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. 2020 Feb 4;7(2):e672.
doi: 10.1212/NXI.0000000000000672. Print 2020 Mar.

Pharmacodynamics of natalizumab extended interval dosing in MS

Lana Zhovtis Ryerson  1 , Xiaochun Li  2 , Judith D Goldberg  2 , Tamara Hoyt  2 , Angel Christensen  2 , Ryan R Metzger  2 , Ilya Kister  2 , John Foley  2
Affiliations

Pharmacodynamics of natalizumab extended interval dosing in MS

Lana Zhovtis Ryerson et al. Neurol Neuroimmunol Neuroinflamm. .

Abstract

Objective: To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ.

Methods: In a cross-sectional assessment of patients with multiple sclerosis (MS) who received standard interval dosing (every 4 weeks) or EID, serum NTZ concentrations were measured using ELISA, and α4-integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints.

Results: Trough serum concentration was above the "therapeutic" concentration of 2.0 μg/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ.

Conclusions: Trough α4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up.

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Figures

Figure 1
Figure 1. Concentration and saturation in patients on SID and EID schedules
Distribution of (A) serum CONC (μg/mL) and (B) α4-integrin SAT (%) at dosing trough in patients on EID and SID. (C) CONC vs BMI (EID group equation: 26.0 − 0.58 * BMI; SID equation: 63.2 − 1.20 * BMI); (D) SAT vs BMI (EID group equation: 130.5 − 2.47 * BMI; SID equation: 93.2 − 0.20 * BMI) in SID and EID patients. BMI = body mass index; CONC = concentration; EID = extended interval dosing; SAT = saturation; SID = standard interval dosing.
Figure 2
Figure 2. Modeling of minimum frequency of infusions per year
(A) Polynomial regression of log of concentration vs NI. (B) Polynomial regression of log of saturation vs NI. NI = number of infusions/year.
See this image and copyright information in PMC

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