36 results on '"McEneny-King A"'
Search Results
2. Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate-DVI) Concentrate and its Low-Dose Use
- Author
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Dagmar M. Hajducek, Fitri Primacakti, Novie Chozie, Roser Mir, Alanna McEneny-King, Alfonso Iorio, and Andrea Edginton
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Population pharmacokinetics (popPK) has been reliably leveraged to generate individual PK in hemophilia patients. Specific popPK models are suited to predict individual PK under a variety of scenarios that may not be captured by clinical trials, allowing for individualized prophylactic treatment. The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project generates individually predicted pharmacokinetic profiles relying on concentrate-specific popPK models used for Bayesian forecasting. Objective Specification of a popPK model for the plasma-derived factor VIII (FVIII) concentrate Koate-DVI and its suitability for pharmacokinetic estimation in low-dose scenarios. Methods A popPK model was developed for Koate-DVI WAPPS-Hemo PK data in combination with the existing WAPPS-Hemo Fanhdi/Alphanate model derivation dataset using nonlinear mixed effects modelling, and was validated via cross-validation and prediction-corrected Visual Predictive Checks (pcVPC). Bootstrap and PK outcomes between the Fanhdi/Alphanate and the Fanhdi/Alphanate/Koate models were compared, and the relative error distributions from a limited sampling analysis (LSA) under the latter model for low and normal doses (10 vs 50 IU/kg) and inclusion/exclusion of pre-dose measurements. Results A Fanhdi/Alphanate/Koate model was derived (126 patients, ages 1–71 years) after deeming a Koate-brand covariate not clinically significant, resulting in similar parameter estimates than the Fanhdi/Alphanate model with satisfactory goodness of fit, cross-validation and pcVPC results. Low-dose predictions resulted in a higher accuracy and slightly lower precision of half-life ( β -phase) and time to 2% trough (TAT2%) estimates than normal dose (median absolute bias for half-life: 0.12 vs 0.5%; median interquartile range, IQR: 11.79% vs 9.95%). Precision improved under pre-dose designs by 2 to 3% and remained similar between 5- and 2-sample designs (IQR reduction
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- 2021
- Full Text
- View/download PDF
3. Development and evaluation of a generic population pharmacokinetic model for standard half-life factor VIII for use in dose individualization
- Author
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McEneny-King, Alanna, Chelle, Pierre, Foster, Gary, Keepanasseril, Arun, Iorio, Alfonso, and Edginton, Andrea N.
- Published
- 2019
- Full Text
- View/download PDF
4. Pharmacokinetic and Pharmacodynamic Evaluation of Ravulizumab in Adults with Severe Coronavirus Disease 2019
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Stephan Ortiz, Shamsah D. Kazani, Alanna C. McEneny-King, and Jonathan P. R. Monteleone
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0301 basic medicine ,Microbiology (medical) ,Humanized/therapeutic use ,030106 microbiology ,Lung injury ,Pharmacology ,medicine.disease_cause ,Antibodies ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Complement C5/antagonists and inhibitors ,Pharmacokinetics ,Intensive care ,Monoclonal ,medicine ,030212 general & internal medicine ,Terminal complement pathway ,Complement inactivating agents/therapeutic use ,Coronavirus ,Coronavirus disease 2019 ,Ravulizumab ,business.industry ,Brief Report ,Complement system ,Regimen ,Infectious Diseases ,Pharmacodynamics ,business - Abstract
Introduction Terminal complement amplification is hypothesized to be a key contributor to the clinical manifestations of severe coronavirus disease 2019 (COVID-19). Ravulizumab, a humanized monoclonal antibody that binds with high affinity to complement protein C5 and inhibits terminal complement activation, is being evaluated as a treatment for COVID-19-related severe pneumonia, acute lung injury, and acute respiratory distress syndrome in an ongoing phase 3 randomized controlled trial (ALXN1210-COV-305). To address the overactivation of terminal complement in severe COVID-19 compared to the diseases in which ravulizumab is currently approved, a modified dosing regimen was adopted. This analysis evaluates preliminary pharmacokinetic/pharmacodynamic data to confirm the modified dosing regimen. Methods Weight-based ravulizumab doses were administered on days 1, 5, 10, and 15. Serum levels of ravulizumab and free C5 were measured before and after administration of ravulizumab and any time on day 22. Free C5 levels 175 μg/mL, the concentration above which C5 is completely inhibited. Results Twenty-two patients were included in this evaluation. At baseline, mean C5 concentration was 240 ± 67 μg/mL. In all patients and at all individual timepoints after the first dose was administered, ravulizumab concentrations remained > 175 μg/mL and free C5 concentrations remained, Plain Language Summary While many people have no or mild COVID-19 symptoms, a small number of people become very sick and require hospitalization in intensive care units. One part of their immune system, known as complement, overreacts and attacks the lungs and other organs. Researchers are looking for a way to keep the immune system from attacking the body instead of protecting it. Ravulizumab is a medication currently used to do this in other diseases. Ravulizumab is being studied to see if it can reduce the destructive and deadly effects of the coronavirus infection. In this evaluation, ravulizumab effectively reduced complement in patients with severe COVID-19.
