Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery

Essentials Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. Population PK parameter values for clearance and V1 were 284 mL h−170 kg−1 and 5450 mL70 kg−1. Perioperative PK parameters differ from those during non-surgical prophylactic treatment. Summary: Background Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative setting, patients receive FIX concentrates to ensure hemostasis. Although FIX is usually dosed according to bodyweight, under- and overdosing occurs frequently during surgery. Aim The objective was to quantify and explain the interpatient variability of perioperatively administered plasma-derived (pd) and recombinant (r) FIX concentrates. Methods Data were collected from 118 patients (median age, 40 years [range, 0.2–90]; weight, 79 kg [range, 5.3–132]) with moderate (28%) or severe hemophilia B (72%), undergoing 255 surgical procedures. Population pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effect modeling in NONMEM. Results Measured perioperative FIX level vs. time profiles were adequately described using a three-compartment PK model. For a typical 34-year-old patient receiving rFIX, clearance (CL), intercompartmental clearance (Q2, Q3), distribution volume of the central compartment (V1) and peripheral compartments (V2, V3) plus interpatient variability (%CV) were: CL, 284 mL h−170 kg−1 (18%); V1, 5450 mL70 kg−1 (19%); Q2, 110 mL h−170 kg−1; V2, 4800 mL70 kg−1; Q3, 1610 mL h−170 kg−1; V3, 2040 mL70 kg−1. From 0.2 years, CL and V1 decreased 0.89% and 1.15% per year, respectively, until the age of 34 years. Patients receiving pdFIX exhibited a lower CL (11%) and V1 (17%) than patients receiving rFIX. Interpatient variability was successfully quantified and explained. Conclusions The estimated perioperative PK parameters of both pdFIX and rFIX are different from those reported for prophylactic treatment. The developed model may be used to apply PK-guided dosing of FIX concentrates during surgery

Validation of PROMIS Profile-29 in adults with hemophilia in the Netherlands

Background The Patient-Reported Outcomes Measurement Information System (PROMIS) Profile-29 questionnaire is widely used worldwide, but it has not yet been validated in the Netherlands, nor in persons with hemophilia. Objective To validate the Dutch-Flemish version of the PROMIS-29 Profile v2.01 in adults with hemophilia. Methods Dutch males with hemophilia (all severities) completed questionnaires that contained sociodemographic and clinical characteristics, the PROMIS-29, RAND-36, and the Hemophilia Activities List (HAL). Structural validity of each subscale was assessed with confirmatory factor analysis (CFA). Internal consistency was calculated for each subscale with sufficient model fit in CFA. Construct validity was assessed by testing hypotheses about (1) correlations of each PROMIS-29 subscale with corresponding scales of RAND-36 and domains of HAL, and (2) mean differences in T-scores between subgroups with different hemophilia severities, self-reported joint impairment, and HIV infection status. We considered >= 75% of data in accordance with the hypotheses evidence for construct validity. Results In total, 770 persons with hemophilia participated in this cross-sectional study. CFA revealed sufficient structural validity for five subscales: Physical Function, Depression, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference. Internal consistency was high and Cronbach's alpha ranged from 0.79 for Sleep Disturbance to 0.96 for Pain Interference. Differences between clinical subgroups were in the expected direction. Construct validity was confirmed for Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, and Pain Intensity. Conclusion This study revealed sufficient evidence for structural validity, internal consistency, and construct validity for most PROMIS Profile-29 subscales among people with hemophilia in the Netherlands.Clinical epidemiolog

Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001–2018

Background: Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands. Objective: This observational cohort study aimed to assess all-cause and cause-specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward. Patients/methods: All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018. Results: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2–1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic hear

Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery

Essentials Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. Population PK parameter values for clearance and V1 were 284 mL h−170 kg−1 and 5450 mL70 kg−1. Perioperative PK parameters differ from those during non-surgical prophylactic treatment. Summary: Background Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative sett

One piece of the puzzle: Population pharmacokinetics of FVIII during perioperative Haemate P®/Humate P® treatment in von Willebrand disease patients

Introduction: Many patients with von Willebrand disease (VWD) are treated on demand with von Willebrand factor and factor VIII (FVIII) containing concentrates present with VWF and/or FVIII plasma levels outside set target levels. This carries a risk for bleeding and potentially for thrombosis. Development of a population pharmacokinetic (PK) model based on FVIII levels is a first step to more accurate on-demand perioperative dosing of this concentrate

Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications

Thrombosis and Hemostasi

Validation of a perioperative population factor VIII pharmacokinetic model with a large cohort of pediatric hemophilia a patients

AIMS: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. METHODS: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03-15.2) and body weight of 14 kg (4-57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. RESULTS: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL(-1) . Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03-77.6) and body weight of 30 kg (4-111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h(-1)  68 kg(-1) , 2930 mL 68 kg(-1) , 1810 mL 68 kg(-1) , and 172 mL h(-1)  68 kg(-1) , respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL(-1) . CONCLUSIONS: This study emphasizes the importance of external validation of population PK models using real-life data

Patients' and health care providers' perspectives on quality of hemophilia care in the Netherlands: a questionnaire and interview study

Background: Hemophilia care has improved greatly because of advances in treatment options and comprehensive care. In-depth insight into the perspectives of persons with hemophilia and health care providers on their care may provide targets for further improvements. Objectives: To assess satisfaction of the hemophilia population with their care, to explore factors determining care satisfaction, and to identify areas for potential health care improvements, including digital health tools. Methods: First, to assess care satisfaction and factors determining satisfaction and health care improvements, data from a nationwide, cross-sectional questionnaire among 867 adult and pediatric Dutch persons with hemophilia A or B were analyzed. This included the Hemophilia Patient Satisfaction Scale questionnaire, Canadian Hemophilia Outcomes Kids' Life Assessment Tool satisfaction questions, a visual analog scale satisfaction score, and open questions. Second, to further explore factors determining satisfaction and health care improvements, semistructured interviews were conducted with 19 persons with hemophilia or their parents and 18 health care providers. Results: High care satisfaction was found, with an overall median Hemophilia Patient Satisfaction Scale score of 12 (IQR, 6-21). Participants in the interviews reported that patient-professional interactions, availability of care, and coordination of care were major factors determining satisfaction. Suggested health care improvements included improved information provision and coordination of care, especially shared care with professionals not working within comprehensive care centers. Participants suggested that digital health tools could aid in this. Conclusion: Satisfaction with hemophilia care is high among persons with hemophilia in the Netherlands, although several potential improvements have been identified. Accentuating these is especially relevant in the current era of treatment innovations, in which we might focus less on other aspects of care.Public Health and primary carePrevention, Population and Disease management (PrePoD