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

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

Percentage change from baseline in absolute lymphocyte counts at day 28 following treatment with CDP323 for 28 days (per protocol population).

a<p>n<i> = </i>14 per group except for CD34+ cells, where n = 5 for placebo and CDP323 1000 mg bid and n = 4 for CDP323 100 mg bid, CDP323 500 mg bid, and CDP323 1000 mg qd.</p>b<p>Least squares mean from analysis of variance (ANOVA).</p>c<p>Statistical comparisons were made using univariate ANOVA.</p><p>bid = twice daily; CI = confidence interval; NK = natural killer; NR = not reported (linear trend test for dose-response relationship was not statistically significant); qd = once daily.</p><p>Note: For all lymphocyte types, differences between the 500-mg bid and 1000-mg qd dosages were not statistically significant and are not displayed in this table.</p

Summary of adverse events reported by ≥2 subjects in any treatment group (safety population).

<p>AE = adverse event; bid = twice daily; qd = once daily.</p

Geometric mean time profile for total lymphocyte count by administered treatment (per protocol population).

<p>bid = twice daily; qd = once daily.</p

Summary statistics on absolute counts of lymphocytes subsets at baseline, day 1, and day 28 after treatment.

a<p>Mean value over 24 hours.</p><p>bid = twice a day; NK = natural killer; qd = once daily; SD = standard deviation.</p

Subject baseline characteristics.

a<p>Determined by Cockroft formula: males = [(140 − age)×body weight]/[72×serum creatinine (mg/dL)]; females = [(140 − age)×body weight]/[72×serum creatinine (mg/dL)]×0.85.</p>b<p>Although 12 subjects had not experienced a relapse in the previous 12 months (4 in the 1000-mg bid group, 3 in each of the 100-mg bid and 500-mg bid groups, and 1 in each of the 1000-mg qd and placebo groups), they all fulfilled the inclusion criteria of having had at least one relapse in the previous 24 months.</p><p>bid = twice daily; BMI = body mass index; EDSS = Expanded Disability Status Scale; qd = once daily; SD = standard deviation.</p