• Thuy Vu, Peiming Ma, Jiyun Sunny Chen, Jan de Hoon, Anne Van Hecken, Lucy Yan, Liviawati Sutjandra Wu, Lisa Hamilton, and Gabriel Vargas.
• Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California, 91320-1799, USA. thuy@amgen.com.
• Pharm. Res. 2017 Sep 1; 34 (9): 1784-1795.

PurposeCapsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects.MethodsRepeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined. A population analysis was conducted using a nonlinear mixed-effects modeling approach. Effects of body weight, gender, and age on model parameters were evaluated.ResultsTwo-compartment target-mediated drug disposition (TMDD) model assuming binding of erenumab in the central compartment best described the nonlinear PK of erenumab. Subcutaneous absorption half-life was 1.6 days and bioavailability was 74%. Erenumab produced a maximum inhibition of 89% (95% confidence interval: 87-91%). Erenumab concentrations required for 50% and 99% of maximum inhibition were 255 ng/mL and 1134 ng/mL, respectively. Increased body weight was associated with increased erenumab clearance but had no effect on the inhibitory effect on CIDBF.ConclusionsOur results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF.

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