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.
Evaluation of factor F(V)III replacement in patients with haemophilia A undergoing surgery is critical for FVIII concentrates, yet large scale, multi-center prospective studies, particularly using ...continuous infusion, are generally lacking for new products. This study evaluated efficacy and safety of a newly developed recombinant FVIII (rAHF-PFM) administered by bolus or continuous infusion in haemophilia A patients undergoing surgery. Subjects > or =5 years of age with baseline FVIII:C < or =2%, and > or =150 prior FVIII exposure days were included in this prospective, international, open-label, uncontrolled clinical trial. rAHF-PFM was administered perioperatively by bolus infusion (BI) or continuous infusion (CI) according to the standard use at the center to prevent bleeding complication. Both the surgeon and haematologist rated efficacy during hospitalization. Fifty-eight subjects underwent 65 surgical procedures (22 major haemorrhagic risk; 35 minor, 8 dental procedures). Bolus infusion was used exclusively in 47 procedures and continuous infusion, with or without supplemental bolus infusions, in 18. Haemostatic efficacy was assessed as excellent or good for 100% of intraoperative ratings (17 CI, 44 BI, 61 total procedures), and 100% of postoperative ratings performed at time of discharge (18 CI, 44 BI, 62 total procedures). Median total consumption of rAHF-PFM during hospitalization was 822 IU/kg/surgery with CI and 910 IU/kg/surgery with BI. Overall rAHF-PFM was well tolerated, and FVIII inhibitors were not detected. In conclusion, rAHF-PFM administered via continuous infusion or bolus injections is safe, non-immunogenic, and effective for perioperative hemostatic management in previously treated haemophilia A patients.
Abstract 1416
A population pharmacokinetic (PK) model of a recombinant FVIII (rFVIII) was established on ADVATE® (Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method) studies in pediatric ...and adult patients with hemophilia A. The objective of this analysis was to evaluate the effect of reduced PK sampling time points on the estimated PK parameters in the population PK model.
Plasma FVIII activity PK data were collected for 3 ADVATE® clinical trials in previously treated patients: 184 full PK data sets (11 time points) for 100 adults/adolescents, aged 10 to 65 years, and from 52 reduced sample PK data sets (5 time points) for 52 children, aged 1 to 6 years. A population PK analysis was conducted on a two-compartment structure model and the covariate effect of age and weight was explored.
Four reduced sampling scenarios from the full 10 post-infusion sampling time points, were investigated: 1) Reduced to 4 (1 hr, 9 hr, 24 hr, and 48 hr), 2) Reduced to 3 (6 hr, 24 hr, and 48 hr), 3) Reduced to 2 (6 hr and 24 hr), and 4) Reduced to 1 sampling time points (24 hr post-infusion). After applying the reduced sampling on a random 10% of sampling set at a time in the population PK model, the differences in model estimates and individual PK estimates between full and reduced sampling, were evaluated.
The two-compartment population PK model adequately described the data. Clearance (CL) was significantly correlated with age and body weight and central volume of distribution was also related with body weight.
Absolute deviations (%) from the estimates using full PK sampling in the Individual PK estimates (CL, Vss, and Half-life) using each of the reduced sampling time points were showed in the below table.
Median Absolute Deviation % from Full SamplingReduced to 4Reduced to 3Reduced to 2Reduced to 1Clearance mL/(Kg*hr)2.793.153.065.34Volume dL/kg2.233.883.944.20Half-life hr2.673.754.034.43
It appears that PK parameters estimated using population PK model are robust to reduced sampling time points. Accurate measurement of PK on reduced samples gives patients and clinicians the opportunity to design treatment regimens that are better tailored to individuals.
Oh:Baxter: Employment. Björkman:Baxter: Consultancy; Octapharma: Consultancy. Schroth:Baxter: Employment. Fritsch:Baxter: Employment. Collins:NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fischer:Baxter: Consultancy; NovoNordisk: Consultancy. Blanchette:Bayer: Consultancy; Baxter: Research Support. Casey:Baxter: Employment. Spotts:Baxter: Employment. Ewenstein:Baxter Bioscience: Employment.
