testing with stool PCR, rectal swab or anal swab, 86% returned a positive result. The mean duration of viral shedding via the gastrointestinal tract was 23.6 ± 8.8 days from symptom onset. In 89% of cases, viral shedding via the gastrointestinal tract persisted after nasopharyngeal or throat swabs became negative, for as long as 4 weeks. CONCLUSIONS: To our knowledge, this is the first attempt to systematically review the duration of respiratory and gastrointestinal viral shedding of SARS-CoV-2 in pediatric patients. These findings may have important implications for infection control strategies during the COVID-19 pandemic.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #630302
Database	COVID19

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Article: Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals.

Zhou, Hang / Kember, Rachel L / Deak, Joseph D / Xu, Heng / Toikumo, Sylvanus / Yuan, Kai / Lind, Penelope A / Farajzadeh, Leila / Wang, Lu / Hatoum, Alexander S / Johnson, Jessica / Lee, Hyunjoon / Mallard, Travis T / Xu, Jiayi / Johnston, Keira J A / Johnson, Emma C / Galimberti, Marco / Dao, Cecilia / Levey, Daniel F /

Overstreet, Cassie / Byrne, Enda M / Gillespie, Nathan A / Gordon, Scott / Hickie, Ian B / Whitfield, John B / Xu, Ke / Zhao, Hongyu / Huckins, Laura M / Davis, Lea K / Sanchez-Roige, Sandra / Madden, Pamela A F / Heath, Andrew C / Medland, Sarah E / Martin, Nicholas G / Ge, Tian / Smoller, Jordan W / Hougaard, David M / Børglum, Anders D / Demontis, Ditte / Krystal, John H / Gaziano, J Michael / Edenberg, Howard J / Agrawal, Arpana / Justice, Amy C / Stein, Murray B / Kranzler, Henry R / Gelernter, Joel

medRxiv : the preprint server for health sciences

2023

Abstract: Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross- ...

Abstract	Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.
Language	English
Publishing date	2023-01-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.24.23284960
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Article ; Online: Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Zhou, Hang / Kember, Rachel L / Deak, Joseph D / Xu, Heng / Toikumo, Sylvanus / Yuan, Kai / Lind, Penelope A / Farajzadeh, Leila / Wang, Lu / Hatoum, Alexander S / Johnson, Jessica / Lee, Hyunjoon / Mallard, Travis T / Xu, Jiayi / Johnston, Keira J A / Johnson, Emma C / Nielsen, Trine Tollerup / Galimberti, Marco / Dao, Cecilia /

Levey, Daniel F / Overstreet, Cassie / Byrne, Enda M / Gillespie, Nathan A / Gordon, Scott / Hickie, Ian B / Whitfield, John B / Xu, Ke / Zhao, Hongyu / Huckins, Laura M / Davis, Lea K / Sanchez-Roige, Sandra / Madden, Pamela A F / Heath, Andrew C / Medland, Sarah E / Martin, Nicholas G / Ge, Tian / Smoller, Jordan W / Hougaard, David M / Børglum, Anders D / Demontis, Ditte / Krystal, John H / Gaziano, J Michael / Edenberg, Howard J / Agrawal, Arpana / Justice, Amy C / Stein, Murray B / Kranzler, Henry R / Gelernter, Joel

Nature medicine

2023 Volume 29, Issue 12, Page(s) 3184–3192

Abstract: Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1, ... ...

Abstract	Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.
MeSH term(s)	Humans ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Phenotype ; Polymorphism, Single Nucleotide ; Racial Groups ; Alcoholism/genetics
Language	English
Publishing date	2023-12-07
Publishing country	United States
Document type	Meta-Analysis ; Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-023-02653-5
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Article ; Online: Magnetic Resonance Imaging-Guided Frameless Stereotactic Injections of the Bilateral Cerebellar Dentate Nuclei in Nonhuman Primates: Technical Note.

Qiu, Liming / Xu, Emily / Chambule, Sydney / LaTourette, Philip / Dyer, Cecilia D / Wallace, Chelsea K / Donocoff, Rachel / Wilson, James M / Lucas, Timothy H / Chen, H Isaac

Operative neurosurgery (Hagerstown, Md.)

2024

Abstract: Background and objectives: Nonhuman primates (NHPs) are important preclinical models for evaluating therapeutics because of their anatomophysiological similarities to humans, and can be especially useful for testing new delivery targets. With the ... ...

