Intact natalizumab pharmacokinetics is impacted by endogenous IgG4 concentration.

BACKGROUND: Natalizumab (NAT) pharmacokinetics and pharmacodynamics are complicated by arm exchange with endogenous IgG4, resulting in a mixture of a more potent intact, bivalent form and a less potent, functionally monovalent form. Total NAT and endogenous IgG4 concentrations vary considerably across patients. This study assessed the concentration of intact NAT, and how it relates to total NAT and endogenous IgG4 levels in blood and saliva. METHODS: Paired serum and saliva samples from a small cohort of relapsing-remitting multiple sclerosis patients were measured for levels of intact NAT, total NAT, IgG and IgG4. RESULTS: Intact NAT concentration was dependent on both total NAT and endogenous IgG4 levels. Low endogenous IgG4 led to a higher ratio of intact NAT to total NAT, while the opposite was observed in subjects with high endogenous IgG4. Serum and saliva measurements show good concordance. CONCLUSIONS: Intact NAT concentration is influenced by both NAT pharmacokinetics and endogenous IgG4 levels. Patients with low IgG4 levels can have high concentrations of intact NAT even with lower levels of total NAT, which may explain cases of NAT-associated progressive multifocal leukoencephalopathy (PML) in such patients. Monitoring both forms of NAT could better guide dosing, maximizing drug efficacy and safety.

Pharmacodynamics of natalizumab extended interval dosing in MS.

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.

Evaluation of natalizumab pharmacokinetics and pharmacodynamics with standard and extended interval dosing.

BACKGOUND: Natalizumab (NTZ) is a highly efficacious therapeutic for multiple sclerosis (MS), but treatment is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Extended interval dosing (EID) of NTZ has been proposed as an alternative dosing strategy to reduce PML risk. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles of standard interval dosing (SID) and EID under real-world circumstances remain poorly characterized. OBJECTIVE: To evaluate PK and PD parameters of NTZ for SID and EID in the context of patient and treatment characteristics. METHODS: An observational cohort study was conducted to measure NTZ serum concentrations in MS patients at SID and EID nadir timepoints. NTZ occupancy of α4-integrin receptor sites, and cell surface expression of α4-integrin, was also measured. Patient body weight, age, and treatment exposure metrics were collected. RESULTS: NTZ serum concentrations were lower for EID than SID (mean = 18.2 versus 35.7 µg/ml, respectively; p < 0.001). Patient body weight, age, and treatment duration impacted concentrations with SID, though their influences were reduced or absent with EID. α4-integrin receptor occupancy by NTZ was lower for EID than SID (mean = 78.2 versus 87.4%, respectively; p < 0.001). Body weight impacted α4-integrin receptor occupancy differentially for EID versus SID. α4-integrin cell surface expression was modestly higher for EID than SID (267.2 versus 238.1 MFI, respectively; p < 0.001). CONCLUSIONS: EID of NTZ reduces nadir serum drug levels and α4-integrin receptor occupancy, as well as increases α4-integrin cell surface expression. The resulting increase in the number of open α4-intregrin receptors may enhance immune surveillance of JCV and prevention of PML. Body weight plays a significant role in the pharmacokinetic and pharmacodynamic responses to NTZ treatment. Further research is warranted to help establish pharmacological thresholds of NTZ efficacy and safety, which could help guide decision-making for dosing of NTZ.