Hemophilia A is an X-linked bleeding disorder that results from insufficient levels of factor VIII (FVIII) coagulant activity.
To evaluate the efficacy and safety of ADVATE rAHF-PFM (Baxter ...Healthcare Corporation), a recombinant FVIII concentrate manufactured without human or bovine blood-derived additives, and to assess the effect of compliance with prophylactic use in preventing bleeding episodes (BEs).
Clinical data were integrated from six prospective studies. Two hundred thirty-four hemophilia A subjects (FVIII levels < or = 2%) (median age 14.7 (range: 0.02 - 72.7) years) were included.
BEs were managed with one or two infusions and nearly all (1953/1956) responded to treatment. Compliance with a prophylactic treatment regimen significantly reduced the incidence of BEs (p = 0.0061) and prevented non-traumatic joint BEs (median annualized BE rate was 0). One previously treated subject developed an inhibitor; no other safety concerns were observed.
These results reinforce the efficacy and safety of rAHF-PFM and suggest that compliance is an essential contributor to the effectiveness of prophylaxis in the treatment of hemophilia A.
Abstract 3492
Poster Board III-429
The objective of this analysis was to characterize the population pharmacokinetic (PK) model of ADVATE® (Antihemophilic Factor (Recombinant), Plasma/Albumin-Free ...Method) in hemophilia A patients. This included estimation of typical population pharmacokinetic parameters and inter-individual and residual variability and identification of covariates that are significant predictors of variability in a pooled population of children and adults.
Plasma FVIII activity PK data were collected for 3 ADVATE® clinical trials in previously treated patients: 184 full PK data sets for 100 adults/adolescents, aged 10 to 65 years, and from 52 reduced sample PK data sets for 52 children, aged 1 to 6 years. Population PK analysis was conducted using non-linear mixed effects modeling with the first-order integral approximation method in SAS® software (NLMIXED procedure). A two-compartment model was used as the base model and the influence of age and weight were explored.
Two-compartment PK models with additive plus proportional residual variability model and exponential inter-individual variability model adequately described the data. Clearance (CL) is significantly correlated with age and body weight and central volume of distribution (V1) is also related with body weight. The estimated population PK parameters were (mean parameter, (inter-individual variability %)): CL (2.92 mL/kg·h, 22%), V1 (0.46 dL/kg, 5.2%), peripheral volume V2 (0.09 dL/kg) and inter-compartmental clearance Q (2.07 mL/ kg·h).
A population PK model that describes the combined PK data from adults and pediatric studies has been constructed. A significant portion of inter-individual variability in both volume and clearance can be explained by subject weight. An additional smaller effect of age on clearance but not volume was observed. A population PK model for Factor VIII could provide the clinician with advantages in designing a patient specific treatment regimen. It could provide more relevant guidance in individual patient pharmacokinetics than just incremental recovery without the burden of a full PK assessment of the patient.
Oh:Baxter: Employment. Off Label Use: Prophylaxis is not indicated in the US. Björkman:Baxter: Consultancy; Octapharma: Consultancy. Schroth:Baxter: Employment. Fritsch:Baxter: Employment. Collins:Bayer: Consultancy; Novo Nordisk: Consultancy; Baxter: Consultancy. Fischer:Bayer: Consultancy; Wyeth: Consultancy; Baxter: Consultancy. Blanchette:Bayer: Consultancy; Baxter: Consultancy. Casey:Baxter: Employment. Spotts:Baxter: Employment. Ewenstein:Baxter: Employment.
