The efficacy of the entire-vial dosing of emicizumab: Real-world evidence on plasma concentrations, bleeds, and drug waste

Background: Prophylaxis with emicizumab provides effective bleeding protection in persons with hemophilia A (PwHA) but pressures healthcare budgets. The body weight–adjusted dosing at 7-, 14-, or 28-day intervals, according to the label, often mismatches the vial content. Entire-vial dosing resulted in therapeutic concentrations according to pharmacokinetic simulations and was introduced to avoid waste. Objectives: The objective of this study was to evaluate the efficacy of entire-vial dosing of emicizumab by investigating real-world evidence of plasma concentrations, bleeds, and drug waste. Methods: This is a single-center, observational study with PwHA receiving emicizumab in mg/kg doses according to label but dosing interval extrapolated to the nearest vial size. Patient characteristics and bleeds were compared 1 year before starting emicizumab and during emicizumab until January 2022. Concentrations were assessed at weeks 4, 12, and annually. The mean (95% CI) annualized bleed rates were compared by using negative binomial regression. Drug waste between label-based dosing and entire-vial dosing was compared. Results: A total of 112 individuals (94% severe phenotype and 9% positive FVIII inhibitors) were followed for a median of 56 weeks (interquartile range [IQR] 52-68) before and 51 weeks (IQR 29-75) after starting emicizumab. The median emicizumab dose was 5.9 (IQR 5.5-6.2) mg/kg/4 wk with median concentrations of 63 (IQR 51-80) μg/mL. The annualized bleed rate of treated bleeds before emicizumab was 3.6 (95% CI 2.9-4.4) and was 0.8 (95% CI 0.6-1.1) during emicizumab (P < .001). Drug waste was reduced by 9%. Conclusion: The entire-vial dosing of emicizumab is an attractive treatment option for PwHA leading to therapeutic plasma concentrations, good bleeding control, and drug waste avoidance

Quantification of emicizumab by mass spectrometry in plasma of people with hemophilia A: A method validation study

Background: Emicizumab is a new treatment option for people with hemophilia A. Emicizumab was approved with a body-weight-based dosage regimen, without laboratory monitoring requirements. Guidelines, however, recommend measuring emicizumab concentrations when the presence of antidrug antibodies is suspected. Furthermore, drug monitoring can be useful in clinical decision making, in adherence checking, and for research purposes. Therefore, we developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for quantifying emicizumab. We performed a validation study on this LC-MS/MS method quantifying emicizumab in the plasma of people with hemophilia A. Methods: Sample preparation for LC-MS/MS analysis included ammonium sulfate protein precipitation and trypsin digestion. A signature peptide of emicizumab and a matching stable isotope-labeled internal standard were used to quantify emicizumab by LC-MS/MS analysis. Validation was performed in accordance with the “Guideline on Bioanalytical Method Validation” of the European Medicines Agency (EMA). The LC-MS/MS method was cross validated against a modified and calibrated (r2 Diagnostics) one-stage clotting assay (OSA). Conclusions: The LC-MS/MS method demonstrated linearity over a wide range of emicizumab concentrations, far exceeding the concentrations observed in people with hemophilia A. Precision and accuracy were excellent, and all other validation parameters were also within the acceptance EMA criteria. Cross validation showed that the LC-MS/MS method and the OSA-based method can be used interchangeably for drug monitoring of emicizumab without the application of a correction factor

Perceived Immune Status and Sleep : A Survey among Dutch Students

Reduced immune functioning may have a negative impact on sleep and health, and vice versa. A survey among Dutch young adults (18-35 years old) was administered to collect information on perception of reduced immunity and its relationship to sleep disorders, sleep duration, and quality. Sleep disorders were assessed with the SLEEP-50 questionnaire subscales of sleep apnea, insomnia, circadian rhythm disorder, and daily functioning. Dutch young adults (N = 574) completed the survey. Among them, subjects (N = 209; 36.4%) reported perceived reduced immunity. Relative to those with a normal immune status, subjects reporting reduced immunity had significantly higher scores (p = 0.0001) on sleep apnea (2.6 versus 3.6), insomnia (5.1 versus 6.8), and circadian rhythm disorder (2.1 versus 2.7). Subjects reporting reduced immunity also had significantly poorer daily functioning scores (5.4 versus 7.6, p = 0.0001). No differences were observed in total sleep time, but those reporting reduced immunity had significantly poorer ratings of sleep quality (6.8 versus 7.2, p = 0.0001). Our findings suggest that perceived reduced immunity is associated with sleep disturbances, impaired daily functioning, and a poorer sleep quality. Experimental studies including the assessment of immune biomarkers and objective measures of sleep (polysomnography) should confirm the current observations