Abstract	Background and objectives: Nonhuman primates (NHPs) are important preclinical models for evaluating therapeutics because of their anatomophysiological similarities to humans, and can be especially useful for testing new delivery targets. With the growing promise of cell and gene therapies for the treatment of neurological diseases, it is important to ensure the accurate and safe delivery of these agents to target structures in the brain. However, a standard guideline or method has not been developed for stereotactic targeting in NHPs. In this article, we describe the safe use of a magnetic resonance imaging-guided frameless stereotactic system to target bilateral cerebellar dentate nuclei for accurate, real-time delivery of viral vector in NHPs. Methods: Seventeen rhesus macaques (Macaca mulatta) underwent stereotactic surgery under real-time MRI guidance using the ClearPoint® system. Bilateral cerebellar dentate nuclei were targeted through a single parietal entry point with a transtentorial approach. Fifty microliters of contrast-impregnated infusate was delivered to each dentate nucleus, and adjustments were made as necessary according to real-time MRI monitoring of delivery. Perioperative clinical outcomes and postoperative volumes of distribution were recorded. Results: All macaques underwent bilateral surgery successfully. Superficial pin site infection occurred in 4/17 (23.5%) subjects, which resolved with antibiotics. Two episodes of transient neurological deficit (anisocoria and unilateral weakness) were recorded, which did not require additional postoperative treatment and resolved over time. Volume of distribution of infusate achieved satisfactory coverage of target dentate nuclei, and only 1 incidence (2.9%) of cerebrospinal fluid penetration was recorded. Mean volume of distribution was 161.22 ± 39.61 mm3 (left, 173.65 ± 48.29; right, 148.80 ± 23.98). Conclusion: MRI-guided frameless stereotactic injection of bilateral cerebellar dentate nuclei in NHPs is safe and feasible. The use of this technique enables real-time modification of the surgical plan to achieve adequate target coverage and can be readily translated to clinical use.
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2767575-0
ISSN	2332-4260 ; 2332-4252
ISSN (online)	2332-4260
ISSN	2332-4252
DOI	10.1227/ons.0000000000001050
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Article ; Online: Population pharmacokinetic analysis of danvatirsen supporting flat dosing switch.

Xu, Hongmei / Tong, Xiao / Mugundu, Ganesh / Scott, Martin L / Cook, Carl / Arfvidsson, Cecilia / Pease, Elizabeth / Zhou, Diansong / Lyne, Paul / Al-Huniti, Nidal

Journal of pharmacokinetics and pharmacodynamics

2019 Volume 46, Issue 1, Page(s) 65–74

Abstract: ... of AUC: 62.5 vs. 63.4 mg h/L and Cmax: 26.2 vs. 26.5 mg/L for two dose groups) with slightly less overall ...

Abstract	Danvatirsen is a Generation 2.5 antisense oligonucleotide under clinical development. Population PK modelling was conducted using data from 3 available danvatirsen Phase I/II studies in oncology patients to investigate the impact of flat dosing on exposure compared to ideal body weight-based dosing. A total of 126 patients who received danvatirsen doses ranging from 1 to 4 mg/kg as monotherapy or in combination with durvalumab, most at 3 mg/kg (n = 70), was used in the danvatirsen population PK analysis. A 2-compartment model with linear elimination described the data well. Covariate analysis revealed ideal body weight was not a significant covariate on the PK of danvatirsen; nor was age, sex or race. The model-based simulation suggested that steady state weekly AUC and Cmax were very similar between 3 mg/kg and 200 mg flat dosing (geometric mean of AUC: 62.5 vs. 63.4 mg h/L and Cmax: 26.2 vs. 26.5 mg/L for two dose groups) with slightly less overall between-subject variability in the flat dosing regimen. The switch to flat dosing was approved by multiple regulatory agencies, including FDA, EMA, PMDA and ANSM. Several ongoing studies have been evaluating flat dosing. Interim analysis from an ongoing study (D5660C00016, NCT03421353) has shown the observed steady state concentration from 200 mg flat dose is in agreement with the model predictions. The population PK model could be further utilized in subsequent exposure-response efficacy and safety modelling.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacokinetics ; Body Weight/physiology ; Computer Simulation ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Metabolic Clearance Rate/physiology ; Middle Aged ; Models, Biological ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Oligonucleotides/administration & dosage ; Oligonucleotides/pharmacokinetics ; Oligonucleotides, Antisense/pharmacokinetics
Chemical Substances	Antibodies, Monoclonal ; Oligonucleotides ; Oligonucleotides, Antisense ; durvalumab (28X28X9OKV) ; danvatirsen (31N550RD05)
Language	English
Publishing date	2019-01-19
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-019-09619-6
Database	MEDical Literature Analysis and Retrieval System OnLINE

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Full text online

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In stock of ZB MED Cologne/Königswinter

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Inter-library loan at ZB MED

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Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Full text online

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In stock of ZB MED Cologne/Königswinter

Order via subito