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- 2021
5. Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS‐Hemo project
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Dagmar M. Hajducek, Alanna McEneny-King, Alfonso Iorio, Andrea N. Edginton, Cedric Hermans, Pierre Chelle, and Jacky K. Yu
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Male ,Bayesian probability ,Population ,Population pharmacokinetics ,030204 cardiovascular system & hematology ,Hemophilia A ,factor IX ,factor VIII ,population pharmacokinetics ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Prior probability ,Statistics ,Covariate ,Limited sampling ,Humans ,Medicine ,education ,Genetics (clinical) ,education.field_of_study ,business.industry ,Hematology ,General Medicine ,Female ,business ,030215 immunology ,Prophylactic treatment - Abstract
Background The Web-Accessible Population Pharmacokinetic Service (WAPPS) project generates individually predicted pharmacokinetic (PK) profiles and tailored prophylactic treatment regimens for haemophilic patients, which rely on a set of population PK (PopPK) models providing concentrate-specific priors for the Bayesian forecasting methodology. Aim To describe the predictive performance of the WAPPS PopPK models in use on the WAPPS-Hemo platform. Methods Data for modelling include dense PK data obtained from industry sponsored and independent PK studies, and dense and sparse data accumulated through WAPPS-Hemo. WAPPS PopPK models were developed via non-linear mixed-effect modelling taking into account the effects of covariates and between-individual-and sometimes between-occasion-variability. Model evaluation consisted of (a) prediction-corrected Visual Predictive Check (pcVPC), (b) Limited Sampling Analysis (LSA) and (c) repeated hold-out cross-validation. Results Thirty-three WAPPS PopPK models built on data from 3188 patients (ages 1-78 years) under treatment by factor VIII or IX products (FVIII, FIX) were evaluated. Overall, models exhibit excellent performance characteristics. The pcVPC shows that the observed PK data fall within acceptable 90% interpercentile predictive bands. A slight overprediction beyond the expected half-life, an anticipated result of using sparse data, occurs for some models. The LSA results in lower than 3% of relative error for FVIII and FIX products and 16% for engineered FIX products. Cross-Validation analysis yields relative errors lower than 1.5% and 1.4% in estimates of half-life and time to 0.02 IU/mL, respectively. Conclusion The WAPPS-Hemo models consistently showed excellent performance characteristics for the intended use for Bayesian forecasting of individual PK profiles.
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- 2020
6. Impact of Adopting Population Pharmacokinetics for Tailoring Prophylaxis in Haemophilia A Patients: A Historically Controlled Observational Study
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Alfonso Iorio, Andrea N. Edginton, Sylvia von Mackensen, Elisabeth Schmit, Karin Kurnik, M. Stemberger, Cindy H. T. Yeung, Felix Kallenbach, Federico Germini, and Alanna McEneny-King
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Population ,Haemophilia A ,haemophilia ,030204 cardiovascular system & hematology ,Hemophilia A ,Haemophilia ,Models, Biological ,Severity of Illness Index ,Drug Administration Schedule ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Models ,Internal medicine ,Hemarthrosis ,Severity of illness ,medicine ,Humans ,Prospective Studies ,education ,Prospective cohort study ,Retrospective Studies ,education.field_of_study ,Coagulants ,business.industry ,individualized ,personalized ,pharmacokinetics ,prophylaxis ,Bayes Theorem ,Middle Aged ,Quality of Life ,Treatment Outcome ,Retrospective cohort study ,Hematology ,Biological ,medicine.disease ,030104 developmental biology ,Quartile ,business - Abstract
Background Performing individual pharmacokinetics (PK) studies in clinical practice can be simplified by adopting population PK-based profiling on limited post-infusion samples. The objective of this study was to assess the impact of population PK in tailoring prophylaxis in patients with haemophilia A. Patients and Methods Individual weekly treatment plans were developed considering predicted plasma factor activity levels and patients' lifestyle. Patients were trained using a visual traffic-light scheme to help modulate their level of physical activity with respect to factor infusions timing. Annualized joint bleeding rate (ABJR), haemophilia-specific quality of life questionnaire for adults (Haemo-QoL-A) and factor utilization were measured for 12 months before and after tailoring, compared within patients and analysed separately for those previously on prophylaxis (P), situational prophylaxis (SP) or on-demand (OD). Results Sixteen patients previously on P, 10 on SP and 10 on OD were enrolled in the study. The median (lower, upper quartile) ABJR changed from 2.0 (0, 4.0) to 0 (0, 1.6) for P (p = 0.003), from 2.0 (2.0, 13.6) to 3.0 (1.4, 7.2) for SP (p = 0.183) and from 16.0 (13.0, 25.0) to 2.3 (0, 5.0) for OD (p = 0.003). The Haemo-QoL-A total score improved for 58% of P, 50% of SP and 29% of OD patients. Factor utilization (IU/kg/patient/year) increased by 2,400 (121; 2,586) for P, 1,052 (308; 1,578) for SP and 2,086 (1,498; 2,576) for OD. One of 138 measurements demonstrated a factor activity level below the critical threshold of 0.03 IU/mL while the predicted level was above the threshold. Conclusion Implementing tailored prophylaxis using a Bayesian forecasting approach in a routine clinical practice setting may improve haemophilia clinical outcomes.
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- 2019
7. Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis
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Alanna McEneny-King, Pierre Chelle, Severine Henrard, Cedric Hermans, Alfonso Iorio, and Andrea N. Edginton
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hemophilia A ,conventional factor VIII ,dose metrics ,obesity ,population pharmacokinetics ,Pharmacy and materia medica ,RS1-441 - Abstract
The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.