We have previously shown that break-through bleeding in children with severe hemophilia A on prophylaxis is associated with time/week with FVIII less than 1IU/dL (P<0.0001) (Collins et al. JTH. ...2008;O-T-018). In clinical practice many clinicians use the trough FVIII to monitor prophylaxis. These parameters depend on dose and frequency of infused FVIII and the patient's FVIII recovery and elimination half-life (t½). To help guide prescription of prophylactic regimens in clinical practice we aimed to establish the relative importance of these variables on FVIII levels using results from 48 patients aged 1–6 yrs who had undergone a 48h, 50IU/kg pharmacokinetic (PK) study with Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (Advate). The median (5–95 percentile) recovery was 1.8 (1.4–2.8) IU/dL/IU/kg and t½ 9.4 (7.4–13.1) h. A standard prophylactic regimen (30IU/kg on alternate days) in an average patient (recovery 1.8, t ½ 9.4h) was considered baseline. Each variable was individually adjusted within the observed normal range or clinical practice whilst holding the other variables constant and the effect on trough level and time/week FVIII <1IU/dL was calculated (table).
VariableTrough (IU/dL)Time/wk <1IU/dL (h)t½ (hrs)7.4<117.59.41.6*0*13.14.40Recovery1.41.201.81.6*0*(IU/dL)/(IU/kg) Dose (IU/kg)2.82.50201.10301.6*0*502.70Frequency (days)Daily (15 IU/kg)4.80Alternate day (30 IU/kg)1.6*0*Every 3rdday (45<127.8
The in silico modelling showed that the standard regimen in the average patient resulted in a trough level of 1.6IU/dL and no time per week with FVIII <1 (* in table). In contrast, the commonly used regimen of 30IU/kg on Mon/Wed/Fri in the same patient would result in FVIII <1IU/dL for 17.4h on Sunday. The Friday dose would have to be increased to 108.5IU/kg to maintain a trough level above 1IU/dL. Dosing frequency and t½ both had large effects on trough FVIII level and time/week <1IU/dL. Recovery and dose had no effect on time/week with FVIII <1IU/dL and a relatively small effect on trough level. Patients on a standard regimen (30IU/kg alternate day), who have a recovery and t½ on the 5th percentile (1.4IU/dL/IU/kg and 7.4h, respectively), would have a trough level <1IU/dL for approximately 29h per week. In contrast, a patient at the 95th percentile for these parameters (2.8 IU/dL/IU/kg and 13.1h, respectively), would have a trough level of approximately 7IU/dL, spending no time below 1IU/dL. After a 30IU/kg infusion, variation in t½ from 5th to 95th percentile results in a 33h difference from 43 to 76h in time until FVIII falls below 1IU/dL. A similar variation in recovery leads to a 10h difference from 50 to 60h. Increasing the infused dose from 20–50IU/kg in the average patient results in an increase in time until FVIII falls below 1IU/dL of 12h from 50 to 62h. These data confirm that tailoring prophylaxis to bleeding patterns may be enhanced by knowledge of individual patients' PK. The use of standard 48h PK studies are not practical in clinical practice but techniques are available to estimate individual PK from sparse data that can be obtained in clinical practice. A population PK model under development is one method that will allow individual patient's PK to be calculated from 3–4 sample points and facilitate the measurement of PK in routine clinical practice. An algorithm based on PK and desired FVIII levels can be used to calculate individualised dosing schedules for patients. In conclusion, to maintain FVIII at a pre-determined level, the frequency of infusion and half life have a more pronounced affect than dose and recovery.
