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Article ; Online: Population Pharmacokinetic Modeling and Exposure-Efficacy and Body Weight-Response Analyses for Tezepelumab in Patients With Severe, Uncontrolled Asthma.

Zheng, Yanan / Abuqayyas, Lubna / Quartino, Angelica / Guan, Ye / Gao, Yuying / Liu, Lu / Hellqvist, Åsa / Colice, Gene / MacDonald, Alexander

Journal of clinical pharmacology

2024

Abstract: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed-dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, ... ...

Abstract	Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed-dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients with asthma or healthy participants enrolled in 8 clinical studies (phases 1-3). Tezepelumab exposure-efficacy relationships were analyzed in the phase 3 NAVIGATOR study (NCT03347279), using asthma exacerbation rates over 52 weeks and changes in pre-bronchodilator forced expiratory volume in 1 s at week 52. Tezepelumab pharmacokinetics were well characterized by a 2-compartment linear disposition model with first-order absorption and elimination following subcutaneous and intravenous administration at 2.1-420 and 210-700 mg, respectively. There were no clinically relevant effects on tezepelumab pharmacokinetics from age (≥12 years), sex, race/ethnicity, renal or hepatic function, disease severity (inhaled corticosteroid dose level), concomitant asthma medication use, smoking history, or anti-drug antibodies. Body weight was the most influential covariate on tezepelumab exposure, but no meaningful differences in efficacy or safety were observed across body weight quartiles in patients with asthma who received tezepelumab 210 mg subcutaneously Q4W. There was no apparent relationship between tezepelumab exposure and efficacy at this dose regimen, suggesting that it is on the plateau of the exposure-response curve of tezepelumab. In conclusion, a fixed-dose regimen of tezepelumab 210 mg subcutaneously Q4W is appropriate for eligible adults and adolescents with severe, uncontrolled asthma.
Language	English
Publishing date	2024-04-17
Publishing country	England
Document type	Journal Article
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.2433
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Article ; Online: Population pharmacokinetics of a novel PCSK9 antisense oligonucleotide.

Clewe, Oskar / Rekić, Dinko / Quartino, Angelica L / Carlsson, Björn / Higashimori, Mitsuo / Wernevik, Linda / Hofherr, Alexis / Rydén-Bergsten, Tina / Nilsson, Catarina / Knöchel, Jane

British journal of clinical pharmacology

2024

Abstract: Aims: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an antisense oligonucleotide (ASO) that targets the PCSK9 transcript to reduce hepatocyte PCSK9 protein production and plasma levels. AZD8233 utilizes generation ...

Abstract	Aims: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an antisense oligonucleotide (ASO) that targets the PCSK9 transcript to reduce hepatocyte PCSK9 protein production and plasma levels. AZD8233 utilizes generation 2.5 S-constrained ethyl motif (cET) chemistry and is conjugated to a triantennary N-acetylgalactosamine (GalNAc3) ligand for targeted hepatocyte uptake. Methods: A non-linear mixed-effect modelling approach utilizing NONMEM software was applied to AZD8233 concentration-time data from 3416 samples in 219 participants from four phase 1-2 studies, one in healthy volunteers (NCT03593785) and three in patients with dyslipidaemia (NCT04155645, NCT04641299 and NCT04823611). Results: The final model described the AZD8233 plasma concentration-time profile from four phase 1-2 studies in healthy volunteers or participants with dyslipidaemia, covering a dose range of 4 to 120 mg. The pharmacokinetics of AZD8233 were adequately described by a two-compartment model with first-order absorption. The supra-proportional increase in maximum plasma concentration (C Conclusions: Covariate analysis showed body weight to be the main factor affecting exposure to AZD8233, which largely explained the higher C
Language	English
Publishing date	2024-03-19
Publishing country	England
Document type	Journal Article
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.16046
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Article ; Online: Tumor growth inhibition modeling of individual lesion dynamics and interorgan variability in HER2-negative breast cancer patients treated with docetaxel.

