Gerald Spotts

Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A

Summary.  Background: The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level <1 IU dL−1. Studies to date, however, have not demonstrated a strong link between FVIII level and the bleeding rate. Objectives: To assess the effect of FVIII level on break‐through bleeding in patients with severe hemophilia A on prophylaxis. Patients/methods: This study analysed data from 44 patients aged 1–6 and 99 patients aged 10–65 years with severe hemophilia A (FVIII <1 IU dL−1) who were treated with prophylactic FVIII as part of clinical studies assessing pharmacokinetics, safety and efficacy of a recombinant FVIII (Advate®). Each patient had pharmacokinetic measurements and FVIII infusions recorded, and these were used to calculate time spent with a FVIII below 1, 2 and 5 IU dL−1. Results: The data demonstrate that increasing time with a FVIII below 1 IU dL−1 is associated with increased total bleeds and hemarthroses. Lack of adherence to the intended frequency of FVIII infusion was the most important determinant of low FVIII and increased bleeding. In children aged 1–6 years, the rate of bleeding was also influenced by FVIII half‐life and clearance. Conclusions: These data have important implications for the management of patients with severe hemophilia.

Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens

Summary.  Background: Prophylactic factor (F)VIII has been shown to reduce bleeds and arthropathy in patients with severe hemophilia A. Objectives: Assuming that the trough FVIII level is an important determinant of the efficacy of prophylaxis, this paper addresses the effect of the inter‐patient variability in pharmacokinetics and different dosing regimens on trough levels. Methods: Simulations used FVIII half‐lives and in vivo recoveries (IVR), observed during clinical trials with Advate [Antihemophilic Factor (Recombinant), Plasma/Albumin‐Free Method], and commonly used prophylactic regimens to calculate their effect on FVIII levels during prophylaxis. Results and conclusions: Half‐life and dose frequency had a larger effect on trough FVIII and time per week with FVIII < 1 IU dL−1 than IVR and infused dose per kg. The combined effect of these parameters resulted in substantial inter‐patient variability in the amount of FVIII required to sustain a desired trough level. Prophylactic regimens based on Monday, Wednesday, Friday dosing were less cost effective in maintaining a desired trough level throughout the week. Dose escalation on Friday to cover the weekend would require potentially harmful doses of FVIII in many patients, especially in young children where more than 50% would require a Friday dose of over 100 IU kg−1 and some would require more than 400 IU kg−1. Knowledge of individual patients’ half‐lives and alteration of frequency of infusions may allow the more cost‐effective use of FVIII and potentially expand access to prophylaxis to a greater number of patients, especially in regions where healthcare resources are scarce.

Population pharmacokinetics of recombinant factor VIII : the relationships of pharmacokinetics to age and body weight

Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PK-based dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling.

Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients.

Summary.  Background: The pharmacokinetics of factor VIII replacement therapy in preschool previously treated patients (PTPs) with hemophilia A have not been well characterized. Objectives: To assess the pharmacokinetics, efficacy and safety of a plasma‐free recombinant FVIII concentrate, ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin‐Free Method, rAHF‐PFM], in children < 6 years of age with severe hemophilia. Patients/methods: Fifty‐two boys, one girl, mean (± SD) age 3.1 ± 1.5 years and ≥ 50 days of prior FVIII exposure, were enrolled in a prospective study of ADVATE rAHF‐PFM at 23 centers. Results: The mean terminal phase half‐life (t1/2) was 9.88 ± 1.89 h, and the mean adjusted in vivo recovery (IVR) was 1.90 ± 0.43 IU dL−1 (IU kg−1)−1. Over the 1–6‐year age range, t1/2 of rAHF‐PFM increased by 0.40 h year−1. IVR increased by 0.095IU dL−1(IU kg−1)−1 (kg m−2)−1 in relation to body mass index (BMI). Patients primarily received prophylaxis. Median (range) annual joint bleeds were 0.0 (0.0–5.8), 0.0 (0.0–6.1) and 14.2 (0.0–34.5) for standard prophylaxis, modified prophylaxis and on‐demand treatment, respectively. Bleeds were managed in 90% (319/354) of episodes with one or two rAHF‐PFM infusions; response was rated excellent/good in 93.8% of episodes. Over a median 156 exposure days, no FVIII inhibitors were detected and no related severe adverse events or unusual non‐serious adverse events were seen. Conclusions: Children < 6 years of age appear to have shorter FVIII t1/2 and lower IVR values than older subjects. However, these parameters increased with age (t1/2) and BMI (adjusted IVR), respectively. rAHF‐PFM was clinically effective and well tolerated, with no signs of increased immunogenicity in previously treated young children with hemophilia A.

Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring

Summary.  Background: Dose tailoring of coagulation factors requires reliably estimated and reproducible pharmacokinetics (PK) in the individual patient. Objectives: To investigate the contribution of both biological and methodological factors to the observed variability of factor VIII (FVIII) PK, with the focus on differences between children and adults, and to examine the implications for dosing. Patients: Data from 52 1–6‐year‐old and 100 10–65‐year‐old patients with hemophilia A (FVIII ≤ 2 IU dL−1) in three clinical studies were included. Results: In vivo recovery was lower, weight‐adjusted clearance was higher and FVIII half‐life was on average shorter in children than in adults. However, a reduced blood sampling schedule for children was estimated to account for up to one half of the total observed differences. Intrapatient variance in PK was smaller than interpatient variance in 10–65‐year‐olds. Age and ratio of actual to ideal weight only showed weak relationships with PK parameters. Variance in PK caused large variance in the calculated dose required to maintain a target FVIII trough level during prophylactic treatment. Conclusion: Differences in blood sampling schedules should be taken into account when results from different PK studies are compared. However, even with this consideration, PK cannot be predicted from observable patient characteristics but must be determined for the individual. Because the influence of reducing the blood sampling was minor in comparison to the true variance between patients, a reduced blood sampling protocol can be used. Low intrapatient variability supports the use of PK measurements for dose tailoring of FVIII.

Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials

Summary.  Replacement therapy or prophylaxis, has become the standard of care for the treatment of severe haemophilia A. To describe bleeding patterns in children, adolescents and adults on prophylaxis and their observed relationships to times of infusion (during the week and during the day) as well as season of the year. Data from Advate pre‐licensure prospective clinical trials from 145 patients with factor VIII (FVIII) <1%, were used. All patients underwent a 48‐h pharmacokinetic study. The 10–65 year group had ≥75 exposure days on fixed prophylaxis (25–40 IU kg−1 3–4x per week). Prophylaxis was not fixed but similar for 1–6 year olds. Bleeding patterns were analysed. Overall, 700 bleeds were observed in 110/145 patients. All were treated with prophylaxis, mean dose 108 IU kg−1 week−1 in on average 2.9 infusions (1–6 years), 86 IU kg −1week−1 in 2.7 infusions (10–17 years),and 75 IU kg −1week−1 in 2.6 infusions (18–65 years), respectively. On prophylaxis, median total bleeds per year were low at 3.1 for patients aged 1–6 years, 3.3 for those aged 10–17 years and 2.1 for patients aged 18–65 years. Patients aged 1–6 years had predominantly soft tissue bleeds (79%). Incidence of joint bleeding was not associated with season, but was significantly lower in patients who infused FVIII in the mornings: median 0 per year (IQR 0.0–0.4) compared to those who infused later [median 1.8 per year (IQR 0.0–5.2)]. Older patients predominantly experienced joint bleeds (50% and 62%, respectively). More joint bleeds occurred during the summer [43 and 46% respectively, (P < 0.01)]. Bleeding patterns in patients on prophylaxis varied according to age. In addition, the 10–65 year olds showed increased bleeding during the summer. After confirmation in prospective studies, this information may be used to improve tailoring of prophylactic treatment.

Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method] demonstrates efficacy, safety and low-risk for immunogenicity in routine clinical practice

