Population Pharmacokinetics of Galcanezumab, an Anti-CGRP Antibody, Following Subcutaneous Dosing to Healthy Individuals and Patients With Migraine
William Kielbasa, Tonya Quinlan, William Kielbasa, Tonya Quinlan
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
References
- Benschop RJ, Collins EC, Darling RJ, et al. Development of a novel antibody to calcitonin gene‐related peptide for the treatment of osteoarthritis‐related pain. Osteoarthritis Cartilage. 2014;22(4):578‐585.
- Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine: the randomized, double‐blind, placebo‐controlled REGAIN study. Neurology. 2018;91(24):e2211‐e2221.
- Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE‐2 phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442‐1454.
- Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE‐1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080‐1088.
- Stauffer VL, Sides R, Lanteri‐Minet M, et al. Comparison between prefilled syringe and autoinjector devices on patient‐reported experiences and pharmacokinetics in galcanezumab studies. Patient Prefer Adherence. 2018;12:1785‐1795.
- Skljarevski V, Oakes TM, Zhang Q, et al. Effect of different doses of galcanezumab vs placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol. 2018;75(2):187‐193.
- Monteith D, Collins EC, Vandermeulen C, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the CGRP binding monoclonal antibody LY2951742 (galcanezumab) in healthy volunteers. Front Pharmacol. 2017;8:740.
- Kielbasa W, Williams DW, Coutant DE, King A, Ayan‐Oshodi MA. Tolerability, Pharmacokinetics, and Pharmacodynamics of Galcanezumab in Healthy Subjects Following a Subcutaneous Administration of a Lyophilized Formulation or a Solution Formulation. 59th Annual Scientific Meeting of the American Headache Society; June 8‐11, 2017. Boston, MA.
- Nakano M, Uenaka K, Kielbasa W, Matsuyama Y, Ayan‐Oshodi MA. Safety, tolerability, pharmacokinetics, and pharmacodynamics of galcanezumab, a monoclonal antibody to calcitonin gene‐related peptide, in healthy Japanese and Caucasian subjects. Rinshο yakuri/Jpn J Clin Pharmacol Ther. 2017;48(4):131‐139.
- Kielbasa W, Helton D. A new era for migraine: pharmacokinetic and pharmacodynamic insights into monoclonal antibodies with a focus on galcanezumab, an anti‐CGRP antibody. Cephalalgia. 2019;39(10):1284‐1297.
- Oakes TMM, Skljarevski V, Zhang Q, et al. Safety of galcanezumab in patients with episodic migraine: a randomized placebo‐controlled dose‐ranging phase 2b study. Cephalalgia. 2018;38(6):1015‐1025.
- Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction‐corrected visual predictive checks for diagnosing nonlinear mixed‐effects models. AAPS J. 2011;13(2):143‐151.
- Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004;93(11):2645‐2668.
- Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548‐558.
- Emgality (package insert) . Indianapolis, IN: Eli Lilly and Company; 2018.
- Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010;2(3):256‐265.
- Martinez JM, Garce S, Anglin G, et al. Immunogenicity findings from phase 3 galcanezumab trials in patients with episodic or chronic migraine. 12th European Headache Federation Congress jointly with 32nd National Congress of the Italian Society for the Study of Headaches [P25]. J Headache Pain. 2018;19(suppl 1):80.
- Meibohm B, Zhou H. Characterizing the impact of renal impairment on the clinical pharmacology of biologics. J Clin Pharmacol. 2012;52(1 Suppl):54S‐62S.
- Mould DR, Meibohm B. Drug development of therapeutic monoclonal antibodies. BioDrugs. 2016;30(4):275‐293.
- Roberts BV, Susano I, Gipson DS, Trachtman H, Joy MS. Contribution of renal and non‐renal clearance on increased total clearance of adalimumab in glomerular disease. J Clin Pharmacol. 2013;53(9):919‐924.
- Struemper H, Chen C, Cai W. Population pharmacokinetics of belimumab following intravenous administration in patients with systemic lupus erythematosus. J Clin Pharmacol. 2013;53(7):711‐720.
Source: PubMed