Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis

Abstract

BackgroundDaclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the α subunit (CD25) of the high-affinity interleukin-2 receptor, has demonstrated efficacy for treatment of relapsing forms of multiple sclerosis in Phase II and III clinical trials.ObjectiveTo characterize the pharmacokinetics (PK) of DAC HYP following repeated administration of the 150 mg subcutaneous (SC) dose every 4 weeks (q4wk), the proposed clinical regimen in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsTwenty-six patients with RRMS received DAC HYP 150 mg SC q4wk for a total of six doses. Serial PK blood samples were collected over the first and last dosing intervals and trough PK samples were collected between these doses. Blood samples for immunogenicity assessment were collected throughout the study. Serum DAC HYP levels and anti-DAC HYP antibodies were characterized using validated immunoassays. PK parameters were estimated using noncompartmental analysis.ResultsDAC HYP showed slow SC absorption with a median time to reach maximum observed concentration (Cmax) value of ~1 week. Steady state was reached by the fourth injection. At steady state, DAC HYP mean serum Cmax, minimum observed concentration (Cmin), and area under the concentration–time curve within a dosing interval (AUCtau) values were 29.1 µg/mL, 14.9 µg/mL, and 638 µg · day/mL, respectively, with intersubject variability of 35%–40%. The AUC accumulation ratio was ~2.5 at steady state. DAC HYP had a long elimination half-life of ~22 days and low apparent clearance (0.274 L/day). Nine patients tested positive for anti-DAC HYP antibodies, with no impact on DAC HYP clearance in this limited data set.ConclusionThe PK of DAC HYP in patients with RRMS are consistent with those previously reported in healthy volunteers. The half-life of ~3 weeks and the low fluctuations in peak and trough concentrations of serum DAC HYP support the once-monthly SC dosing regimen.

Therapeutic protein–drug interaction assessment for daclizumab high‐yield process in patients with multiple sclerosis using a cocktail approach

“…Pre-dose serum DAC HYP concentrations. The mean (SD) predose serum concentration of DAC HYP at the third dose was 16.5 (8.46) μg ml À1 , which is consistent with the previously characterized mean steady-state trough concentration of 14.9 (6.33) μg ml À1 following repeated dosing of DAC HYP 150 mg SC in patients with multiple sclerosis [16].…”

Daclizumab high-yield process in the treatment of relapsing–remitting multiple sclerosis

“…As we currently understand the effects of DAC in MS, the blockage of CD25 results in several changes [Wiendl and Gross, 2013;Bielekova et al 2011 Pharmacokinetics DAC HYP has characteristics of a typical immunoglobulin G, subclass 1 (IgG1) monoclonal antibody with slow absorption, linear PK at doses above 100 mg administered subcutaneously, high bioavailability, small volume distribution and slow clearance. Baseline CD25 levels, age and sex did not influence DAC HYP PK, and variability related to body weight does not seem to be clinically relevant [Diao et al 2016;Tran et al 2016].…”

Daclizumab: Development, Clinical Trials, and Practical Aspects of Use in Multiple Sclerosis

“…It undergoes catabolism similar to that that of endogenous IgG proteins. Monthly (every 4 weeks) dosing resulted in achievement of steady state by the fourth dose [63]. Additionally, a larger study of 17,139 patients by Diao et al [64] demonstrated that the pharmacokinetics of DAC-β did not change with age, sex, or baseline T-cell (CD4+/CD25+) count.…”

“…The pharmacokinetics of DAC-β have been investigated in both healthy controls [62] and patients with MS, and were found to be similar in both populations [63,64]. DAC-β has a half-life of 21 days, and a median T max of 5 to 7 days.…”