Perceived immune status and sleep: a survey among Dutch students

Reduced immune functioning may have a negative impact on sleep and health, and vice versa. A survey among Dutch young adults (18&#8211;35 years old) was administered to collect information on perception of reduced immunity and its relationship to sleep disorders, sleep duration, and quality. Sleep disorders were assessed with the SLEEP-50 questionnaire subscales of sleep apnea, insomnia, circadian rhythm disorder, and daily functioning. Dutch young adults (N = 574) completed the survey. Among them, subjects (N = 209; 36.4%) reported perceived reduced immunity. Relative to those with a normal immune status, subjects reporting reduced immunity had significantly higher scores on sleep apnea (2.6 versus 3.6), insomnia (5.1 versus 6.8), and circadian rhythm disorder (2.1 versus 2.7). Subjects reporting reduced immunity also had significantly poorer daily functioning scores (5.4 versus 7.6, ). No differences were observed in total sleep time, but those reporting reduced immunity had significantly poorer ratings of sleep quality (6.8 versus 7.2, ). Our findings suggest that perceived reduced immunity is associated with sleep disturbances, impaired daily functioning, and a poorer sleep quality. Experimental studies including the assessment of immune biomarkers and objective measures of sleep (polysomnography) should confirm the current observations

Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review

Introduction: Emicizumab is an effective new treatment option for people with hemophilia A (PwHA). The approved dosing regimens are based on body weight, without the necessity for laboratory monitoring. This assumes a clear dose–concentration–response relationship, with acceptable variability due to factors other than body weight. To investigate this assumption, a systematic review on the pharmacokinetics (PK) and associated efficacy of emicizumab in humans was conducted. Methods: The EMBASE, Pubmed and CENTRAL databases were systematically searched to November 2020 to identify studies on the PK data of emicizumab in humans. Data on the study, population, PK and efficacy (annualized bleeding rate of treated [joint] bleeds) were extracted and synthesized, and exposure effects modeling was performed using non-linear least squares regression in a maximum effect (Emax) model. Results: The 15 included studies reported on data for 140 volunteers and 467 PwHA, including children (0 to <12 years) and adolescents and adults (≥12 years), both with and without factor VIII (FVIII) inhibitors. Emicizumab demonstrated dose-linear PK. The interindividual variability of trough concentrations was moderate (32%) and was similar across various subgroups, such as FVIII inhibitor status, age group and dosing interval. The control of bleeds did not further improve above emicizumab concentrations of 30 µg/mL, potentially enabling lower dosing in a substantial proportion of PwHA. Conclusion: This review supports body weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing

Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review

Introduction: Emicizumab is an effective new treatment option for people with hemophilia A (PwHA). The approved dosing regimens are based on body weight, without the necessity for laboratory monitoring. This assumes a clear dose–concentration–response relationship, with acceptable variability due to factors other than body weight. To investigate this assumption, a systematic review on the pharmacokinetics (PK) and associated efficacy of emicizumab in humans was conducted. Methods: The EMBASE, Pubmed and CENTRAL databases were systematically searched to November 2020 to identify studies on the PK data of emicizumab in humans. Data on the study, population, PK and efficacy (annualized bleeding rate of treated [joint] bleeds) were extracted and synthesized, and exposure effects modeling was performed using non-linear least squares regression in a maximum effect (Emax) model. Results: The 15 included studies reported on data for 140 volunteers and 467 PwHA, including children (0 to <12 years) and adolescents and adults (≥12 years), both with and without factor VIII (FVIII) inhibitors. Emicizumab demonstrated dose-linear PK. The interindividual variability of trough concentrations was moderate (32%) and was similar across various subgroups, such as FVIII inhibitor status, age group and dosing interval. The control of bleeds did not further improve above emicizumab concentrations of 30 µg/mL, potentially enabling lower dosing in a substantial proportion of PwHA. Conclusion: This review supports body weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing

Quantification of emicizumab by mass spectrometry in plasma of people with hemophilia A: A method validation study