Krishnan, Sreenath M / Laarif, Sofiene S / Bender, Brendan C / Quartino, Angelica L / Friberg, Lena E

CPT: pharmacometrics & systems pharmacology

2021 Volume 10, Issue 5, Page(s) 511–521

Abstract: Information on individual lesion dynamics and organ location are often ignored in pharmacometric modeling analyses of tumor response. Typically, the sum of their longest diameters is utilized. Herein, a tumor growth inhibition model was developed for ... ...

Abstract	Information on individual lesion dynamics and organ location are often ignored in pharmacometric modeling analyses of tumor response. Typically, the sum of their longest diameters is utilized. Herein, a tumor growth inhibition model was developed for describing the individual lesion time-course data from 183 patients with metastatic HER2-negative breast cancer receiving docetaxel. The interindividual variability (IIV), interlesion variability (ILV), and interorgan variability of parameters describing the lesion time-courses were evaluated. Additionally, a model describing the probability of new lesion appearance and a time-to-event model for overall survival (OS), were developed. Before treatment initiation, the lesions were largest in the soft tissues and smallest in the lungs, and associated with a significant IIV and ILV. The tumor growth rate was 2.6 times higher in the breasts and liver, compared with other metastatic sites. The docetaxel drug effect in the liver, breasts, and soft tissues was greater than or equal to 1.2 times higher compared with other organs. The time-course of the largest lesion, the presence of at least 3 liver lesions, and the time since study enrollment, increased the probability of new lesion appearance. New lesion appearance, along with the time to growth and time-course of the largest lesion at baseline, were identified as the best predictors of OS. This tumor modeling approach, incorporating individual lesion dynamics, provided a more complete understanding of heterogeneity in tumor growth and drug effect in different organs. Thus, there may be potential to tailor treatments based on lesion location, lesion size, and early lesion response to provide better clinical outcomes.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Docetaxel/pharmacology ; Docetaxel/therapeutic use ; Female ; Humans ; Middle Aged ; Neoplasm Metastasis ; Patient-Specific Modeling ; Receptor, ErbB-2/metabolism
Chemical Substances	Antineoplastic Agents ; Docetaxel (15H5577CQD) ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2021-05-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12629
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Article ; Online: Mechanistic Modeling of Soluble Aβ Dynamics and Target Engagement in the Brain by Anti-Aβ mAbs in Alzheimer's Disease.

Ferl, Gregory Z / Fuji, Reina N / Atwal, Jasvinder K / Sun, Tony / Ramanujan, Saroja / Quartino, Angelica L

Current Alzheimer research

2020 Volume 17, Issue 4, Page(s) 393–406

Abstract: Background: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer's disease.: Objectives: To address the complexity of Aβ target engagement profiles, improve the understanding of crenezumab ... ...

Abstract	Background: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer's disease. Objectives: To address the complexity of Aβ target engagement profiles, improve the understanding of crenezumab Pharmacokinetics (PK) and Aβ Pharmacodynamics (PD) in the brain, and facilitate comparison of anti-Aβ therapies with different binding characteristics. Methods: A mechanistic mathematical model was developed describing the distribution, elimination, and binding kinetics of anti-Aβ mAbs and Aβ (monomeric and oligomeric forms of Aβ1-40 and Aβ1-42) in the brain, Cerebrospinal Fluid (CSF), and plasma. Physiologically meaningful values were assigned to the model parameters based on the previous data, with remaining parameters fitted to clinical measurements of Aβ concentrations in CSF and plasma, and PK/PD data of patients undergoing anti-Aβ therapy. Aβ target engagement profiles were simulated using a Monte Carlo approach to explore the impact of biological uncertainty in the model parameters. Results: Model-based estimates of in vivo affinity of the antibody to monomeric Aβ were qualitatively consistent with the previous data. Simulations of Aβ target engagement profiles captured observed mean and variance of clinical PK/PD data. Conclusion: This model is useful for comparing target engagement profiles of different anti-Aβ therapies and demonstrates that 60 mg/kg crenezumab yields a significant increase in Aβ engagement compared with lower doses of solanezumab, supporting the selection of 60 mg/kg crenezumab for phase 3 studies. The model also provides evidence that the delivery of sufficient quantities of mAb to brain interstitial fluid is a limiting step with respect to the magnitude of soluble Aβ oligomer neutralization.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/antagonists & inhibitors ; Amyloid beta-Peptides/metabolism ; Animals ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/metabolism ; Brain/drug effects ; Brain/metabolism ; Drug Delivery Systems/methods ; Humans ; Models, Theoretical ; Peptide Fragments/antagonists & inhibitors ; Peptide Fragments/metabolism
Chemical Substances	Amyloid beta-Peptides ; Antibodies, Monoclonal, Humanized ; Peptide Fragments ; amyloid beta-protein (1-40) ; amyloid beta-protein (1-42) ; crenezumab (O8AS5277H0)
Language	English
Publishing date	2020-03-01
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205170-3
ISSN	1875-5828 ; 1567-2050
ISSN (online)	1875-5828
ISSN	1567-2050
DOI	10.2174/1567205017666200302122307
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Zs.A 6235: Show issues

