A Randomized Trial Evaluating Various Administration Routes of Natalizumab in Multiple Sclerosis

Abstract

The study's primary objective was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of single subcutaneous (SC) or intramuscular (IM) 300-mg doses of natalizumab with IV 300-mg doses of natalizumab in patients with multiple sclerosis (MS). Secondary objectives included investigation of the safety, tolerability, and immunogenicity of repeated SC and IM natalizumab doses. DELIVER was a 32-week, open-label, multicenter study of natalizumab-naive patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) randomized to receive 300 mg natalizumab by SC injection, IM injection, or IV infusion. PK and PD were evaluated over 8 weeks after the first natalizumab treatment (Part 1) and over 24 weeks with repeated dosing every 4 weeks, beginning at week 8 (Part 2). Seventy-six patients (24 with RRMS and 52 with SPMS) were enrolled in DELIVER. Following SC or IM administration of natalizumab, peak serum concentrations were approximately 40% of those observed with IV administration and showed no major differences in elimination characteristics. Mean bioavailability relative to IV administration was 57.1% to 71.3% with SC administration and 48.7% with IM administration; mean trough serum concentrations were similar with SC or IV administration and lower with IM administration. Following single or multiple doses of natalizumab, PD response was comparable across administration routes and disease stages. No meaningful differences were observed across administration groups in the incidence or nature of overall adverse events, serious adverse events, administration site reactions, hypersensitivity reactions, or antinatalizumab antibodies. These findings support the comparability of PD measures of natalizumab administered IV, SC, or IM.

Population Pharmacokinetics and Target Engagement of Natalizumab in Patients With Multiple Sclerosis

“…With respect to alpha‐4 integrin binding following subcutaneous administration, maximum saturation was attained within a day of dosing, although peak natalizumab concentrations occur approximately 7 days postdose . The rapid onset in the alpha‐4 integrin saturation following subcutaneous administration may be related to natalizumab absorption from subcutaneous sites or to saturation achieved with lower than peak concentrations.…”

“…With respect to alpha-4 integrin binding following subcutaneous administration, maximum saturation was attained within a day of dosing, although peak natalizumab concentrations occur approximately 7 days postdose. 11 The rapid onset in the alpha-4 integrin saturation following subcutaneous administration may be related to natalizumab absorption from subcutaneous sites or to saturation achieved with lower than peak concentrations. As mononuclear leukocytes are transported through the lymphatic system as well as the blood system, it appears probable that natalizumab is absorbed relatively rapidly into the lymphatic space following subcutaneous injection, where it can bind to its target even as blood natalizumab concentrations are still rising.…”

“…As part of the postapproval strategy, an alternate route of administration, namely, subcutaneous administration and extended interval dosing, was explored in MS subjects. Toward this commitment, 2 additional studies were conducted: (1) a pilot study evaluating the PK‐PD of single and multiple (once‐every‐4‐week) 300‐mg subcutaneous or intravenous administrations and (2) a multiple‐dose efficacy study testing 150 or 300 mg intravenously or subcutaneously given once every 4 or 12 weeks in MS subjects…”

“…9,10 As part of the postapproval strategy, an alternate route of administration, namely, subcutaneous administration and extended interval dosing, was explored in MS subjects. Toward this commitment, 2 additional studies were conducted: (1) a pilot study evaluating the PK-PD of single and multiple (onceevery-4-week) 300-mg subcutaneous or intravenous administrations 11 and (2) a multiple-dose efficacy study testing 150 or 300 mg intravenously or subcutaneously given once every 4 or 12 weeks in MS subjects. 12 In this article, we have combined the natalizumab PK-PD data from 11 clinical studies (1 phase 1, 1 phase 2, 3 phase 3, 2 bridging bioequivalence, and 4 postmarketing clinical studies) to perform a comprehensive population PK-PD (popPK-PD) analysis that (1) characterizes natalizumab PK after intravenous and subcutaneous administration, (2) describes the natalizumab PK-PD relationship, and (3) quantifies the impact of covariates that may contribute to differences in natalizumab PK and alpha-4 integrin saturation dynamics.…”

Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review

“…3). Anxiety and panic attacks were reported in three RCTs, with IPs ranging from 0 to 1.5% (Biogen, 2011(Biogen, , 2012bPlavina et al, 2016), and RDs (95%CI) ranging from −7.7% (−16.1%, 5.6%) to 1.5% (−51.5%, 4.3%). Other APE included one suicide attempt (IP 1.5%) (Plavina et al, 2016), bipolar disorder (IP 0.35%) (Biogen, 2014a), and schizophrenia (IP 1.0%) (Biogen, 2014a).…”