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- 2017
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8. Limited sampling strategies for accurate determination of extended half-life factor VIII pharmacokinetics in severe haemophilia A patients
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Pierre Chelle, Patricia J. Barker, Alanna McEneny-King, John C. Panetta, Ulrike M. Reiss, Timothy W. Jacobs, Margaret H Goggans, and Ellis J. Neufeld
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Adult ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,Population ,030204 cardiovascular system & hematology ,Hemophilia A ,Hemostatics ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Limited sampling ,medicine ,Humans ,education ,Child ,Genetics (clinical) ,education.field_of_study ,Factor VIII ,business.industry ,Half-life ,Sampling (statistics) ,Hematology ,General Medicine ,medicine.disease ,3. Good health ,Regimen ,Severe haemophilia A ,business ,030215 immunology ,Half-Life - Abstract
BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in hemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring. OBJECTIVE: Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs. METHODS: We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modeled sampling strategies. RESULTS: Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error 20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-hour trough from 25% to
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- 2021
9. Limited sampling strategies for accurate determination of extended half‐life factor VIII pharmacokinetics in severe haemophilia A patients
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McEneny‐King, Alanna, primary, Chelle, Pierre, additional, Goggans, Margaret H., additional, Barker, Patricia J., additional, Jacobs, Timothy W., additional, Neufeld, Ellis J., additional, Reiss, Ulrike M., additional, and Panetta, John C., additional
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- 2021
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10. The effect of unmeasurable endogenous plasma factor activity levels on factor VIII dosing in patients with severe hemophilia A
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Andrea N. Edginton, Pierre Chelle, Alanna McEneny-King, and Alfonso Iorio
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Oncology ,medicine.medical_specialty ,Factor VIII ,Hemophilia A ,Individualized medicine ,Patient-specific modeling ,Pharmacokinetics ,Humans ,Precision Medicine ,Population ,Plasma factor ,Endogeny ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,In patient ,Dosing ,education ,education.field_of_study ,business.industry ,Hematology ,Assay sensitivity ,Regimen ,business ,030215 immunology - Abstract
Background Patients with hemophilia A are defined as “severe” if they present Objective This work aims to assess the consequences of different assumptions when selecting a prophylaxis regimen for the treatment of hemophilia A using a pharmacokinetics (PK)-driven approach. Methods Using a validated population PK model for conventional FVIII, we simulated the dose and frequency required to maintain various target troughs as a function of different postulated baseline levels. Results Patients with a true baseline of 0 IU mL−1 would require an additional 40 IU kg−1 to achieve any target trough below 0.05 IU mL−1, as compared to those with a true baseline close to 0.01 IU mL−1. When tailoring individual treatment regimens using a PK-based approach, baseline assumptions were highly influential and the assumption producing the most conservative dosing regimen was not consistent; rather, it depended on the particular scenario (e.g. increase vs. decrease of an observed trough). Conclusions Targeting a trough close to the assay sensitivity creates a unique problem in forecasting the dose needed for optimal treatment of hemophilia that, while still without solution, deserves consideration when making dosing decisions.
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- 2018
11. Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS‐Hemo project
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Hajducek, Dagmar M., primary, Chelle, Pierre, additional, Hermans, Cedric, additional, Iorio, Alfonso, additional, McEneny‐King, Alanna, additional, Yu, Jacky, additional, and Edginton, Andrea, additional
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- 2020
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12. Clinical application of Web Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS‐Hemo): Patterns of blood sampling and patient characteristics among clinician users
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McEneny‐King, Alanna, primary, Yeung, Cindy HT, additional, Edginton, Andrea N., additional, Iorio, Alfonso, additional, and Croteau, Stacy E., additional
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- 2019
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13. What is the role for population pharmacokinetics in hemophilia?
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Andrea N. Edginton, Alanna McEneny-King, Alfonso Iorio, Arun Keepanasseril, and Gary Foster
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International research ,Clotting factor ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Plasma levels ,Population pharmacokinetics ,030204 cardiovascular system & hematology ,Pharmacology ,Accessible Population ,030226 pharmacology & pharmacy ,Dose individualization ,03 medical and health sciences ,0302 clinical medicine ,Target level ,medicine ,Intensive care medicine ,business ,education - Abstract
Prevention of bleeding in hemophilia requires that plasma levels of the deficient factor exceed the desired minimum target level. Large interindividual variability suggests that knowledge of individual pharmacokinetic (PK) would help to achieve this goal, simultaneously minimizing infusion frequency and the amount of concentrate used. Population PK (PopPK) allows for the incorporation of determinants of interpatient variability and eliminates the need for extensive postinfusion plasma sampling. Barriers to implementation of PopPK are the need for concentrate specific models, Bayesian calculation power, specific expertise for validation and appraisal of forecasted estimates. The Web Accessible Population Pharmacokinetic Service – Hemophilia ( www.wapps-hemo.org ), developed by an international research network of hemophilia centers will test if PK-guided dose individualization can improve patient important outcomes in hemophilia.
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- 2017
14. Derivation of a Pharmacokinetic Model to Include a Plasma-Derived, von Willebrand Factor-Containing Factor VIII (Koate®-DVI) Concentrate and its Low-Dose Use.
