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

Jonathan Q Tran,1 Ahmed A Othman,2,3 Alvydas Mikulskis,4 Paul Wolstencroft,5 Jacob Elkins6 1Clinical Pharmacology, Biogen, Cambridge, MA, USA; 2Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA; 3Faculty of Pharmacy, Cairo University, Cairo, Egypt; 4Global Biomarker Disc...

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Autores principales:	Tran JQ, Othman AA, Mikulskis A, Wolstencroft P, Elkins J
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2016
Materias:	Pharmacokinetics daclizumab high-yield process multiple sclerosis Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/825bb9c9b25d4e2c8e4a5b15221ed180
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spelling	oai:doaj.org-article:825bb9c9b25d4e2c8e4a5b15221ed1802021-12-02T07:44:49ZPharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis1179-1438https://doaj.org/article/825bb9c9b25d4e2c8e4a5b15221ed1802016-02-01T00:00:00Zhttps://www.dovepress.com/pharmacokinetics-of-daclizumab-high-yield-process-with-repeated-admini-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438Jonathan Q Tran,1 Ahmed A Othman,2,3 Alvydas Mikulskis,4 Paul Wolstencroft,5 Jacob Elkins6 1Clinical Pharmacology, Biogen, Cambridge, MA, USA; 2Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA; 3Faculty of Pharmacy, Cairo University, Cairo, Egypt; 4Global Biomarker Discovery and Development, Cambridge, MA, USA; 5Global Clinical Operation, Biogen, Maidenhead, Berkshire, UK; 6Global Clinical Development, Biogen, Cambridge, MA, USA Background: Daclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the a 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. Objective: To 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). Methods: Twenty-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. Results: DAC 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. Conclusion: The 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. Keywords: pharmacokinetics, daclizumab high-yield process, multiple sclerosisTran JQOthman AAMikulskis AWolstencroft PElkins JDove Medical PressarticlePharmacokineticsdaclizumab high-yield processmultiple sclerosisTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol 2016, Iss Issue 1, Pp 9-13 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pharmacokinetics daclizumab high-yield process multiple sclerosis Therapeutics. Pharmacology RM1-950
spellingShingle	Pharmacokinetics daclizumab high-yield process multiple sclerosis Therapeutics. Pharmacology RM1-950 Tran JQ Othman AA Mikulskis A Wolstencroft P Elkins J Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis
description	Jonathan Q Tran,1 Ahmed A Othman,2,3 Alvydas Mikulskis,4 Paul Wolstencroft,5 Jacob Elkins6 1Clinical Pharmacology, Biogen, Cambridge, MA, USA; 2Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA; 3Faculty of Pharmacy, Cairo University, Cairo, Egypt; 4Global Biomarker Discovery and Development, Cambridge, MA, USA; 5Global Clinical Operation, Biogen, Maidenhead, Berkshire, UK; 6Global Clinical Development, Biogen, Cambridge, MA, USA Background: Daclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the a 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. Objective: To 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). Methods: Twenty-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. Results: DAC 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. Conclusion: The 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. Keywords: pharmacokinetics, daclizumab high-yield process, multiple sclerosis
format	article
author	Tran JQ Othman AA Mikulskis A Wolstencroft P Elkins J
author_facet	Tran JQ Othman AA Mikulskis A Wolstencroft P Elkins J
author_sort	Tran JQ
title	Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis
title_short	Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis
title_full	Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis
title_fullStr	Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis
title_full_unstemmed	Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis
title_sort	pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis
publisher	Dove Medical Press
publishDate	2016
url	https://doaj.org/article/825bb9c9b25d4e2c8e4a5b15221ed180
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Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis

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