Abstract Background Emicizumab is a new treatment option for people with hemophilia A. Emicizumab was approved with a body‐weight‐based dosage regimen, without laboratory monitoring requirements. Guidelines, however, recommend measuring emicizumab concentrations when the presence of antidrug antibodies is suspected. Furthermore, drug monitoring can be useful in clinical decision making, in adherence checking, and for research purposes. Therefore, we developed a liquid chromatography–tandem mass spectrometry (LC‐MS/MS) method for quantifying emicizumab. We performed a validation study on this LC‐MS/MS method quantifying emicizumab in the plasma of people with hemophilia A. Methods Sample preparation for LC‐MS/MS analysis included ammonium sulfate protein precipitation and trypsin digestion. A signature peptide of emicizumab and a matching stable isotope‐labeled internal standard were used to quantify emicizumab by LC‐MS/MS analysis. Validation was performed in accordance with the “Guideline on Bioanalytical Method Validation” of the European Medicines Agency (EMA). The LC‐MS/MS method was cross validated against a modified and calibrated (r2 Diagnostics) one‐stage clotting assay (OSA). Conclusions The LC‐MS/MS method demonstrated linearity over a wide range of emicizumab concentrations, far exceeding the concentrations observed in people with hemophilia A. Precision and accuracy were excellent, and all other validation parameters were also within the acceptance EMA criteria. Cross validation showed that the LC‐MS/MS method and the OSA‐based method can be used interchangeably for drug monitoring of emicizumab without the application of a correction factor

Comparison between coagulation factor VIII quantified with one-stage activity assay and with mass spectrometry in haemophilia A patients: Proof of principle

INTRODUCTION: Haemophilia A is a hereditary bleeding disorder caused by a factor VIII (FVIII) deficiency. As biomarker, FVIII activity is used to classify disease severity and to monitor treatment. The one-stage clotting assay (OSA) is performed to measure FVIII activity, but OSA's limitations may result in misclassification of disease severity or suboptimal monitoring of treatment. Measurement of FVIII plasma concentration with liquid chromatography-tandem mass spectrometry (LC-MS/MS) might overcome these challenges. The objective is to investigate the correlation between FVIII activity and concentration, and determinants for differences between the two methods. METHODS: In this cross-sectional study, all haemophilia A patients receiving standard-of-care were eligible for inclusion. Within the activity categories of 5-40 IU/dL, >40-150 IU/dL and >150-600 IU/dL, we randomly selected 15-20 plasma samples and compared FVIII concentration (LC-MS/MS) to FVIII activity (OSA) with linear regression and Bland-Altman analysis. Potential determinants for differences were analysed with linear regression. RESULTS: Inclusion was 87 samples. Bland-Altman analysis demonstrated an overall mean difference of -1% with an SD of 64% between the two methods. Large differences were correlated with the presence of anti-FVIII antibodies (133% [95% CI: 81, 185] n = 5) and use of exogenous FVIII products (-37% [95% CI: -65,-9] n = 58), for example plasma-derived and B-domain-modified FVIII products. CONCLUSIONS: Despite good overall correlation between the two methods, relative differences were large, especially for samples with anti-FVIII antibodies or exogenous FVIII products. These differences may have clinical impact. More research is needed to determine the value of FVIII plasma concentration in comparison with FVIII activity

Comparison between coagulation factor VIII quantified with one-stage activity assay and with mass spectrometry in haemophilia A patients: Proof of principle

INTRODUCTION: Haemophilia A is a hereditary bleeding disorder caused by a factor VIII (FVIII) deficiency. As biomarker, FVIII activity is used to classify disease severity and to monitor treatment. The one-stage clotting assay (OSA) is performed to measure FVIII activity, but OSA's limitations may result in misclassification of disease severity or suboptimal monitoring of treatment. Measurement of FVIII plasma concentration with liquid chromatography-tandem mass spectrometry (LC-MS/MS) might overcome these challenges. The objective is to investigate the correlation between FVIII activity and concentration, and determinants for differences between the two methods. METHODS: In this cross-sectional study, all haemophilia A patients receiving standard-of-care were eligible for inclusion. Within the activity categories of 5-40 IU/dL, >40-150 IU/dL and >150-600 IU/dL, we randomly selected 15-20 plasma samples and compared FVIII concentration (LC-MS/MS) to FVIII activity (OSA) with linear regression and Bland-Altman analysis. Potential determinants for differences were analysed with linear regression. RESULTS: Inclusion was 87 samples. Bland-Altman analysis demonstrated an overall mean difference of -1% with an SD of 64% between the two methods. Large differences were correlated with the presence of anti-FVIII antibodies (133% [95% CI: 81, 185] n = 5) and use of exogenous FVIII products (-37% [95% CI: -65,-9] n = 58), for example plasma-derived and B-domain-modified FVIII products. CONCLUSIONS: Despite good overall correlation between the two methods, relative differences were large, especially for samples with anti-FVIII antibodies or exogenous FVIII products. These differences may have clinical impact. More research is needed to determine the value of FVIII plasma concentration in comparison with FVIII activity