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Hajducek, Dagmar M., Primacakti, Fitri, Chozie, Novie, Mir, Roser, McEneny-King, Alanna, Iorio, Alfonso, and Edginton, Andrea
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HEMOPHILIA ,BLOOD coagulation tests ,BODY weight ,PHARMACOKINETICS ,GOODNESS-of-fit tests ,ENZYME-linked immunosorbent assay ,DESCRIPTIVE statistics ,BLOOD coagulation factors ,STATISTICAL correlation ,VON Willebrand disease ,DOSE-response relationship in biochemistry - Abstract
BACKGROUND: Population pharmacokinetics (popPK) has been reliably leveraged to generate individual PK in hemophilia patients. Specific popPK models are suited to predict individual PK under a variety of scenarios that may not be captured by clinical trials, allowing for individualized prophylactic treatment. The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project generates individually predicted pharmacokinetic profiles relying on concentrate-specific popPK models used for Bayesian forecasting. OBJECTIVE: Specification of a popPK model for the plasma-derived factor VIII (FVIII) concentrate Koate-DVI and its suitability for pharmacokinetic estimation in low-dose scenarios. METHODS: A popPK model was developed for Koate-DVI WAPPS-Hemo PK data in combination with the existing WAPPS-Hemo Fanhdi/ Alphanate model derivation dataset using nonlinear mixed effects modelling, and was validated via cross-validation and prediction-corrected Visual Predictive Checks (pcVPC). Bootstrap and PK outcomes between the Fanhdi/Alphanate and the Fanhdi/Alphanate/Koate models were compared, and the relative error distributions from a limited sampling analysis (LSA) under the latter model for low and normal doses (10 vs 50 IU/kg) and inclusion/exclusion of pre-dose measurements. RESULTS: A Fanhdi/Alphanate/Koate model was derived (126 patients, ages 1-71 years) after deeming a Koate-brand covariate not clinically significant, resulting in similar parameter estimates than the Fanhdi/Alphanate model with satisfactory goodness of fit, cross-validation and pcVPC results. Low-dose predictions resulted in a higher accuracy and slightly lower precision of half-life (^-phase) and time to 2% trough (TAT2%) estimates than normal dose (median absolute bias for half-life: 0.12 vs 0.5%; median interquartile range, IQR: 11.79% vs 9.95%). Precision improved under pre-dose designs by 2 to 3% and remained similar between 5- and 2-sample designs (IQR reduction<1.8%). CONCLUSIONS: The Fanhdi/Alphanate/Koate model is appropriate for Bayesian forecasting in the WAPPS-Hemo platform, providing a comparable prediction capability for low and normal dosing regimens (10 vs 50 IU/Kg). [ABSTRACT FROM AUTHOR]
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- 2021
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15. Clinical application of Web Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Patterns of blood sampling and patient characteristics among clinician users
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Alfonso Iorio, Cindy H. T. Yeung, Andrea N. Edginton, Alanna McEneny-King, and Stacy E. Croteau
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Adult ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Haemophilia A ,haemophilia ,Sample (statistics) ,PopPK ,030204 cardiovascular system & hematology ,Haemophilia ,Hemophilia A ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pharmacokinetics ,Physicians ,Medicine ,Humans ,Sampling (medicine) ,Haemophilia B ,extended half-life ,Child ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Blood Specimen Collection ,Internet ,Factor VIII ,Dose-Response Relationship, Drug ,business.industry ,Infant ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,factor concentrate ,Child, Preschool ,Cohort ,business ,pharmacokinetics ,030215 immunology ,Blood sampling - Abstract
Background Use of population pharmacokinetics (PopPK) to facilitate PK-informed prophylaxis in clinical practice has gained momentum among haemophilia providers due to the accessibility of tools such as the Web Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) and availability of extended half-life (EHL) factor concentrates. It is unknown how clinicians implement PopPK. Aim To investigate the evolution of PopPK use in clinical practice by comparing blood sampling strategies, patient features, and factor group between initial and recent periods of WAPPS-Hemo availability. Methods PK data for haemophilia A and haemophilia B patients from two time periods were extracted from the WAPPS-Hemo database: early availability (10/2015-09/2016) and recent use (10/2017-09/2018). We compared patient characteristics (age, body weight, haemophilia type), product type and dose, and blood sampling times between the time frames. Results Over 1900 eligible infusions were submitted to WAPPS-Hemo during the periods studied, with 85% representing FVIII concentrates. In the recent cohort, PK profiles were requested for younger patients (median age 18 vs 26 years), with increased proportional EHL FVIII use (29% vs 14% of infusions). High-use centres generally submitted fewer blood samples per infusion than non-high-use centres, although the number of samples collected by non-high-use centres decreased significantly over time. During both periods, blood sample timing was generally consistent with ISTH recommended windows. Conclusion The use of WAPPS-Hemo by haemophilia providers grew by over threefold between the time periods investigated. While sampling times have included key time points proposed first by Bjorkman since early WAPPS-Hemo usage, a trend towards minimizing sampling was observed.
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- 2019
16. Development and evaluation of a generic population pharmacokinetic model for standard half-life factor VIII for use in dose individualization
- Author
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Alfonso Iorio, Andrea N. Edginton, Gary Foster, Pierre Chelle, Arun Keepanasseril, and Alanna McEneny-King
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Oncology ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,Population ,Pharmacology toxicology ,Population pharmacokinetics ,Hemophilia A ,Dose individualization ,030226 pharmacology & pharmacy ,Models, Biological ,Bayesian forecasting ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pharmacokinetics ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Drug Dosage Calculations ,Hemophilia ,Precision Medicine ,education ,Child ,Pharmacology ,education.field_of_study ,Factor VIII ,business.industry ,Half-life ,Infant ,Middle Aged ,3. Good health ,030220 oncology & carcinogenesis ,Child, Preschool ,business - Abstract
Hemophilia A is a rare bleeding disorder resulting from a lack of functional factor VIII (FVIII). Therapy consists of replacement with exogenous FVIII, but is complicated by high inter-patient variability. A population pharmacokinetics (PopPK) approach can facilitate the uptake of an individualized approach to hemophilia therapy. We developed a PopPK model using data from seven brands of standard half-life FVIII products. The final model consists of a 2-compartment structure, with a proportional residual error model and between-subject variability on clearance and central volume. Fat-free mass, age, and brand were found to significantly affect pharmacokinetic (PK) parameters. Internal and external evaluations found that the model is fit for Bayesian forecasting and capable of predicting PK for brands not included in the modelling dataset, and useful for determining individualized prophylaxis regimens for hemophilia A patients.
