ABSTRACT
BACKGROUND: Routine prophylaxis with replacement factor VIII (FVIII) - the standard of care for severe hemophilia A - often requires frequent intravenous infusions (three or four times weekly). An FVIII molecule with an extended half-life could reduce infusion frequency. The A-LONG study established the safety, efficacy and prolonged pharmacokinetics of recombinant FVIII Fc fusion protein (rFVIIIFc) in previously treated adolescents and adults with severe hemophilia A. OBJECTIVE: In this post hoc analysis, we investigated the relationship between subjects' prestudy (FVIII) and on-study (rFVIIIFc) regimens. METHODS: We analyzed two subgroups of subjects: prior prophylaxis and on-study individualized prophylaxis (n = 80), and prior episodic treatment and on-study weekly prophylaxis (n = 16). Subjects' prestudy dosing regimens and bleeding rates were compared with their final rFVIIIFc regimens and annualized bleeding rates (ABRs) in the last 3 months on-study. Dosing regimen simulations based on population pharmacokinetics models for rFVIII and rFVIIIFc were performed. RESULTS: As compared with their prestudy regimen, 79 of 80 (98.8%) subjects on individualized rFVIIIFc prophylaxis decreased their infusion frequency. Overall ABRs were low, with comparable factor consumption. Longer dosing intervals, including 5-day dosing, were associated with higher baseline von Willebrand factor antigen levels. Simulated dosing regimens predicted a greater proportion of subjects with steady-state FVIII activity trough levels of ≥ 1 IU dL(-1) (1%) with rFVIIIFc than with equivalent rFVIII regimens. CONCLUSION: These results suggest that patients on rFVIIIFc prophylaxis can reduce their infusion frequency as compared with their prior FVIII regimen while maintaining low bleeding rates, affording more patients trough levels of ≥ 1 IU dL(-1) than with rFVIII products requiring more frequent dosing regimens.
Subject(s)
Coagulants/administration & dosage , Factor VIII/administration & dosage , Hemophilia A/drug therapy , Hemorrhage/prevention & control , Hemostasis/drug effects , Immunoglobulin Fc Fragments/administration & dosage , Recombinant Fusion Proteins/administration & dosage , von Willebrand Factor/metabolism , Adolescent , Adult , Biomarkers/blood , Coagulants/adverse effects , Coagulants/blood , Coagulants/pharmacokinetics , Computer Simulation , Drug Administration Schedule , Drug Monitoring , Factor VIII/adverse effects , Factor VIII/pharmacokinetics , Half-Life , Hemophilia A/blood , Hemophilia A/diagnosis , Hemorrhage/chemically induced , Humans , Immunoglobulin Fc Fragments/adverse effects , Immunoglobulin Fc Fragments/blood , Infusions, Intravenous , Male , Models, Biological , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/blood , Recombinant Fusion Proteins/pharmacokinetics , Severity of Illness Index , Time Factors , Treatment Outcome , Young AdultABSTRACT
AIM: This feasibility study explores relative myocardial perfusion characterization with an investigational T2/T2 contrast agent. METHODS: Dysprosium-DTPA bis (methylamide) was administered peripherally in six patients with thallium defects. Rest and stress multi-section, gated, T2-weighted images were acquired with a 1.5 T echo-planar imager. Change in transverse relaxation rate was calculated in four segments for each subject. RESULTS: Magnetic resonance (MR) identified five of five instances of ischemia or infarction, at a dose of agent (0.25 mmol/kg) that was comparable to that currently used with clinically approved gadolinium agents. Injection at twice this dose resulted in saturation of the signal change, and the one ischemic segment corresponding to the higher dose was not identified by MR. MR was negative in two segments which, on final diagnosis, were determined to manifest thallium attenuation artifact. CONCLUSION: MR perfusion imaging with high susceptibility agents has the potential to characterize myocardial perfusion deficits.
Subject(s)
Magnetic Resonance Imaging , Myocardial Infarction/diagnosis , Myocardial Ischemia/diagnosis , Adult , Aged , Artifacts , Contrast Media/administration & dosage , Dysprosium/administration & dosage , Feasibility Studies , Female , Humans , Image Enhancement , Male , Middle Aged , Pentetic Acid/administration & dosage , Sensitivity and SpecificityABSTRACT
The purpose of this study was to investigate the dependence of contrast-to-noise ratio (CNR) on the dose and rate of sprodiamide injection in magnetic resonance relative cerebral blood volume (rCBV) imaging. rCBV maps for 35 normal volunteers were constructed from dynamic MR image sets acquired with echo-planar spin-echo imaging after intravenous injection of sprodiamide. Doses of .1, .2, and .3 mmol/kg, at rates of 2 ml/second and 5 ml/second, were tested. CNRs and blood/volume ratios of gray to white matter were computed. CNR depended on dose (P < .0001) but was independent of injection rate (P < .69). rCBV ratios of gray to white matter were dose independent (P < .38) and rate independent (P < .97). The dependence of CNR on dose, but not injection rate, has practical implications in optimal protocol design. The independence of gray/white ratios supports the theory underlying the generation of rCBV maps.
