Papers of the Week

Galcanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, was recently approved for migraine prophylaxis. The pharmacokinetic/pharmacodynamic (PK/PD) relationship between galcanezumab concentration and inhibition of capsaicin-induced dermal blood flow (CIDBF) was evaluated using first-in-human data following 6 single subcutaneous doses (1 to 600 mg) or multiple (4) 150-mg doses every 2 weeks in 7 cohorts (7 actively treated subjects and 2 placebo-treated healthy subjects). Galcanezumab pharmacokinetics were best described by a 1-compartment model with delayed first-order absorption/linear elimination. Apparent estimates (between-subject variability) of clearance, volume of distribution, absorption rate constant, and lag time were 0.0106 L/h (27%CV), 11.2 L (21%CV), 0.0192 h (89%CV), and 0.202 hours, respectively. Estimated elimination half-life was about 30 days. An effect compartment link model described the concentration-effect relationship; estimated maximum inhibitory effect was 70.5%, and 50% maximum inhibitory effect concentration (IC ) was 1060 ng/mL. Galcanezumab showed dose- and concentration-dependent potent and durable inhibition of CIDBF. Simulated effect compartment concentrations were maintained above IC after 12 weeks of dosing. Near-maximal CIDBF inhibition occurred with 150 mg biweekly for 12 weeks lasting ≥24 weeks or with ≥30 mg every 2 weeks or 195 mg every 13 weeks. Quantitative modeling of galcanezumab PK/PD supported dose selection for the phase 2 proof-of-concept study.