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  1. Article ; Online: Application of a Precision-Dosing Model to a Real-World Cohort of Patients on Infliximab Maintenance Therapy: Drug Usage and Cost Analysis.

    Nguyen, Anke L / Gibson, Peter R / Upton, Richard N / Mould, Diane R / Sparrow, Miles P

    Journal of clinical pharmacology

    2023  Volume 64, Issue 4, Page(s) 399–409

    Abstract: Precision-dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses ... ...

    Abstract Precision-dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses determined by iDOSE precision dosing with standard dosing, and the associated drug costs, in patients with IBD. In this retrospective study, patients with IBD treated with infliximab every 8 weeks at 5 mg/kg were included. An infliximab dose was named dose X if 3 previous infliximab doses, laboratory values including trough infliximab concentrations, and the patient's weight were recorded. The actual dose X was compared to an iDOSE-predicted dose X. Net drug use and costs were evaluated. A total of 174 patients-56% men; median age, 36 (interquartile range, 29-47) years; 135 with Crohn disease; and 31 with ulcerative colitis-were included, with 417 dose X recordings. Median prior infliximab therapy was 2 (0-4) years. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough concentrations of 5-10 and 3-7 μg/mL, respectively. Treatment costs increased by 102% and 29% for the 2 trough ranges, respectively. On multivariate regression analysis, subtherapeutic infliximab concentrations were associated with ulcerative colitis compared with Crohn disease (odds ratio, 9.81; 95% confidence interval, 1.28-75.40; P = .028) and predose X infliximab trough concentration [odds ratio, 0.07; 95% confidence interval, 0.03-0.15; P < .001]. Over half of maintenance infliximab drug doses were too low to achieve infliximab blood concentrations of 5 μg/mL or greater. While applying precision dosing may improve patient outcomes, drug costs could be considerably greater.
    MeSH term(s) Male ; Humans ; Adult ; Female ; Infliximab ; Crohn Disease/drug therapy ; Colitis, Ulcerative/drug therapy ; Gastrointestinal Agents ; Retrospective Studies ; Inflammatory Bowel Diseases/drug therapy ; Costs and Cost Analysis ; Drug Monitoring
    Chemical Substances Infliximab (B72HH48FLU) ; Gastrointestinal Agents
    Language English
    Publishing date 2023-12-03
    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.2384
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  2. Article ; Online: Personalized Dosing of Infliximab in Patients With Inflammatory Bowel Disease Using a Bayesian Approach: A Next Step in Therapeutic Drug Monitoring.

    Desai, Devendra C / Dherai, Alpa J / Strik, Anne / Mould, Diane R

    Journal of clinical pharmacology

    2022  Volume 63, Issue 4, Page(s) 480–489

    Abstract: Although biological agents have revolutionized the management of inflammatory bowel diseases (IBDs), a significant proportion of patients show primary non-response or develop secondary loss of response. Therapeutic drug monitoring (TDM) is advocated to ... ...

    Abstract Although biological agents have revolutionized the management of inflammatory bowel diseases (IBDs), a significant proportion of patients show primary non-response or develop secondary loss of response. Therapeutic drug monitoring (TDM) is advocated to maintain the efficacy of biologic agents. Reactive TDM can rationalize the management of primary non-response and secondary loss of response and has shown to be more cost-effective compared with empiric dose escalation. Proactive TDM is shown to increase clinical remission and the durability of the response to a biologic agent. However, the efficacy of proactive and reactive TDM has been questioned in recent studies and meta-analyses. Hence, we need a different approach to TDM, which addresses inflammatory burden, the individual patient, and disease factors. Bayesian approaches, which use population pharmacokinetic models, enable clinicians to make better use of TDM for dose adjustment. With rapid improvement in computer technology, these Bayesian model-based software packages are now available for clinical use. Bayesian dashboard systems allow clinicians to apply model-based dosing to understand an individual's pharmacokinetics and achieve a target serum drug concentration. The model is updated using previously measured drug concentrations and relevant patient factors, such as body weight, C-reactive protein, and serum albumin concentration, to maintain effective drug concentrations in the serum. Initial studies have found utility for the Bayesian approach in induction and maintenance, in adult and pediatric patients, in clinical trials, and in real-life situations for patients with IBD treated with infliximab. This needs confirmation in larger studies. This article reviews the Bayesian approach to therapeutic drug monitoring in IBD.
    MeSH term(s) Adult ; Humans ; Child ; Infliximab ; Gastrointestinal Agents ; Bayes Theorem ; Drug Monitoring ; Inflammatory Bowel Diseases/drug therapy
    Chemical Substances Infliximab (B72HH48FLU) ; Gastrointestinal Agents
    Language English
    Publishing date 2022-12-29
    Publishing country England
    Document type Review ; 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.2189
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  3. Article ; Online: The Pharmacokinetics of Biologics: A Primer.