The utility of pharmacokinetic (PK) measurements in clinical hemophilia practice remains to be proven. To address this issue data from 152 patients with severe hemophilia A (FVIII <1%) from the ...ADVATE rAHF-PFM clinical trials were analyzed. Studies involved infusion of 50 IU/Kg rAHF-PFM and FVIII measurement pre-infusion and at 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32 and 48 hrs post-infusion in 100 patients aged ≥12 yrs, and at timepoints 1, 9, 24 and 48 hrs in 52 children ages 1–6 yrs. Data were analyzed by compartmental and non-compartmental methods. In the patients >12 yrs with more than one PK measurement, there was a low within patient variance in respect to between patient variance for clearance, MRT and AUC. This suggests that these parameters are more reliably measured for individual patients. Association of PK parameters with age and observed weight/ideal weight ratio was assessed using regression analysis. Median elimination t½ in patients was significantly shorter in children ages 1–6 yrs versus patients ≥ 12. Approximately 20% of this overall difference was due to fewer sampling timepoints in children but the remainder may reflect true biological differences; t½ increased by 0.41 h·y−1 (CI, 0.08–0.74) in children between 1–6 yrs and remained stable in older subjects. The relationship between PK parameters and age and ideal weight/weight ratio differed according to age table - signs represent the direction of the change (increase, +; decrease, −); numbers are the associated P values for regression on age and weight/ideal weight for each parameter. In children ages 1–6 yrs, both t½ and MRT of rAHF-PFM increased significantly with age. In subjects ≥ 12 years old, however, recovery, AUC/dose, rates of clearance and Vss increased significantly with both age and increasing weight/ideal weight. Differences noted in the PK parameters and age and body habitus in the two groups may reflect physical differences such as proportionately larger liver size and weight-adjusted plasma volume in children versus adults but may also reflect other yet undefined age-related biological differences. Initial analysis of bleed event data showed a different rate of bleeding on certain days of the week in children ages 1–6 but not in older subjects. Whether this is due to dosing practices, difference in PK or other factors is currently being investigated. These results have important implications for clinicians managing patients with hemophilia, and treatment regimens tailored to individual PK parameters are more likely to allow a more cost effective use of FVIII. In particular, dosing schedules based on the ratio of actual to ideal weight rather than weight appears to be appropriate. The implications of these PK findings on bleeding events whilst on prophylactic FVIII replacement therapy will be further analysed.
Age 1–6 (N=52)Age ≥ 12 (N=100)Pharmacokinetic ParameterAgeWeight/Ideal WeightAgeWeight/Ideal WeightRecovery− 0.60− 0.07+ 0.01+ <0.001AUC/d− 0.15− 0.50+ 0.0003+ 0.02Elimination t½+ 0.01− 0.50− 0.21− 0.97Clearance− 0.15− 0.52+ 0.0003+ 0.02MRT+ 0.003− 0.57− 0.07− 0.34Volume of distribution (Vss)− 0.25− 0.15+ 0.001+ <0.0001
To optimise bleeding control in severe haemophiliacs on prophylaxis, treatment should be individualised, considering patient-related and external determinants. Independent effects of both ...determinants were assessed using data from Advate pre-licensure trials. Data from 148 patients with FVIII<1% were analysed. All had a 48-hr PK study and were followed prospectively on prophylaxis. The 10–65y group was treated for 75 exposure days on fixed prophylaxis (25–40 IU/kg 3–4 times/wk), after which prophylaxis could be modified. Prophylaxis was not fixed for the 1-6y group. Bleeds defined as events requiring FVIII. Seasonal bleeding rate adjusted for age and time with FVIII activity <1%, as well as age and adherence to frequency of infusions, was analysed by multivariate regression with a negative binomial model. Median total annual bleed rates were 3.1, 3.3, and 2.1 for children, adolescents, and adults. 740 bleeds in 76 subjects (10–65y) on standard prophylaxis and 39 subjects (1–6y) on any prophylaxis were analysed (table). Median prophylactic dose varied with age (100 to 83 IU/kg/wk) with a mean of 2.8 infusions/wk. Adherence to prophylactic dose was high and did not differ among age groups. Adherence to frequency was lower in older patients (p < 0.004). Half-life was shorter and weekly time below 1% was highest in the 1–6y group. Bleeding rates on prophylaxis were low. Bleeding patterns and determinants varied according to age. Patients 1–6y had predominantly soft tissue bleeds. Bleeding was dependent on adherence to frequency of infusions or time below 1% FVIII. Bleeding was not dependent on season adjusted for either of these two factors. Patients aged 10–65y predominantly experienced joint bleeds. Bleeding was dependent on adherence to frequency of infusions or time below 1% FVIII. Bleeding adjusted for adherence to frequency of dose or time below 1% FVIII was different for season (p <0.0032). Bleeding rate appeared to be higher in the summer, lower in the winter, and most likely represents variation in physical activity during these times. Bleeding patterns vary according to age, even with prophylaxis. Breakthrough bleeding in patients aged 1–6y was dependent on time < 1% FVIII and adherence, but not season. The apparent effects of season, time below 1% FVIII activity, and adherence to frequency of infusions in patients 10–65y support the need for individual tailoring of prophylaxis according to activity and bleeding pattern (external factors) as well as the internal factor of pharmacokinetics.