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Article ; Online: Modeling Alzheimer's disease progression utilizing clinical trial and ADNI data to predict longitudinal trajectory of CDR-SB.

Jamalian, Samira / Dolton, Michael / Chanu, Pascal / Ramakrishnan, Vidya / Franco, Yesenia / Wildsmith, Kristin / Manser, Paul / Teng, Edmond / Jin, Jin Y / Quartino, Angelica / Hsu, Joy C

CPT: pharmacometrics & systems pharmacology

2023 Volume 12, Issue 7, Page(s) 1029–1042

Abstract: There is strong interest in developing predictive models to better understand individual heterogeneity and disease progression in Alzheimer's disease (AD). We have built upon previous longitudinal AD progression models, using a nonlinear, mixed-effect ... ...

Abstract	There is strong interest in developing predictive models to better understand individual heterogeneity and disease progression in Alzheimer's disease (AD). We have built upon previous longitudinal AD progression models, using a nonlinear, mixed-effect modeling approach to predict Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) progression. Data from the Alzheimer's Disease Neuroimaging Initiative (observational study) and placebo arms from four interventional trials (N = 1093) were used for model building. The placebo arms from two additional interventional trials (N = 805) were used for external model validation. In this modeling framework, CDR-SB progression over the disease trajectory timescale was obtained for each participant by estimating disease onset time (DOT). Disease progression following DOT was described by both global progression rate (RATE) and individual progression rate (α). Baseline Mini-Mental State Examination and CDR-SB scores described the interindividual variabilities in DOT and α well. This model successfully predicted outcomes in the external validation datasets, supporting its suitability for prospective prediction and use in design of future trials. By predicting individual participants' disease progression trajectories using baseline characteristics and comparing these against the observed responses to new agents, the model can help assess treatment effects and support decision making for future trials.
MeSH term(s)	Humans ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/drug therapy ; Prospective Studies ; Mental Status and Dementia Tests ; Research Design ; Disease Progression
Language	English
Publishing date	2023-05-02
Publishing country	United States
Document type	Observational Study ; Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12974
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Article ; Online: Population Pharmacokinetics of Ranibizumab Delivered via the Port Delivery System Implanted in the Eye in Patients with Neovascular Age-Related Macular Degeneration.

Kågedal, Matts / Alskär, Oskar / Petersson, Klas / Hanze, Eva / Maia, Mauricio / Lu, Tong / Vakhavkar, Shweta / Quartino, Angelica / Willis, Jeffrey R / Jin, Jin Y / Maass, Katie F

Journal of clinical pharmacology

2023 Volume 63, Issue 11, Page(s) 1210–1220

Abstract: The port delivery system with ranibizumab (PDS) is designed to continuously deliver ranibizumab to maintain therapeutic drug concentrations in the vitreous of the eye for an extended duration. The PDS has been evaluated for the treatment of neovascular ... ...