    Mould, Diane R

    Digestive diseases (Basel, Switzerland)

    2015  Volume 33 Suppl 1, Page(s) 61–69

    Abstract: Monoclonal antibodies (MAbs) exhibit complex pharmacokinetics (PK) and pharmacodynamics (PD, response) against tumor necrosis factor (TNF). Many factors impact anti-TNF MAb PK, altering MAb clearance and therefore the half-life: albumin, weight ( ... ...

    Abstract Monoclonal antibodies (MAbs) exhibit complex pharmacokinetics (PK) and pharmacodynamics (PD, response) against tumor necrosis factor (TNF). Many factors impact anti-TNF MAb PK, altering MAb clearance and therefore the half-life: albumin, weight (particularly, obesity), disease (severity, stage and co-morbidities) and concomitant administration of immunosuppressants (e.g. methotrexate). These factors can alter MAb exposure, impacting on the likelihood of clinical response. Formation of anti-drug antibodies (ADAs) is another potential factor that can affect MAb PK. Factors impacting the likelihood of developing ADA are classified as patient-related (concomitant immunosuppressants, prior ADA against other anti-TNF MAb) or product-related (structure, manufacturing process, aggregate formation, route of administration and dosing regimen). Repeated episodic exposure can induce ADAs, shortening the effective treatment interval. Avoiding intervals where anti-TNF MAbs are non-measurable is important for efficacy and may delay onset of ADAs. Thus, patients whose factors predispose them to having faster clearance (or short half-life) such as severe disease, low albumin or high body weight may need shorter dose intervals to reduce the likelihood of intermittent exposure. ADAs can have no effect or can impact efficacy through MAb binding, thus inhibiting its function or potentially causing hypersensitivity reactions (PD). ADA can also increase MAb clearance (PK). Because of their impact on MAb clearance, ADAs have been linked to lower serum drug concentrations, potentially negatively impacting clinical response. ADAs have been reported for biologics in most therapeutic areas. ADAs are well documented in clinical studies due to the Food and Drug Administration and the European Medicines Agency recommendations regarding testing and impact of immunogenicity. Lastly, the dose metrics (e.g. mg vs. mg/kg) can cause issues as well. MAbs such as infliximab are dosed on a mg/kg basis, which commonly results in low concentrations in patients with low body weight. Conversely MAbs such as adalimumab are administered as a flat (mg) dose, which can result in low concentrations in high weight patients.
    Language English
    Publishing date 2015-09-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 632798-9
    ISSN 1421-9875 ; 0257-2753
    ISSN (online) 1421-9875
    ISSN 0257-2753
    DOI 10.1159/000437077
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  4. Article ; Online: Critical Considerations in Anticancer Drug Development and Dosing Strategies: The Past, Present, and Future.

    Mould, Diane R / Hutson, Paul R

    Journal of clinical pharmacology

    2017  Volume 57 Suppl 10, Page(s) S116–S128

    MeSH term(s) Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/history ; Antineoplastic Agents/pharmacology ; Drug Administration Schedule ; Drug Development/history ; History, 20th Century ; History, 21st Century ; Humans ; Neoplasms/drug therapy ; Neoplasms/history
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2017-09-01
    Publishing country England
    Document type Historical Article ; 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.983
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  5. Article: Model Informed Precision Dosing Tool Forecasts Trough Infliximab and Associates with Disease Status and Tumor Necrosis Factor-Alpha Levels of Inflammatory Bowel Diseases.

