Population Pharmacokinetics of Daclizumab High-Yield Process in Healthy Volunteers: Integrated Analysis of Intravenous and Subcutaneous, Single- and Multiple-Dose Administration

作者：Othman Ahmed A^*; Tran Jonathan Q; Tang Meina T; Dutta Sandeep

来源：Clinical Pharmacokinetics, 2014, 53(10): 907-918.

DOI：10.1007/s40262-014-0159-9

Background and Objective Daclizumab is a humanized monoclonal antibody that blocks the alpha-subunit of the interleukin-2 receptor with demonstrated benefits in the treatment of multiple sclerosis. The present work aimed to characterize the pharmacokinetics of daclizumab high-yield process (HYP) in healthy volunteers. %26lt;br%26gt;Methods Three double-blind, randomized, placebo-controlled, phase I studies evaluated the pharmacokinetics of daclizumab HYP in healthy volunteers following single subcutaneous administration (50, 150, or 300 mg), multiple subcutaneous administrations (100 or 200 mg biweekly with a 200 mg loading dose), or single intravenous administration (200 or 400 mg). Measurable serum concentrations (n = 925) from 70 subjects treated with daclizumab HYP in the three studies were analyzed using non-linear mixed-effects modeling. %26lt;br%26gt;Results A two-compartment model with a first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Daclizumab HYP clearance, inter-compartmental clearance, and central and peripheral volumes of distribution were 10 mL/h, 44 mL/h, 3.89 L, and 2.52 L, respectively, scaled by [bodyweight (kg)/70] with 0.54 and 0.64 exponents for clearance and volume parameters, respectively. Lag-time, mean absorption time, and absolute bioavailability (100-300 mg) for subcutaneous administration were 2 h, 4.6 days, and 84 %, respectively. Bodyweight explained only similar to 20 % of daclizumab HYP pharmacokinetic variability. With this limited dataset, sex, age, race, or presence of antibodies did not correlate with daclizumab HYP clearance. The estimated effective half-life was 21-25 days. The developed model was robust in bootstrap evaluation and predicted the data adequately in stochastic simulations. %26lt;br%26gt;Conclusions Daclizumab HYP is characterized by slow clearance, linear pharmacokinetics (at doses %26gt;= 100 mg), high subcutaneous bioavailability, and a half-life suitable for monthly administration.

• 出版日期2014-10
• 单位Biogen Idec