Pharmacology, Efficacy and Safety of a Triple-Secured Fibrinogen Concentrate in Children Less than or Equal to 12 Years with Afibrinogenaemia.

OBJECTIVE: To date, the use of a fibrinogen concentrate (FC) administered in children with inherited fibrinogen deficiency is poorly documented. Treatment modalities may differ from those of adults. The aim of this study was to investigate the pharmacokinetics (PK), efficacy (bleeding/surgery) and safety of a triple-secured FC (FibCLOT, LFB, France) in young patients aged of 12 years or less. METHODS: This was a prospective, non-comparative, multicentre, phase 2-3 study. Estimated PK parameters were based on population PK modelling. Target fibrinogen levels were 1.2 and 1.0 g/L for major and minor events, respectively. In vivo recovery (IVR) was calculated at study entry to tailor the dose. RESULTS: Sixteen afibrinogenaemia patients were treated with FC: 12 included in the PK study (6 aged ≤ 6 years and 6 aged 7-12 years). IVR at 1 hour post-infusion (geometric mean [coefficient of variation]) was 1.91 [20%] mg/dL per mg/kg and results were similar between the two age groups (1.87 [14%]) and (1.96 [27%]) with no statistical differences. Estimated half-life (t 1/2) was 49.0 hours [12%] with no observed differences between groups (46.6 hours [10%] and 51.6 hours [12%]). Overall efficacy was rated as excellent/good in 96.9% of 32 bleeds and in 100% of 11 surgeries. Most of the events (39/43, 90.7%) were managed with one infusion. There was no serious adverse drug reaction. CONCLUSION: Individually tailored dosing was efficacious in children who exhibited a lower IVR and shorter t 1/2 than those previously reported in adolescent and adult patients emphasising the importance of individualised dose optimisation.

Population pharmacokinetics of a triple-secured fibrinogen concentrate administered to afibrinogenaemic patients: Observed age- and body weight-related differences and consequences for dose adjustment in children.

AIMS: The pharmacokinetics (PK) of a triple-secured fibrinogen concentrate (FC) was assessed in patients ≥40 kg by noncompartmental analysis over a period of 14 days with multiple blood samples. Limited PK time point assessments in children lead to consideration of using Bayesian estimation for paediatric data. The objectives were (i) to define the population PK of FC in patients with afibrinogenaemia; (ii) to detect age- and body weight-related differences and consequences for dose adjustment. METHODS: A population PK model was built using plasma fibrinogen activity data collected in 31 patients aged 1 to 48 years who had participated in a single-dose PK study with FC 0.06 g kg-1 . RESULTS: A 1-compartment model with allometric scaling accounting for body weight was found to best describe the kinetics of FC. Addition of age and sex as covariates did not improve the model. Incremental in vivo recovery assessed at the end of infusion with the predicted maximal concentrations was lower, weight-adjusted clearance was higher, and fibrinogen elimination half-life was shorter in patients <40 kg than patients ≥40 kg. Interpatient variability was similar in both groups. CONCLUSION: Dosing in patients ≥40 kg based on the previous empirical finding using noncompartmental analysis where FC 1 g kg-1 raises the plasma fibrinogen activity by 23 g L-1 was confirmed. In patients <40 kg, (covering the age range from birth up to about 12 years old) FC 1 g kg-1 raises the plasma fibrinogen by 19 g L-1 . Dosing should be adapted accordingly unless therapy is individualized.

99mTc-besilesomab (Scintimun) in peripheral osteomyelitis: comparison with 99mTc-labelled white blood cells.

PURPOSE: The diagnosis of osteomyelitis is a challenge for diagnostic imaging. Nuclear medicine procedures including white blood cell imaging have been successfully used for the identification of bone infections. This multinational, phase III clinical study in 22 European centres was undertaken to compare anti-granulocyte imaging using the murine IgG antibody besilesomab (Scintimun) with (99m)Tc-labelled white blood cells in patients with peripheral osteomyelitis. METHODS: A total of 119 patients with suspected osteomyelitis of the peripheral skeleton received (99m)Tc-besilesomab and (99m)Tc-hexamethylpropyleneamine oxime (HMPAO)-labelled white blood cells (WBCs) in random order 2-4 days apart. Planar images were acquired at 4 and 24 h after injection. All scintigraphic images were interpreted in an off-site blinded read by three experienced physicians specialized in nuclear medicine, followed by a fourth blinded reader for adjudication. In addition, clinical follow-up information was collected and a final diagnosis was provided by the investigators and an independent truth panel. Safety data including levels of human anti-mouse antibodies (HAMA) and vital signs were recorded. RESULTS: The agreement in diagnosis across all three readers between Scintimun and (99m)Tc-HMPAO-labelled WBCs was 0.83 (lower limit of the 95% confidence interval 0.8). Using the final diagnosis of the local investigator as a reference, Scintimun had higher sensitivity than (99m)Tc-HMPAO-labelled WBCs (74.8 vs 59.0%) at slightly lower specificity (71.8 vs 79.5%, respectively). All parameters related to patient safety (laboratory data, vital signs) did not provide evidence of an elevated risk associated with the use of Scintimun except for two cases of transient hypotension. HAMA were detected in 16 of 116 patients after scan (13.8%). CONCLUSION: Scintimun imaging is accurate, efficacious and safe in the diagnosis of peripheral bone infections and provides comparable information to (99m)Tc-HMPAO-labelled WBCs.

Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases.

PURPOSE: (153)Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated. METHODS: Patients with hormone-refractory prostate cancer were treated with 18.5 MBq/kg (153)Sm-EDTMP in weeks 1 and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg zoledronic acid began in week 3 and continued every 4 weeks through week 23. In weeks 3 and 15, zoledronic acid was administered 2 days before (153)Sm-EDTMP treatment. Urine was collected 48 h after injection of (153)Sm-EDTMP, and whole-body images were obtained 6, 24 and 48 h post-injection. The effect of zoledronic acid on total bone uptake of (153)Sm-EDTMP was measured indirectly by the cumulative activity excreted in the urine in weeks 1, 3 and 15. Biodistribution, safety, tolerability and effect on prostate-specific antigen level were also studied. RESULTS: The urinary excretion in week 3 divided by the urinary excretion in week 1 (baseline) times 100% was mean 98.4 +/- 11.6% (median 96.2%). From week 1 to 15, after four zoledronic acid treatments, the mean ratio was 101.9 +/- 10.7% (median 101.8%). Bioequivalence could be concluded by using a two-sample t test for both per-protocol (n = 13) and full-analysis sets (n = 18). Toxicity was comparable to of monotherapy with (153)Sm-EDTMP. CONCLUSION: Zoledronic acid treatment does not influence (153)Sm-EDTMP skeletal uptake. Combined treatment is feasible and safe.