    Primas, Christian / Reinisch, Walter / Panetta, John C / Eser, Alexander / Mould, Diane R / Dervieux, Thierry

    Journal of clinical medicine

    2022  Volume 11, Issue 12

    Abstract: Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough ... ...

    Abstract Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings’s regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. Results: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/mL from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming’s slope = 0.90 and R2 = 0.87. Observed end cycle and forecasted trough levels above 5 µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7−30.2; OR = 21.0 CI95%: 3.4−127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/mL from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). Conclusions: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.
    Language English
    Publishing date 2022-06-09
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm11123316
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  6. Article ; Online: Tumor growth inhibition modeling in patients with second line biliary tract cancer and first line non-small cell lung cancer based on bintrafusp alfa trials.

    Milenković-Grišić, Ana-Marija / Terranova, Nadia / Mould, Diane R / Vugmeyster, Yulia / Mrowiec, Thomas / Machl, Andreas / Girard, Pascal / Venkatakrishnan, Karthik / Khandelwal, Akash

    CPT: pharmacometrics & systems pharmacology

    2023  Volume 13, Issue 1, Page(s) 143–153

    Abstract: This analysis aimed to quantify tumor dynamics in patients receiving either bintrafusp alfa (BA) or pembrolizumab, by population pharmacokinetic (PK)-pharmacodynamic modeling, and investigate clinical and molecular covariates describing the variability ... ...

    Abstract This analysis aimed to quantify tumor dynamics in patients receiving either bintrafusp alfa (BA) or pembrolizumab, by population pharmacokinetic (PK)-pharmacodynamic modeling, and investigate clinical and molecular covariates describing the variability in tumor dynamics by pharmacometric and machine-learning (ML) approaches. Data originated from two clinical trials in patients with biliary tract cancer (BTC; NCT03833661) receiving BA and non-small cell lung cancer (NSCLC; NCT03631706) receiving BA or pembrolizumab. Individual drug exposure was estimated from previously developed population PK models. Population tumor dynamics models were developed for each drug-indication combination, and covariate evaluations performed using nonlinear mixed-effects modeling (NLME) and ML (elastic net and random forest models) approaches. The three tumor dynamics' model structures all included linear tumor growth components and exponential tumor shrinkage. The final BTC model included the effect of drug exposure (area under the curve) and several covariates (demographics, disease-related, and genetic mutations). Drug exposure was not significant in either of the NSCLC models, which included two, disease-related, covariates in the BA arm, and none in the pembrolizumab arm. The covariates identified by univariable NLME and ML highly overlapped in BTC but showed less agreement in NSCLC analyses. Hyperprogression could be identified by higher tumor growth and lower tumor kill rates and could not be related to BA exposure. Tumor size over time was quantitatively characterized in two tumor types and under two treatments. Factors potentially related to tumor dynamics were assessed using NLME and ML approaches; however, their net impact on tumor size was considered as not clinically relevant.
    MeSH term(s) Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/pathology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Biliary Tract Neoplasms/drug therapy
    Language English
    Publishing date 2023-12-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2697010-7
    ISSN 2163-8306 ; 2163-8306
    ISSN (online) 2163-8306
    ISSN 2163-8306
    DOI 10.1002/psp4.13068
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  7. Article ; Online: Pharmacokinetic and Pharmacodynamic Effects of Oral CXA-10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects.

    Garner, Rachel M / Mould, Diane R / Chieffo, Carla / Jorkasky, Diane K

    Clinical and translational science

    2019  Volume 12, Issue 6, Page(s) 667–676

    Abstract: 10-nitro-9(E)-octadec-9-enoic acid (CXA-10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play ... ...

