Population pharmacokinetics of a new long-acting recombinant coagulation factor IX albumin fusion protein for patients with severe hemophilia B

Essentials The new recombinant factor IX (FIX) albumin fusion protein (rIX-FP) has a prolonged half-life. A population pharmacokinetic (PK) model was based on FIX activity levels of hemophilia B patients. The model was used to simulate different dosing scenarios of rIX-FP to help guide dosing. The population PK model supported prolonged dosing of rIX-FP with intervals of up to 2 weeks. Click to hear Prof.Makris's presentation on new treatments in hemophilia SUMMARY: Background The recombinant fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP; Idelvion® ) exhibits a longer half-life than plasma-derived factor IX (FIX) and the commercially available recombinant FIX products. Objectives (i) Characterize the population pharmacokinetics (PK) of rIX-FP in hemophilia B patients, (ii) identify covariates that are potential determinants of rIX-FP PK variability and (iii) simulate different dosing scenarios of rIX-FP following single and steady-state dosing. Patients/Methods A population PK model was developed based on FIX activity levels of 104 patients who had received treatment with rIX-FP. Patients were aged 1-65 years with FIX activity ≤ 2 IU dL-1 . PK sampling was performed for up to 14 days (336 h). Results Simulation of a single intravenous infusion of rIX-FP (25-75 IU kg-1 ) predicted that the median trough exogenous FIX activity levels would remain > 5 IU dL-1 for up to 16 days in adolescents/adults aged ≥ 12 years, up to 12 days in children aged 6 to 5 IU dL-1 for the duration of the dosing interval for the 25, 35 and 40 IU kg-1 weekly regimens and for 75 IU kg-1 every 14 days in adolescents/adults, and for the 35 and 40 IU kg-1 weekly regimens in children. Conclusion The population PK model developed here correlates well with observed clinical data and supports prolonged dosing of rIX-FP with intervals of up to 2 weeks

Simple microscale high-performance liquid chromatographic method for determination of furosemide in neonatal plasma

A simple microscale high-performance liquid chromatographic method using fluorescence detection for the quantitation of furosemide in neonatal plasma is described. Sample pre-treatment involved protein precipitation of 25 μl of plasma with 100 μl of acetonitrile. The mobile phase consisted of acetonitrile (460 ml) and 0.08 M orthophosphoric acid (540 ml) and was delivered at 1.1 ml/min. Calibration curves were linear from 0.1 to 25 μg/ml. Within-day and between-day imprecision (coefficient of variation) was 3.9-6.1, and 6.1-12.2%, respectively. Furosemide was eluted after 6.5 min and naproxen (internal standard) after 11.5 min. The assay was validated for application in neonatal plasma containing a wide range of albumin concentrations

Gentamicin dosing in elderly patients based on bioelectrical impedance analysis

The relationship between gentamicin pharmacokinetics and measures of bioelectrical impedance (BI) in elderly patients was investigated with the aim of developing a potential noninvasive means of individualising gentamicin dosage. Linear regression analyses identified height/resistance2 as a statistically significant predictor of gentamicin distribution volume, V, [adjusted (adj)r2 = 0.53, coefficient of variation (CV) = 15.2%], and resistance/reactance and creatinine clearance (CL(cr)) as predictors of total systemic clearance, CL, adj r2 = 0.52, CV = 20.1%. Individualisation of gentamicin dosage regimens based on these relationships to achieve steady-state (SS), peak gentamicin concentrations, C(ss,max), and SS trough concentrations, C(ss,min), of 7.0 and 1.0 mug/ml, respectively, in an independent group of elderly patients resulted in serum gentamicin levels of 5.9 +/- 0.7 and 0.8 +/- 0.4 mug/ml. Mean absolute prediction errors averaged 0.7 +/- 0.5 mug/ml for C(ss,max) and 0.5 +/- 0.3 mug/ml for C(ss,min) Measures of BI provided the best predictions of C(ss,max), whereas models based on CL(cr) alone were the best predictors of C(ss,min). This technique provides a means of complementing routine pharmacokinetic monitoring of gentamicin pharmacotherapy in the elderly hospitalised patient with reductions in patient discomfort and potential savings in time and cost. invasive