Abstract	The port delivery system with ranibizumab (PDS) is designed to continuously deliver ranibizumab to maintain therapeutic drug concentrations in the vitreous of the eye for an extended duration. The PDS has been evaluated for the treatment of neovascular age-related macular degeneration in the Ladder (PDS 10, 40, and 100 mg/mL, with refill exchanges as needed, versus monthly intravitreal ranibizumab 0.5 mg), Archway (PDS 100 mg/mL with 24-week refill exchanges, versus monthly intravitreal ranibizumab 0.5 mg), and ongoing Portal (PDS 100 mg/mL with 24-week refill exchanges) clinical trials. Data from Ladder, Archway, and Portal were used to develop a population pharmacokinetics (PK) model to estimate the ranibizumab release rate from the PDS implant, describe ranibizumab PK in serum and aqueous humor, and predict the concentration in vitreous humor. A model was developed to adequately describe the serum and aqueous humor PK data, as suggested by goodness-of-fit plots as well as visual predictive checks. In the final model, the first-order implant release rate was estimated to be 0.00654 (1/day), corresponding to a half-life of 106 days, consistent with the implant release rate determined in vitro. The model-predicted vitreous concentrations achieved with PDS 100 mg/mL given every 24 weeks were below the intravitreal peak concentration and above the intravitreal trough concentration of ranibizumab over the entire 24-week refill interval. The results demonstrate a durable release of ranibizumab from the PDS with a half-life of 106 days, providing vitreous exposure to ranibizumab for at least 24 weeks that is within the range of exposure for monthly intravitreal treatment.
MeSH term(s)	Humans ; Ranibizumab/therapeutic use ; Angiogenesis Inhibitors/pharmacokinetics ; Angiogenesis Inhibitors/therapeutic use ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Intravitreal Injections ; Macular Degeneration/drug therapy
Chemical Substances	Ranibizumab (ZL1R02VT79) ; Angiogenesis Inhibitors ; Antibodies, Monoclonal, Humanized
Language	English
Publishing date	2023-06-28
Publishing country	England
Document type	Journal Article
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.2290
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Article ; Online: A longitudinal model for the Mayo Clinical Score and its sub-components in patients with ulcerative colitis.

Kawakatsu, Sonoko / Zhu, Rui / Zhang, Wenhui / Tang, Meina T / Lu, Tong / Quartino, Angelica L / Kågedal, Matts

Journal of pharmacokinetics and pharmacodynamics

2021 Volume 49, Issue 2, Page(s) 179–190

Abstract: Clinical trials in patients with ulcerative colitis (UC) face the challenge of high and variable placebo response rates. The Mayo Clinical Score (MCS) is used widely as the primary endpoint in clinical trials to describe the clinical status of patients ... ...

Abstract	Clinical trials in patients with ulcerative colitis (UC) face the challenge of high and variable placebo response rates. The Mayo Clinical Score (MCS) is used widely as the primary endpoint in clinical trials to describe the clinical status of patients with UC. The MCS is comprised of four subscores, each scored 0, 1, 2 and 3: rectal bleeding (RB), stool frequency (SF), physician's global assessment (PGA), and endoscopy (ENDO) subscore. Excluding the PGA subscore gives the modified MCS. Quantitative insight on the placebo response, and its impact on the components of the MCS over time, can better inform clinical trial design and interpretation. Longitudinal modeling of the MCS, and the modified MCS, can be challenging due to complex clinical trial design, population heterogeneity, and limited assessments for the ENDO subscore. The current study pooled patient-level placebo/standard of care (SoC) arm data from five clinical trials in the TransCelerate database to develop a longitudinal placebo response model that describes the MCS over time in patients with UC. MCS subscores were modeled using proportional odds models, and the removal of patients from the placebo/SoC arm, or "dropout", was modeled using logistic regression models. The subscore and dropout models were linked to allow for the prediction of the MCS and the modified MCS. Stepwise covariate modeling identified prior exposure to TNF-α antagonists as a statistically significant predictor on the RB + SF subscore. Patients with prior exposure to TNF-α antagonists had higher post-baseline RB + SF subscores than naive patients.
MeSH term(s)	Colitis, Ulcerative/drug therapy ; Double-Blind Method ; Feces ; Humans ; Prostaglandins A/therapeutic use ; Remission Induction ; Treatment Outcome ; Tumor Necrosis Factor-alpha
Chemical Substances	Prostaglandins A ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2021-10-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-021-09789-2
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Zs.A 980: Show issues

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Article ; Online: Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 Inhibition in Type 2 Diabetes: Phase 1 Results.