Summary.  Postauthorization safety surveillance of factor VIII (FVIII) concentrates is essential for assessing rare adverse event incidence. We determined safety and efficacy of ADVATE [antihaemophilic factor (recombinant), plasma/albumin‐free method, (rAHF‐PFM)] during routine clinical practice. Subjects with differing haemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on‐demand therapy. Among 408 evaluable subjects, 386 (95%) received excellent/good efficacy ratings for all on‐demand assessments; the corresponding number for subjects with previous FVIII inhibitors was 36/41 (88%). Among 276 evaluable subjects receiving prophylaxis continuously in the study, 255 (92%) had excellent/good ratings for all prophylactic assessments; the corresponding number for subjects with previous FVIII inhibitors was 41/46 (89%). Efficacy of surgical prophylaxis was excellent/good in 16/16 evaluable procedures. Among previously treated patients (PTPs) with >50 exposure days (EDs) and FVIII ≤2%, three (0.75%) developed low‐titre inhibitors. Two of these subjects had a positive inhibitor history; thus, the incidence of de novo inhibitor formation in PTPs with FVIII ≤2% and no inhibitor history was 1/348 (0.29%; 95% CI, 0.01–1.59%). A PTP with moderate haemophilia developed a low‐titre inhibitor. High‐titre inhibitors were reported in a PTP with mild disease (following surgery), a previously untreated patient (PUP) with moderate disease (following surgery) and a PUP with severe disease. The favourable benefit/risk profile of rAHF‐PFM previously documented in prospective clinical trials has been extended to include a broader range of haemophilia patients, many of whom would have been ineligible for registration studies.

Association of peak factor VIII levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic-guided prophylaxis.

We previously showed that pharmacokinetic‐guided prophylaxis (PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII (FVIII) levels and area under the curve (AUC) with breakthrough bleeding have not been investigated.

Stability of ADVATE, Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method, during simulated continuous infusion.

Continuous infusion of factor VIII (FVIII) concentrates during surgical procedures offers the potential for improved hemostatic control and reduced FVIII consumption, but requires stable FVIII concentrates. The stability of ADVATE, Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (rAHF-PFM), was examined using various simulated conditions. Experiments performed with a multi-therapy 6060 pump showed FVIII recoveries of 95% or more after 48 h for multiple lots of high-potency and mid-potency rAHF-PFM, with or without heparin. Non-infused controls maintained at the same temperature showed similar FVIII recovery, demonstrating that the infusion system did not cause loss of FVIII activity. Supportive data generated using single lots of mid-potency or high-potency rAHF-PFM infused through a MEDEX or HARVARD syringe pump, or a CADD Pump-1, demonstrated FVIII recoveries of 83% or more at 24 or 48 h under all conditions tested. Additionally, rAHF-PFM was stable immediately after dilution in saline or saline/dextrose solutions, and after a 10-h exposure to ultraviolet and visible light. Taken together, these data demonstrate that rAHF-PFM is stable under conditions typically encountered during continuous infusion, and suggest that rAHF-PFM should be safe and effective when used for FVIII replacement by continuous infusion in patients with hemophilia A.

Retrospective analysis of differences in annual factor VIII utilization among haemophilia A patients.

Summary.  Finding differences in drug utilization patterns within rare patient populations is challenging without access to a large sample. Our objective was to identify patient and treatment‐related factors associated with differences in annual recombinant factor VIII (rFVIII) utilization in a large cohort of haemophilia A patients. This retrospective analysis utilized a large, US specialty pharmacy dispensing database from January 2006 to September 2009. Differences in median annual FVIII utilization (IU kg−1year−1) by age, severity, treatment regimen, rFVIII product type and health insurance plan were tested using non‐parametric statistics and regression analysis. A total of 1011 haemophilia A patients were included in the overall analysis. Severe haemophilia patients had higher median annual FVIII utilization than mild/moderate patients (P < 0.0001). Median annual FVIII utilization was also significantly different between treatment regimens (episodic = 1429 IU kg−1year−1 vs. prophylaxis = 3993 IU kg−1year−1 for severe patients, P < 0.0001). Children (0–12 years old), adolescents (13–18 years old) and adults (19+ years old) with severe haemophilia A receiving prophylaxis utilized 4588, 4082 and 3223 IU kg−1year−1 (P < 0.0001). After controlling for age, severity, treatment regimen and insurance type, regression analysis revealed B domain‐deleted recombinant FVIII (BDD‐rFVIII) was associated with 33% higher FVIII consumption compared with full‐length recombinant FVIII (FL‐rFVIII) (P = 0.0172). Similar results were also seen when matching BDD‐rFVIII and FL‐rFVIII patients. Health insurance type was not associated with annual FVIII utilization. As expected, age, severity and treatment regimen were significantly associated with FVIII utilization. After controlling for confounders, patients receiving FL‐rFVIII prophylactically were associated with lower annual FVIII utilization compared with patients receiving BDD‐rFVIII prophylactically.