Population Pharmacokinetics of Galcanezumab, an Anti-CGRP Antibody, Following Subcutaneous Dosing to Healthy Individuals and Patients With Migraine

Abstract

Galcanezumab is a humanized immunoglobulin G (IgG) monoclonal antibody (mAb) indicated for the prevention of migraine that binds to calcitonin gene-related peptide. A population pharmacokinetic (PK) analysis was performed to characterize galcanezumab PK using data pooled from 7 clinical studies. Clinical studies included healthy individuals and patients with episodic or chronic migraine who were administered between 5 and 300 mg galcanezumab. The PK data were analyzed using nonlinear mixed-effects modeling. Galcanezumab concentration-time data were described with a 1-compartment model with first-order absorption following subcutaneous administration and linear elimination. At the median body weight of 74 kg, the estimated population apparent clearance (CL/F) was 0.00785 L/h (34% IIV), the apparent volume of distribution was 7.33 L (34% IIV), and half-life was 27 days. Patient body weight was found to have a modest effect of CL/F, with median galcanezumab concentrations being lower in the heaviest patients compared to the lightest patients, but this outcome was determined not to be clinically relevant in the context of model-estimated random variability. Dosing adjusted for body weight is not warranted in adults. Age, sex, race/ethnicity, immunogenicity, renal/hepatic markers, and injection-site location did not affect galcanezumab PK. In conclusion, galcanezumab exhibits PK parameters typical for an IgG mAb administered subcutaneously. The population PK model developed in this study demonstrates that galcanezumab exhibits linear PK that was not influenced in a clinically relevant manner by the patient factors evaluated.

Trial registration: ClinicalTrials.gov NCT02104765 NCT02576951 NCT02163993 NCT02614196 NCT02614261 NCT02614183 NCT02614287.

Keywords: calcitonin gene-related peptide; galcanezumab; migraine; pharmacokinetics.

Conflict of interest statement

W.K. and T.Q. are employees and stockholders of Eli Lilly and Company.

© 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Goodness‐of‐fit plots for the final pharmacokinetic model. Locally weighted scatterplot smoothing fit, a smoothed value given by a weighted linear least squares regression over the span of observations, for data presented (solid line) in addition to a line of unity (dashed line).

Figure 2

Prediction‐corrected visual predictive check (top panel) and external validation (bottom panel) for the final pharmacokinetic model.

Figure 3

Galcanezumab PK profiles after a dosage regimen of 120 mg monthly and 240‐mg loading dose followed by 120 mg monthly. LD indicates loading dose; QM, monthly; PK, pharmacokinetic.

Figure 4

Relationship of galcanezumab CL/F and body weight (top panel) and galcanezumab concentration‐time profiles at the 5th and 95th percentiles of body weight at a dosage regimen of 240‐mg loading dose followed by 120 mg monthly (bottom panel). In the top panel, dashed horizontal lines represent the 5th (52 kg), 50th (73 kg), and 95th (105 kg) percentiles of body weight, and the solid line represents a locally weighted scatterplot smoothing fit and and circles represent individual subject data points. In the bottom panel, the solid line denotes the median responses, and the hatched and shaded areas denote the 90% prediction interval.

Figure 5

Galcanezumab apparent clearance in patients based on antidrug antibody status (top) and titer (bottom). The middle line in each box plot represents the median; the top and bottom margins of the box represent the 75th and 25th percentiles; the whiskers extend to the 95th and 5th percentiles; data points outside the whiskers represent the points beyond the percentiles. N, number of patients; n, number of PK observations; TE ADA, treatment emergent anti‐drug antibody.

Figure 6

Galcanezumab pharmacokinetic parameters contrasted by injection site location based in population pharmacokinetic analysis. Upper panel: absorption rate constant (Ka). Middle panel: Apparent clearance (CL). Lower panel: Apparent volume of distribution (V). Abdomen (N = 762); arm (N = 949); buttocks (N = 72); thigh (N = 107). The middle line in each box plot represents the median; the top and bottom margins of the box represent the 75th and 25th percentiles; the whiskers extend to the 95th and 5th percentiles.