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- 2019
17. The use of pharmacokinetics in dose individualization of factor VIII in the treatment of hemophilia A
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Andrea N. Edginton, Gary Foster, Alfonso Iorio, and Alanna McEneny-King
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Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Population ,Haemophilia A ,haemophilia A ,030204 cardiovascular system & hematology ,Pharmacology ,Toxicology ,Dose individualization ,factor VIII ,population pharmacokinetics ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,hemic and lymphatic diseases ,Internal medicine ,Subject variability ,medicine ,In patient ,Dosing ,education ,Clotting factor ,education.field_of_study ,business.industry ,General Medicine ,medicine.disease ,business ,030215 immunology - Abstract
Hemophilia A is a bleeding disorder resulting from a lack of clotting factor VIII (FVIII), and treatment typically consists of prophylactic replacement of the deficient factor. However, high between subject variability precludes the development of a 'one size fits all' dosing strategy and necessitates an individualized approach. We sought to summarize the data on the pharmacokinetics of FVIII available as a basis for the development of population pharmacokinetic models to be used in dose tailoring. Areas covered: We reviewed the pharmacokinetics of FVIII as used for the treatment of hemophilia A, with a focus on the variability observed between patients and the application of pharmacokinetic methods to dose individualization. We also explored the covariates affecting pharmacokinetic parameters, the differences between plasma-derived and recombinant FVIII and the development of extended half-life products. Expert opinion: The pharmacokinetics of factor VIII in patients with hemophilia shows a high interpatient variability, and is affected by age, weight, level of von Willebrand factor, and blood group. A population approach to estimating individual pharmacokinetics is likely to provide the most successful strategy to tailor factor concentrate dosing to the individual needs and to ensure optimal patient outcomes, while also improving the cost-effectiveness of prophylactic replacement therapy.
- Published
- 2016
18. Impact of Adopting Population Pharmacokinetics for Tailoring Prophylaxis in Haemophilia A Patients: A Historically Controlled Observational Study
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Stemberger, Michaela, additional, Kallenbach, Felix, additional, Schmit, Elisabeth, additional, McEneny-King, Alanna, additional, Germini, Federico, additional, Yeung, Cindy, additional, Edginton, Andrea, additional, von Mackensen, Sylvia, additional, Kurnik, Karin, additional, and Iorio, Alfonso, additional
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- 2019
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19. Homogeneously magnetically concentrated silver nanoparticles for uniform 'hot spots' in surface enhanced Raman spectroscopy
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Vladimir Kitaev, Andrew J. Frank, Nicole Cathcart, and Alanna McEneny-King
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Materials science ,General Chemical Engineering ,Analytical chemistry ,Maghemite ,Substrate (chemistry) ,Nanoparticle ,General Chemistry ,Surface-enhanced Raman spectroscopy ,engineering.material ,Hydrodynamic trapping ,Silver nanoparticle ,symbols.namesake ,engineering ,symbols ,Surface plasmon resonance ,Raman spectroscopy - Abstract
We report reproducible and sensitive surface-enhanced Raman spectroscopy (SERS) detection achieved with a developed nanoparticle platform, Ag&MH. Ag&MH is comprised of silver nanoparticles (AgNPs), as a sensing substrate that is efficiently and uniformly magnetically concentrated with the assistance of maghemite, γ-Fe2O3, nanoparticles (MHNPs). MNHPs were optimized synthetically for minimal charge interactions with AgNPs and low optical absorbance. At sufficiently high concentrations, magnetic maghemite NPs hydrodynamically trap AgNPs and concentrate them on the inner surface of a quartz optical cell to form an Ag&MH SERS substrate for highly reproducible SERS detection. The reproducibility is a combination of several factors contributing to uniform “hot spots”: homogeneous magnetic concentration by gentle hydrodynamic trapping and weak electrostatic interactions of the same-charge nanoparticles and non-close packing of AgNPs, in particular decahedra. Size-uniform silver decahedra nanoparticles (AgJ13NPs) featuring sharp localized surface plasmon resonance (LSPR) peaks, coupled with minimized optical interference from MHNPs, enable sensitive and reproducible SERS detection, where 5,5′-dithiobis-(2-nitrobenzoic acid), DTNB, was used as a probe molecule. Reproducibility of independent measurements at nanomolar level was ca. 10% – consistently overcoming the “hot spot” problem through uniform distribution of AgJ13NPs in the Ag&MH SERS substrate. Picomolar concentrations were detected using a simple fiber-optic Raman spectrometer. The developed AgJ13&MH sensing platform is promising for convenient and reproducible SERS detection of analytes in common laboratory settings.
- Published
- 2015
20. Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity
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McEneny-King, Alanna, Osman, Wesseem, Edginton, Andrea N., and Rao, Praveen P.N.
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- 2017
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21. Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis
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Pierre Chelle, Andrea N. Edginton, Alfonso Iorio, Cedric Hermans, Séverine Henrard, Alanna McEneny-King, University of Waterloo, ON, Canada - School of Pharmacy, McMaster University, Hamilton, ON, Canada - Department of Health Evidence, Research Methods and Impact, McMaster University, Hamilton, ON, Canada - Department of Medicine, UCL - SSS/IRSS - Institut de recherche santé et société, and UCL - (SLuc) Service d'hématologie
- Subjects
obesity ,Pediatrics ,medicine.medical_specialty ,Population ,lcsh:RS1-441 ,conventional factor VIII ,dose metrics ,hemophilia A ,population pharmacokinetics ,Pharmaceutical Science ,030204 cardiovascular system & hematology ,Overweight ,Hemophilia A ,Body weight ,Article ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,medicine ,Obesity ,Population pharmacokinetics ,Dosing ,education ,education.field_of_study ,Cost efficiency ,business.industry ,Conventional factor VIII ,medicine.disease ,Dose metrics ,3. Good health ,Surgery ,Lean body mass ,medicine.symptom ,business ,030215 immunology - Abstract
The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.