Vavere, Andrea L / Sinsakul, Marvin / Ongstad, Emily L / Yang, Ye / Varma, Vijayalakshmi / Jones, Christopher / Goodman, Joanne / Dubois, Vincent F S / Quartino, Angelica L / Karathanasis, Sotirios K / Abuhatzira, Liron / Collén, Anna / Antoniades, Charalambos / Koren, Michael J / Gupta, Ruchi / George, Richard T

Journal of the American Heart Association

2023 Volume 12, Issue 3, Page(s) e027540

Abstract: Background Blockade of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, ...

Abstract	Background Blockade of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high-affinity monoclonal blocking antibody to LOX-1. Methods and Results This phase 1, first-in-human, placebo-controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive single ascending doses (10, 30, 90, 250, or 500 mg) or multiple ascending doses (90, 150, or 250 mg once monthly for 3 months) of MEDI6570 or placebo. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX-1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half-life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target-mediated drug disposition. Dose-dependent reductions in mean soluble LOX-1 levels from baseline were observed (>66% at 4 weeks and 71.61-82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (-13.45 mm
MeSH term(s)	Humans ; Female ; Middle Aged ; Male ; Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/drug therapy ; Antibodies, Monoclonal/therapeutic use ; Lectins/therapeutic use ; Double-Blind Method ; Dose-Response Relationship, Drug
Chemical Substances	Antibodies, Monoclonal ; Lectins
Language	English
Publishing date	2023-01-23
Publishing country	England
Document type	Randomized Controlled Trial ; Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2653953-6
ISSN	2047-9980 ; 2047-9980
ISSN (online)	2047-9980
ISSN	2047-9980
DOI	10.1161/JAHA.122.027540
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Article ; Online: Population Pharmacokinetics and Exposure-Response Relationships of Astegolimab in Patients With Severe Asthma.

Kotani, Naoki / Dolton, Michael / Svensson, Robin J / Ribbing, Jakob / Friberg, Lena E / Vadhavkar, Shweta / Cheung, Dorothy / Staton, Tracy / Sperinde, Gizette / Jin, Jin / Putnam, Wendy S / Quartino, Angelica

Journal of clinical pharmacology

2022 Volume 62, Issue 7, Page(s) 905–917

Abstract: Astegolimab is a fully human immunoglobulin G2 monoclonal antibody that binds to the ST2 receptor and blocks the interleukin-33 signaling. It was evaluated in patients with uncontrolled severe asthma in the phase 2b study (Zenyatta) at doses of 70, 210, ... ...