1–6y10–17y18–65yN=39N=39N=37|---Median (P25, P75)---|Follow up (days)396 (269, 455)294 (265, 336)305 (268, 341)Adherence to prophylactic dose (% of infusions)100 (75,100)99 (81,100)99 (89,100)Adherence to frequency of prophylaxis (% of time)86 (70,98)78 (62,83)70 (50,87)FVIII half life (hrs)9.3 (8.0,10.7)10.4 (9.3,12.4)11.6 (10.4,13.6)Time below 1% FVIII (hrs/wk)29 (8,45)20 (9,30)12(6,26)Joint bleeds (%)0 (0,33)50 (14,88)72 (24,100)Bleeds in Jun–Aug (%)25 (0,44)29 (0,50)33 (8,55)
Commencement of prophylaxis at an early age for management of severe hemophilia A is widely recommended in order to prevent or minimize disabling arthropathy. Knowledge of the pharmacokinetics of ...replacement clotting factors is key to achieving optimal dosing regimens. However, the majority of pharmacokinetic studies on replacement FVIII have been conducted in older children and adults, and evidence on the pharmacokinetics of FVIII in pre-school children is primarily anecdotal. This study is the first to evaluate the pharmacokinetics of rFVIII in a large cohort of children < 6 y of age. The evaluation was part of an open-label, multicenter study of 53 subjects with FVIII ≤ 2% and ≥ 50 prior FVIII exposure days. The mean age of the cohort was 3.1 ± 1.5 y (range, 1.1–6.0 y). Standard pharmacokinetic parameters were assessed in accordance with the guidelines for pediatric patients of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. A single dose was infused of 50 IU/kg of a recently-developed recombinant FVIII product, ADVATE rAHF-PFM, a full-length FVIII concentrate prepared without the addition of human or animal plasma proteins. In an intent-to-treat analysis of results from 52 subjects, mean plasma half-life (t1/2) was 9.7 ± 1.9 h, the adjusted in vivo recovery (IVR) was 1.9 ± 0.4 IU/dL/IU/kg, and clearance was 0.04 ± 0.01 dL/kg•h. These data contrast with those of a recent study of rAHF-PFM in individuals with a median age of 18 (range, 10–65) in which the t1/2 was 12.0 ± 4.3 y and IVR was 2.4 ± 0.5 (Tarantino et al, Haemophilia, 2004, in press). No previous studies have examined whether pharmacokinetic changes in t1/2 and IVR related to age or weight occur in young pediatric patients. There was no significant correlation between IVR and age (r = −0.09, p = 0.54); however, there was a moderate correlation between IVR and body mass index (BMI) (r =.049; p < 0.001). There was also a weak correlation between t1/2 and age (r =0.34; p = 0.02). A significant inverse correlation was found between IVR and volume of distribution at steady state (Vss) (r = −0.82, p < 0.001). Subsequent assessment of the safety, efficacy and immunogenicity of rAHF-PFM is ongoing in these patients. In an interim analysis, after a total of 3,698 infusions, no inhibitors or other adverse events related to rAHF-PFM have been reported (median exposure days = 74). Of 210 bleeding episodes, 92.4% required ≤ 2 infusions. Median numbers of annual total bleeding episodes (joint + non-joint) for patients on either standard (n = 17) or modified (n = 25) prophylaxis or on-demand treatment (n = 4) were 2.85, 2.31, and 20.07, respectively. This study demonstrates for the first time in pre-school children and toddlers detectable correlations in the pharmacokinetics of rFVIII between age and t1/2, and between IVR and BMI, and that ADVATE rAHF-PFM is efficacious, well-tolerated and non-immunogenic in young children. Further research is required to define factors affecting inter-individual variation in t1/2 of rFVIII and the accelerated pharmacokinetics in children < 6 y old.