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- 2017
- Full Text
- View/download PDF
22. Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity
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Praveen P.N. Rao, Wesseem Osman, Andrea N. Edginton, and Alanna McEneny-King
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0301 basic medicine ,Risk ,Cytochrome ,Stereochemistry ,Cytochrome P-450 CYP1A2 Inhibitors ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Cytochrome P-450 CYP1A2 ,Drug Discovery ,Cytochrome P-450 CYP3A ,medicine ,Humans ,Molecular Biology ,Cholinesterase ,Benzoflavones ,Cytochrome P-450 CYP3A Inhibitors ,Binding Sites ,biology ,CYP3A4 ,Chemistry ,Organic Chemistry ,CYP1A2 ,Cytochrome P450 ,Molecular Docking Simulation ,030104 developmental biology ,Ketoconazole ,Tacrine ,biology.protein ,Molecular Medicine ,Chemical and Drug Induced Liver Injury ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC50=33.0µM; 2, IC50=8.5µM) compared to tacrine (CYP1A2 IC50=1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species.
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- 2017
23. Clinical application of Web Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS‐Hemo): Patterns of blood sampling and patient characteristics among clinician users.
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McEneny‐King, Alanna, Yeung, Cindy HT, Edginton, Andrea N., Iorio, Alfonso, and Croteau, Stacy E.
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WEB-based user interfaces , *BLOOD sampling , *HEMOPHILIA , *BODY weight , *TIME measurements - Abstract
Background: Use of population pharmacokinetics (PopPK) to facilitate PK‐informed prophylaxis in clinical practice has gained momentum among haemophilia providers due to the accessibility of tools such as the Web Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS‐Hemo) and availability of extended half‐life (EHL) factor concentrates. It is unknown how clinicians implement PopPK. Aim: To investigate the evolution of PopPK use in clinical practice by comparing blood sampling strategies, patient features, and factor group between initial and recent periods of WAPPS‐Hemo availability. Methods: PK data for haemophilia A and haemophilia B patients from two time periods were extracted from the WAPPS‐Hemo database: early availability (10/2015‐09/2016) and recent use (10/2017‐09/2018). We compared patient characteristics (age, body weight, haemophilia type), product type and dose, and blood sampling times between the time frames. Results: Over 1900 eligible infusions were submitted to WAPPS‐Hemo during the periods studied, with 85% representing FVIII concentrates. In the recent cohort, PK profiles were requested for younger patients (median age 18 vs 26 years), with increased proportional EHL FVIII use (29% vs 14% of infusions). High‐use centres generally submitted fewer blood samples per infusion than non‐high‐use centres, although the number of samples collected by non‐high‐use centres decreased significantly over time. During both periods, blood sample timing was generally consistent with ISTH recommended windows. Conclusion: The use of WAPPS‐Hemo by haemophilia providers grew by over threefold between the time periods investigated. While sampling times have included key time points proposed first by Björkman since early WAPPS‐Hemo usage, a trend towards minimizing sampling was observed. [ABSTRACT FROM AUTHOR]
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- 2020
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24. The effect of unmeasurable endogenous plasma factor activity levels on factor VIII dosing in patients with severe hemophilia A
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McEneny-King, A., primary, Chelle, P., additional, Iorio, A., additional, and Edginton, A.N., additional
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- 2018
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25. Investigating the binding interactions of the anti-Alzheimer’s drug donepezil with CYP3A4 and P-glycoprotein
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McEneny-King, Alanna, Edginton, Andrea N., and Rao, Praveen P.N.
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- 2015
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26. Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis
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McEneny-King, Alanna, primary, Chelle, Pierre, additional, Henrard, Severine, additional, Hermans, Cedric, additional, Iorio, Alfonso, additional, and Edginton, Andrea, additional
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- 2017
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27. What is the role for population pharmacokinetics in hemophilia?
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Iorio, Alfonso, primary, McEneny-King, Alanna, additional, Keepanasseril, Arun, additional, Foster, Gary, additional, and Edginton, Andrea, additional
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- 2017
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28. Development of a Web-Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS-Hemo): Study Protocol
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Iorio, Alfonso, primary, Keepanasseril, Arun, additional, Foster, Gary, additional, Navarro-Ruan, Tamara, additional, McEneny-King, Alanna, additional, Edginton, Andrea N, additional, and Thabane, Lehana, additional
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- 2016
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29. Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)
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McEneny-King, Alanna, primary, Foster, Gary, additional, Iorio, Alfonso, additional, and Edginton, Andrea N, additional
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- 2016
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30. Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): Study Protocol.
