OBJECTIVE: Multifocal motor neuropathy is a rare chronic immune-mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose-exposure-response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure. METHODS: Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double-blind, placebo-controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic-pharmacodynamic model. RESULTS: The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter-patient variabilities in multifocal motor neuropathy. Model-based simulations for various dosing regimens (0.4-2.0 g/kg every 2-4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength. INTERPRETATION: These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose-splitting provided similar outcomes while offering flexibility and convenience.

INTRODUCTION: Intravenous immunoglobulin (IVIG) is the only approved treatment for multifocal motor neuropathy (MMN), a rare, chronic, immune-mediated demyelinating neuropathy. There is a significant gap in understanding of the role of serum immunoglobulin G (IgG) levels in the efficacy of IVIG in affected patients. We aimed to characterize the interplay between dose and exposure of IVIG and the effects of patient factors on individual variabilities. METHODS: Serum IgG trough concentration data from a phase 3, randomized, double-blind, placebo-controlled, crossover trial of IVIG 10% in 44 patients with MMN (NCT00666263) were analyzed using fit-for-purpose population PK modeling. Patient factors were tested as covariates, and IgG PK profiles following various dosing regimens were simulated. RESULTS: Serum IgG levels, with significant inter-patient variability, correlated with dose and treatment interruptions at the individual patient level. Simulated data for various dosing regimens (0.4-2 g/kg once every 1-4 weeks [Q1-4W]) revealed that more frequent dosing provided more stable IgG levels than less frequent dosing, and dose splitting over multiple days had no significant effects on PK. DISCUSSION: In patients with MMN, stable dosing and consistent serum IgG levels are crucial to avoid negative responses owing to treatment interruptions. Dosing intervals more frequent than Q4W may alleviate periodic symptom deterioration. Dose splitting potentially offers flexibility for patients requiring large volumes of IVIG without negatively affecting serum IgG PK, while maintaining treatment efficacy. Variability in serum IgG levels between patients suggests that individualizing IVIG treatment regimens and target IgG levels may play a key role in managing MMN.