    Abstract 10-nitro-9(E)-octadec-9-enoic acid (CXA-10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA-10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA-10. After single and multiple ascending doses, CXA-10 demonstrated dose-proportional increases in plasma exposure. CXA-10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA-10-202, a consistent decrease from baseline was observed with CXA-10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP-1, and IL-6. In CXA-10-203, after coadministration with CXA-10, geometric mean peak plasma concentration (C
    MeSH term(s) Abdominal Pain/chemically induced ; Abdominal Pain/epidemiology ; Administration, Oral ; Adult ; Area Under Curve ; Biomarkers/blood ; Biomarkers/metabolism ; Diarrhea/chemically induced ; Diarrhea/epidemiology ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Fasting ; Female ; Healthy Volunteers ; Humans ; Incidence ; Inflammation/blood ; Inflammation/drug therapy ; Inflammation/immunology ; Inflammation/metabolism ; Lipid Metabolism/drug effects ; Male ; Middle Aged ; Nausea/chemically induced ; Nausea/epidemiology ; Nitro Compounds/administration & dosage ; Nitro Compounds/adverse effects ; Nitro Compounds/pharmacokinetics ; Obesity/blood ; Obesity/drug therapy ; Obesity/immunology ; Obesity/metabolism ; Oleic Acids/administration & dosage ; Oleic Acids/adverse effects ; Oleic Acids/pharmacokinetics ; Postprandial Period ; Young Adult
    Chemical Substances Biomarkers ; Nitro Compounds ; Oleic Acids ; CXA-10 (1N19AGY57Y)
    Language English
    Publishing date 2019-08-12
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2433157-0
    ISSN 1752-8062 ; 1752-8054
    ISSN (online) 1752-8062
    ISSN 1752-8054
    DOI 10.1111/cts.12672
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  8. Article ; Online: Model Informed Precision Dosing Tool Forecasts Trough Infliximab and Associates with Disease Status and Tumor Necrosis Factor-Alpha Levels of Inflammatory Bowel Diseases

    Christian Primas / Walter Reinisch / John C. Panetta / Alexander Eser / Diane R. Mould / Thierry Dervieux

    Journal of Clinical Medicine, Vol 11, Iss 3316, p

    2022  Volume 3316

    Abstract: Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough ... ...

    Abstract Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings’s regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. Results: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/mL from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming’s slope = 0.90 and R2 = 0.87. Observed end cycle and forecasted trough levels above 5 µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7–30.2; OR = 21.0 CI95%: 3.4–127.9, respectively) ( p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/mL from mid to end of cycle time points, respectively ( p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels ( p < 0.01). Conclusions: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.
    Keywords Infliximab ; therapeutic drug monitoring ; model informed precision dosing ; inflammatory bowel disease ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model.

    Qi, Yulan / Chan, Ming Liang / Mould, Diane R / Larimore, Kevin / Fisheleva, Elena / Cherukuri, Anu / Day, Jonathan / Savarirayan, Ravi / Irving, Melita / Bacino, Carlos A / Hoover-Fong, Julie / Ozono, Keiichi / Mohnike, Klaus / Wilcox, William R / Bober, Michael B / Henshaw, Joshua

    Clinical pharmacokinetics

    2024  

    Abstract: Background and objective: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to ... ...

    Abstract Background and objective: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.
    Methods: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen.
    Results: A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population.
    Conclusions: The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers.
    Clinical trial registration: NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.
    Language English
    Publishing date 2024-04-23
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 197627-8
    ISSN 1179-1926 ; 0312-5963
    ISSN (online) 1179-1926
    ISSN 0312-5963
    DOI 10.1007/s40262-024-01371-6
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  10. Article ; Online: Correction to: Optimization of infliximab therapy in inflammatory bowel disease using a dashboard approach-an Indian experience.

    Dave, Mihika B / Dherai, Alpa J / Desai, Devendra C / Mould, Diane R / Ashavaid, Tester F

    European journal of clinical pharmacology

    2020  Volume 77, Issue 2, Page(s) 273–274

    Language English
    Publishing date 2020-09-23
    Publishing country Germany
    Document type Published Erratum
    ZDB-ID 121960-1
    ISSN 1432-1041 ; 0031-6970
    ISSN (online) 1432-1041
    ISSN 0031-6970
    DOI 10.1007/s00228-020-02989-8
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