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UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'hématologie, Iorio, Alfonso, Keepanasseril, Arun, Foster, Gary, Navarro-Ruan, Tamara, McEneny-King, Alanna, Edginton, Andrea N, Thabane, Lehana, WAPPS-Hemo co-investigator network, Hermans, Cédric, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'hématologie, Iorio, Alfonso, Keepanasseril, Arun, Foster, Gary, Navarro-Ruan, Tamara, McEneny-King, Alanna, Edginton, Andrea N, Thabane, Lehana, WAPPS-Hemo co-investigator network, and Hermans, Cédric
- Abstract
BACKGROUND: Individual pharmacokinetic assessment is a critical component of tailored prophylaxis for hemophilia patients. Population pharmacokinetics allows using individual sparse data, thus simplifying individual pharmacokinetic studies. Implementing population pharmacokinetics capacity for the hemophilia community is beyond individual reach and requires a system effort. OBJECTIVE: The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project aims to assemble a database of patient pharmacokinetic data for all existing factor concentrates, develop and validate population pharmacokinetics models, and integrate these models within a Web-based calculator for individualized pharmacokinetic estimation in patients at participating treatment centers. METHODS: Individual pharmacokinetic studies on factor VIII and IX concentrates will be sourced from pharmaceutical companies and independent investigators. All factor concentrate manufacturers, hemophilia treatment centers (HTCs), and independent investigators (identified via a systematic review of the literature) having on file pharmacokinetic data and willing to contribute full or sparse pharmacokinetic data will be eligible for participation. Multicompartmental modeling will be performed using a mixed-model approach for derivation and Bayesian forecasting for estimation of individual sparse data. NONMEM (ICON Development Solutions) will be used as modeling software. RESULTS: The WAPPS-Hemo research network has been launched and is currently joined by 30 HTCs from across the world. We have gathered dense individual pharmacokinetic data on 878 subjects, including several replicates, on 21 different molecules from 17 different sources. We have collected sparse individual pharmacokinetic data on 289 subjects from the participating centers through the testing phase of the WAPPS-Hemo Web interface. We have developed prototypal population pharmacokinetics models for 11 molecules. The WAPPS-Hemo website (a
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- 2016
31. Investigating the binding interactions of the anti-Alzheimer's drug donepezil with CYP3A4 and P-glycoprotein
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Andrea N. Edginton, Praveen P.N. Rao, and Alanna McEneny-King
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Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Structure-Activity Relationship ,Piperidines ,In vivo ,Alzheimer Disease ,mental disorders ,Drug Discovery ,medicine ,Structure–activity relationship ,Cytochrome P-450 CYP3A ,Humans ,Donepezil ,Drug Interactions ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Binding site ,Molecular Biology ,IC50 ,Nootropic Agents ,CYP3A4 ,Molecular Structure ,Chemistry ,Organic Chemistry ,Indans ,Microsomes, Liver ,Molecular Medicine ,Ketoconazole ,Pharmacophore ,medicine.drug - Abstract
The anti-Alzheimer's agent donepezil is known to bind to the hepatic enzyme CYP3A4, but its relationship with the efflux transporter P-glycoprotein (P-gp) is not as well elucidated. We conducted in vitro inhibition studies of donepezil using human recombinant CYP3A4 and P-gp. These studies show that donepezil is a weak inhibitor of CYP3A4 (IC50=54.68±1.00μM) whereas the reference agent ketoconazole exhibited potent inhibition (CYP3A4 IC50=0.20±0.01μM). P-gp inhibition studies indicate that donepezil exhibits better inhibition relative to CYP3A4 (P-gp EC50=34.85±4.63μM) although it was less potent compared to ketoconazole (P-gp EC50=9.74±1.23μM). At higher concentrations, donepezil exhibited significant inhibition of CYP3A4 (69%, 84% and 87% inhibition at 100, 250 and 500μM, respectively). This indicates its potential to cause drug-drug interactions with other CYP3A4 substrates upon co-administration; however, this scenario is unlikely in vivo due to the low therapeutic concentrations of donepezil. Similarly, donepezil co-administration with P-gp substrates or inhibitors is unlikely to result in beneficial or adverse drug interactions. The molecular docking studies show that the 5,6-dimethoxyindan-1-one moiety of donepezil was oriented closer to the heme center in CYP3A4 whereas in the P-gp binding site, the protonated benzylpiperidine pharmacophore of donepezil played a major role in its binding ability. Energy parameters indicate that donepezil complex with both CYP3A4 and P-gp was less stable (CDOCKER energies=-15.05 and -4.91kcal/mol, respectively) compared to the ketoconazole-CYP3A4 and P-gp complex (CDOCKER energies=-41.89 and -20.03kcal/mol, respectively).
