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.

Perioperative replacement therapy in haemophilia B: An appeal to "B" more precise.

INTRODUCTION: Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. AIM: To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed. METHODS: In this international multicentre study, haemophilia B patients with FIX < 0.05 IU mL-1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines. RESULTS: A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79 kg). Sixty percent of FIX levels within 24 hours of surgery were below target with a median difference of 0.22 IU mL-1 [IQR 0.12-0.36]; while >6 days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IU mL-1 [IQR 0.10-0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%). CONCLUSION: This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment.

Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: Identifying the need for personalized treatment.

INTRODUCTION: Patients with Von Willebrand disease (VWD) are regularly treated with VWF-containing concentrates in case of acute bleeding, trauma and dental or surgical procedures. AIM: In this multicentre retrospective study, current perioperative management with a von Willebrand factor (VWF)/Factor VIII (FVIII) concentrate (Haemate® P) in patients with VWD was evaluated. PATIENTS/METHODS: Patients with VWD undergoing minor or major surgery between 2000 and 2015, requiring treatment with a VWF/FVIII concentrate (Haemate® P), were included. Achieved VWF activity (VWF:Act) and FVIII during FVIII-based treatment regimens were compared to predefined target levels in national guidelines. RESULTS: In total, 103 patients with VWD (148 surgeries) were included: 54 type 1 (73 surgeries), 43 type 2 (67 surgeries) and 6 type 3 (8 surgeries). Overall, treatment resulted in high VWF:Act and FVIII levels, defined as ≥0.20 IU/mL above predefined levels. In patients with type 1 VWD, respectively, 65% and 91% of trough VWF:Act and FVIII levels were higher than target levels. In patients with type 2 and type 3 VWD, respectively, 53% and 57% of trough VWF:Act and 72% and 73% of trough FVIII levels were higher than target level. Furthermore, FVIII accumulation over time was observed, while VWF:Act showed a declining trend, leading to significantly higher levels of FVIII than VWF:Act. CONCLUSION: High VWF:Act and accumulation of FVIII were observed after perioperative FVIII-based replacement therapy in patients with VWD, both underlining the necessity of personalization of dosing regimens to optimize perioperative treatment.

Setting the stage for individualized therapy in hemophilia: What role can pharmacokinetics play?

Replacement therapy with clotting factor concentrates (CFC) is the mainstay of treatment in hemophilia. Its widespread application has led to a dramatic decrease in morbidity and mortality in patients, with concomitant improvement of quality of life. However, dosing is challenging and costs are high. This review discusses benefits and limitations of pharmacokinetic (PK)-guided dosing of replacement therapy as an alternative for current dosing regimens. Dosing of CFC is now primarily based on body weight and based on its in vivo recovery (IVR). Benefits of PK-guided dosing include individualization of treatment with better targeting, more flexible blood sampling, increased insight into association of coagulation factor levels and bleeding, and potential overall lowering of overall costs. Limitations include a slight burden for the patient, and availability of closely collaborating, experienced clinical pharmacologists.

In silico evaluation of limited blood sampling strategies for individualized recombinant factor IX prophylaxis in hemophilia B patients.

Essentials Individual pharmacokinetic (PK) parameters can be obtained by limited sampling strategies (LSSs). Following 100 IU kg-1 rFIX, LSSs with 1 to 3 samples were evaluated in 5000 simulated subjects. For all LSSs, estimated individual PK parameters showed acceptable bias and precision. One sample between 10 min-3 h and two between 48 h-56 h showed best predictive performance. SUMMARY: Background Patients with severe hemophilia B regularly administer prophylactic intravenous doses of clotting factor IX concentrate to maintain a trough level of at least 0.01 IU mL-1 in order to prevent joint bleeds. Assessment of individual pharmacokinetic (PK) parameters allows individualization of the recombinant factor IX (rFIX) dose. Aim To evaluate the predictive performance of limited sampling strategies (LSSs) with one to three samples to estimate individual PK parameters of rFIX. Methods Monte Carlo simulations were performed to obtain 5000 concentration-time profiles by the use of population PK parameters for rFIX from literature. Eleven LSSs were developed with one, two or three samples taken within an 80-h interval following administration of 100 IU kg-1 rFIX. Clearance (CL), half-life (t1/2 ), time to 1% and steady-state distribution volume (Vss ) were estimated for each simulated individual by the use of Bayesian analysis. Results For each LSS, average bias was small for CL (range - 1.5% to 1.4%), t1/2 (range - 4.5% to - 0.7%), time to 1% (range - 2.9% to 0%), and Vss (range - 3.7% to 0.3%). Imprecision for these parameters ranged from 6.4% to 11.9%, from 10.3% to 15.6%, from 7.3% to 10.9%, and from 9% to 20.1%, respectively. The best predictive performance was achieved with one sample taken between 10 min and 3 h and two samples taken between 48 h and 56 h after administration of rFIX. Conclusions This study demonstrates that limited sampling strategies, used for individualized dosing of rFIX in hemophilia B patients, can be developed and evaluated by in silico simulation.

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

UNLABELLED: ESSENTIALS: Targeting of factor VIII values is a challenge during perioperative replacement therapy in hemophilia. This study aims to identify the extent and predictors of factor VIII underdosing and overdosing. Blood group O predicts underdosing and is associated with perioperative bleeding. To increase quality of care and cost-effectiveness of treatment, refining of dosing is obligatory. BACKGROUND: Perioperative administration of factor VIII (FVIII) concentrate in hemophilia A may result in both underdosing and overdosing, leading to respectively a risk of bleeding complications and unnecessary costs. OBJECTIVES: This retrospective observational study aims to identify the extent and predictors of underdosing and overdosing in perioperative hemophilia A patients (FVIII levels < 0.05 IU mL(-1)). PATIENTS AND METHODS: One hundred nineteen patients undergoing 198 elective, minor, or major surgical procedures were included (median age 40 years, median body weight 75 kg). Perioperative management was evaluated by quantification of perioperative infusion of FVIII concentrate and achieved FVIII levels. Predictors of underdosing and (excessive) overdosing were analyzed by logistic regression analysis. Excessive overdosing was defined as upper target level plus ≥ 0.20 IU mL(-1). RESULTS: Depending on postoperative day, 7-45% of achieved FVIII levels were under and 33-75% were above predefined target ranges as stated by national guidelines. A potential reduction of FVIII consumption of 44% would have been attained if FVIII levels had been maintained within target ranges. Blood group O and major surgery were predictive of underdosing (odds ratio [OR] 6.3, 95% confidence interval [CI] 2.7-14.9; OR 3.3, 95% CI 1.4-7.9). Blood group O patients had more bleeding complications in comparison to patients with blood group non-O (OR 2.02, 95% CI 1.00-4.09). Patients with blood group non-O were at higher risk of overdosing (OR 1.5, 95% CI 1.1-1.9). Additionally, patients treated with bolus infusions were at higher risk of excessive overdosing (OR 1.8, 95% CI 1.3-2.4). CONCLUSION: Quality of care and cost-effectiveness can be improved by refining of dosing strategies based on individual patient characteristics such as blood group and mode of infusion.