Abstract	Astegolimab is a fully human immunoglobulin G2 monoclonal antibody that binds to the ST2 receptor and blocks the interleukin-33 signaling. It was evaluated in patients with uncontrolled severe asthma in the phase 2b study (Zenyatta) at doses of 70, 210, and 490 mg subcutaneously every 4 weeks for 52 weeks. This work aimed to characterize astegolimab pharmacokinetics, identify influential covariates contributing to its interindividual variability, and make a descriptive assessment of the exposure-response relationships. A population pharmacokinetic model was developed using data from 368 patients in the Zenyatta study. Predicted average steady-state concentration was used in the subsequent exposure-response analyses, which evaluated efficacy (asthma exacerbation rate) and biomarker end points including forced expiratory volume in 1 second, fraction exhaled nitric oxide, blood eosinophils, and soluble ST2. A 2-compartment disposition model with first-order elimination and first-order absorption best described the astegolimab pharmacokinetics. The relative bioavailability for the 70-mg dose was 15.3% lower. Baseline body weight, estimated glomerular filtration rate, and eosinophils were statistically correlated with pharmacokinetic parameters, but only body weight had a clinically meaningful influence on the steady-state exposure (ratios exceeding 0.8-1.25). The exposure-response of efficacy and biomarkers were generally flat with a weak trend in favor of the highest dose/exposure. This study characterized astegolimab pharmacokinetics in patients with asthma and showed typical pharmacokinetic behavior as a monoclonal antibody-based drug. The exposure-response analyses suggested the highest dose tested in the Zenyatta study (490 mg every 4 weeks) performed close to the maximum effect, and no additional response may be expected above it.
MeSH term(s)	Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Asthma/drug therapy ; Body Weight ; Clinical Trials, Phase II as Topic ; Humans
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; astegolimab (27TW751DTH)
Language	English
Publishing date	2022-02-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.2021
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Article ; Online: Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer's disease.

Yoshida, Kenta / Moein, Anita / Bittner, Tobias / Ostrowitzki, Susanne / Lin, Helen / Honigberg, Lee / Jin, Jin Y / Quartino, Angelica

Alzheimer's research & therapy

2020 Volume 12, Issue 1, Page(s) 16

Abstract: Background: Crenezumab, a fully humanized anti-beta-amyloid (Aβ) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of Aβ. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of crenezumab and its ... ...

Abstract	Background: Crenezumab, a fully humanized anti-beta-amyloid (Aβ) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of Aβ. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of crenezumab and its interaction with monomeric Aβ(1-40) and Aβ(1-42) peptides in serum/plasma and cerebrospinal fluid (CSF) samples from the phase II ABBY and BLAZE studies and the phase Ib GN29632 study. Methods: In ABBY, BLAZE, and GN29632 studies, patients with mild-to-moderate AD were treated with either placebo or crenezumab (300 mg subcutaneously every 2 weeks [q2w], or 15 mg/kg, 30 mg/kg, 45 mg/kg, 60 mg/kg, or 120 mg/kg intravenously q4w). Serum/plasma PK/PD analyses included samples from 131 patients who received crenezumab in all three studies. CSF PK/PD analyses included samples from 76 patients who received crenezumab in ABBY or BLAZE. The impact of baseline patient factors on Aβ profiles was also evaluated. Results: The serum concentration of crenezumab increased in a dose-proportional manner between 15 and 120 mg/kg q4w. Total monomeric plasma Aβ(1-40) and Aβ(1-42) levels significantly increased after crenezumab administration. The mean crenezumab CSF to serum ratio was ~ 0.3% and was similar across dosing cohorts/routes of administration. No clear correlation was observed between crenezumab concentration and Aβ(1-42) increase in CSF at week 69. The target-mediated drug disposition (TMDD) model described the observed plasma concentration-time profiles of crenezumab and Aβ well. Elimination clearance (CL Conclusions: Crenezumab PK was dose proportional up to 120 mg/kg, with a half-life consistent with IgG monoclonal antibodies. Our findings provide evidence for peripheral target engagement in patients with mild-to-moderate AD. The study also showed that a model-based approach is useful in making inference on PK/PD relationship with unmeasured species such as free plasma Aβ levels. Trial registrations: ABBY: ClinicalTrials.gov, NCT01343966. Registered April 28, 2011. Blaze: ClinicalTrials.gov, NCT01397578. Registered July 19, 2011. GN29632: ClinicalTrials.gov, NCT02353598. Registered February 3, 2015.
MeSH term(s)	Aged ; Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/blood ; Amyloid beta-Peptides/cerebrospinal fluid ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Antibodies, Monoclonal, Humanized/therapeutic use ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged
Chemical Substances	Amyloid beta-Peptides ; Antibodies, Monoclonal, Humanized ; crenezumab (O8AS5277H0)
Language	English
Publishing date	2020-01-22
Publishing country	England
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-020-0580-2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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