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- 2014
32. Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo)
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Gary Foster, Alfonso Iorio, Andrea N. Edginton, and Alanna McEneny-King
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Service (systems architecture) ,Operations research ,Population ,030204 cardiovascular system & hematology ,Machine learning ,computer.software_genre ,030226 pharmacology & pharmacy ,03 medical and health sciences ,Patient safety ,0302 clinical medicine ,population pharmacokinetics ,factor IX ,factor VIII ,hemophilia ,tailored prophylaxis ,Covariate ,Protocol ,Medicine ,Dosing ,education ,Protocol (science) ,Clotting factor ,education.field_of_study ,business.industry ,General Medicine ,Regimen ,Artificial intelligence ,business ,computer - Abstract
Background: Hemophilia is an inherited bleeding disorder caused by a deficiency in a specific clotting factor. This results in spontaneous bleeding episodes and eventual arthropathy. The mainstay of hemophilia treatment is prophylactic replacement of the missing factor, but an optimal regimen remains to be determined. Rather, individualized prophylaxis has been suggested to improve both patient safety and resource utilization. However, uptake of this approach has been hampered by the demanding sampling schedules and complex calculations required to obtain individual estimates of pharmacokinetic (PK) parameters. The use of population pharmacokinetics (PopPK) can alleviate this burden by reducing the number of plasma samples required for accurate estimation, but few tools incorporating this approach are readily available to clinicians. Objective: The Web-accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) project aims to bridge this gap by providing a Web-accessible service for the reliable estimation of individual PK parameters from only a few patient samples. This service is predicated on the development of validated brand-specific PopPK models. Methods: We describe the data analysis plan for the development and evaluation of each PopPK model to be incorporated into the WAPPS-Hemo platform. The data sources and structure of the dataset are discussed first, followed by the procedures for handling both data below limit of quantification (BLQ) and absence of such BLQ data. Next, we outline the strategies for building the appropriate structural and covariate models, including the possible need for a process algorithm when PK behavior varies between subjects or significant covariates are not provided. Prior to use in a prospective manner, the models will undergo extensive evaluation using a variety of techniques such as diagnostic plots, bootstrap analysis and cross-validation. Finally, we describe the incorporation of a validated PopPK model into the Bayesian post hoc model to produce individualized estimates of PK parameters. Results: Dense PK data has been collected for more than 20 brands of factor concentrate from both industry-sponsored and investigator-driven studies. The model development process is underway for the majority of molecules, with refinement and validation to be completed in 2017. Further, the WAPPS-Hemo co-investigator network has contributed more than 300 PK assessments for use in model development and evaluation. This constitutes the largest repository of this type of PK data globally. Conclusions: The WAPPS-Hemo service aims to eliminate barriers to the uptake of individualized PK-tailored hemophilia treatment. By incorporating this tool into routine practice, clinicians can implement a personalized dosing strategy without performing rigorous sampling or complex calculations. This service is centred on validated models developed according to the robust approach to PopPK modeling described herein. ClinicalTrial: ClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 (Archived by WebCite at http://www.webcitation.org/6mRIXJh55) [JMIR Res Protoc 2016;5(4):e232]
- Published
- 2016
33. The use of pharmacokinetics in dose individualization of factor VIII in the treatment of hemophilia A
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McEneny-King, Alanna, primary, Iorio, Alfonso, additional, Foster, Gary, additional, and Edginton, Andrea N., additional
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- 2016
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34. Population Pharmacokinetics Profiling to Tailor Prophylaxis in Hemophilia a Patients: A Pilot Feasibility Study
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Stemberger, Michaela, Kallenbach, Felix, Schmit, Elisabeth, McEneny-King, Alanna, Edginton, Andrea N, Iorio, Alfonso, and Kurnik, Karin
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- 2017
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35. Homogeneously magnetically concentrated silver nanoparticles for uniform “hot spots” in surface enhanced Raman spectroscopy
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Frank, Andrew J., primary, McEneny-King, Alanna, additional, Cathcart, Nicole, additional, and Kitaev, Vladimir, additional
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- 2015
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36. Comparative Assessment of the Performance of Pharmacokinetic Tools for Prophylactic Dosing of Antihemophilic Factor Recombinant Plasma/Albumin-Free Method (rAHF-PFM) Concentrate in Patients with Hemophilia A
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Staibano, Phillip, McEneny-King, Alanna, Morfini, Massimo, Foster, Gary, Hobson, Nicholas, Navarro-Ruan, Tamara, Edginton, Andrea N, and Iorio, Alfonso
- Abstract
Background:Optimal treatment ofpatients with moderate to severe hemophilia A (HA) entails prophylactic administration of factor VIII (FVIII) concentrate to prevent spontaneous bleeds. Population pharmacokinetic (PopPK)-based dosing is an effective way to ensure that FVIII plasma activity levels remain above a desired target. Currently, two PK-based dosing tools are available that can individualize FVIII prophylactic therapy with rAHF-PFM (Advate®). Objective:To compare the PK parameter outputs and dosing estimates of two PopPK-based dosing tools (i.e. Web Accessible Population Pharmacokinetics Service - Hemophilia (WAPPS) and myPKFiT) and to compare these outputs to a two-stage PK analysis. Methods:Infusion and post-infusion measurements were extracted from the WAPPS database. The same data were analysed using WAPPS v3.0, the Advate® model (2CO_2_V0, built by externally validating and updating the Bjorkmann published model), myPKFiT v2.0 (web-based Bayesian algorithm), and compartmental analysis in WinNonLin. For each case and for each approach, we reported: (1) success of fitting, (2) clearance (CL; dL/hr/kg), (3) volume at steady state (VdSS; dL/kg), (4) FVIII half-life (HL; hours), and (5) time to 0.01 above baseline IU/mL (hours). We also generated dosing estimates according to a 48-hour dosing schedule and a target trough of 0.03 IU/mL. A two-tailed t-test was used to assess for differences in dosing estimates. Data were anonymized as dictated by the WAPPS user DTA agreement. Results:232 patients on Advate were found in the WAPPS database, of which 92 had post-infusion samples at 4 ± 2, 24 ± 4, and 48 ± 6 hours. Of the 42 cases dosed with 50 ± 5 IU/kg of FVIII, 29 allowed calculation of all required outcome measures and are reported here. Six patients were moderate. A comparison of the results for WAPPS and myPKFiT is shown in Table 1. The best-fit using a two-stage approach was a two-compartment model on 9 patients (CL 0.037, 0.026 - 0.043; HL 11.2, 11.1 - 14.4) and a one- compartment model on 16 patients (CL 0.019, 0.016-0.023; HL 9.9, 9.3 - 10.5). Dose estimates were produced for severe patients and were significantly lower for WAPPS as compared to myPKFIT; t(23) = -3.302, p=0.003. Conclusions:Differences in PopPK individual estimates between WAPPS and myPKFiT are on average small and non-directional. The lower dose estimates from WAPPS were similar to those determined using a NONMEM implementation of the Bjorkman et al 2012 model and similar patients [1939 IU (985-3824)] (van Moort et al. ISTH 207 Congress. ASY 27.3). Prospective studies are required to assess the clinical implications of adopting different PopPK solutions.
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- 2017
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