Population pharmacokinetic and exposure-response analysis of eptinezumab in the treatment of episodic and chronic migraine

Abstract

Eptinezumab is a humanized mAb that targets calcitonin gene-related peptide and is under regulatory review for the prevention of episodic and chronic migraine (EM, CM). It is important to determine whether exposures achieved with intravenous (IV) administration of eptinezumab achieve desired pharmacologic effects. Population pharmacokinetics, including dose- and exposure-response analyses, were performed using patient-level data from the eptinezumab clinical trial program with IV doses ranging from 10 to 1000 mg in pharmacokinetic analyses or 10 to 300 mg in phase 2/3 clinical studies in patients with EM or CM. Exposure-response analysis explored the relationship between eptinezumab exposure metrics and efficacy parameters including monthly migraine days. The pharmacokinetic profile of eptinezumab was characterized by rapid attainment of maximum plasma concentration (ie, end of IV administration) and a terminal half-life of 27 days. Covariate analysis found that patient characteristics had no clinically significant effects on pharmacokinetic parameters and were insufficient to influence dosing. Dose- and exposure-response analyses found exposure with single doses ≥100 mg was associated with greater efficacy compared with doses ≤30 mg and a plateau of effect between 100 and 300 mg. A saturable inhibitory E_max model found the exposure over 12 weeks produced by single-dose eptinezumab 100 and 300 mg exceeded the exposure estimates required to achieve 90% of the maximal efficacy (EC₉₀ ). This pharmacokinetic analysis of eptinezumab supports dosing every 12 weeks with no adjustment for patient characteristics, including exposures associated with 100- or 300-mg doses producing optimal efficacy effects. The similar efficacy profiles support 100 mg as the lowest effective dose of eptinezumab.

Keywords: CGRP; calcitonin gene-related peptide; drug dose-response relationship; eptinezumab; intravenous administration; migraine disorders; monoclonal antibody; pharmacokinetics.

Figure 1

Overview of population pharmacokinetic (PK) model development of eptinezumab

Figure 2

Goodness‐of‐fit for final model of eptinezumab

Figure 3

Visual predictive check by study: (A) linear plots and (B) semi‐log plots

Figure 4

Geometric mean ratios (90% CI) for the effect of covariates on eptinezumab exposure at steady state (AUC_0‐τ). For the continuous covariates (baseline MMD [MDBASE], body weight and CL_{or_cap}) the minimum, 25th quantile, median, 75th quantile, and maximum values of the population are presented on the y‐axis. In addition, the typical body weight for an adult male (70 kg) was presented for the continuous covariate of body weight. On the right, the changes in exposure to eptinezumab are presented as median ratios and associated 95% confidence intervals. The dotted vertical line marks the AUC_0‐τ for a typical patient (healthy female subject, weight = 70 kg; CL_{or_cap} = 118 mL min⁻¹, baseline MMD of 13 days). The effects of “test” covariates are presented relative to the aforementioned reference AUC_0‐τ. AUC_0‐τ, area under concentration‐time curve during a dosing interval (12 weeks) at steady state; CL_{or_cap}, creatinine clearance capped at a physiological value of 150 mL min⁻¹; CM, chronic migraine; EM, episodic migraine; MMD, monthly migraine days

Figure 5

Overall dose‐response relationship (A) and dose‐response relationship by disease status (chronic migraine vs episodic migraine; B). The solid lines with gray shaded area are smooth (loess) regression and 95% confidence interval. CM, chronic migraine; EM, episodic migraine; MMD, monthly migraine days

Figure 6

Exposure‐response relationship over weeks 1‐12. The solid line with gray shaded area is smooth (loess) regression and 95% confidence interval. AUC_0‐12wk, area under the concentration‐time curve from time zero to 12 weeks; MMD, monthly migraine days

Figure 7

Exposure‐response relationship for secondary endpoints. (A) ≥75% migraine responder rate (weeks 1‐4) vs AUC_0‐4wk; (B) ≥75% migraine responder rate (weeks 1‐12) vs AUC_0‐12wk; and (C) ≥50% migraine responder rate (weeks 1‐12) vs AUC_0‐12wk. For each quartile of eptinezumab exposure: Range, the minimum and maximum values; N responder, total number of subjects with a response; Total N, total number of subjects in each quartile of eptinezumab exposure; Proportion, N responder/Total N For each quartile of eptinezumab exposure: the minimum and maximum values are presented next to the distribution of exposure for each quartile of eptinezumab exposure. (A) Slope [95% confidence interval]: 0.428 [0.28922, 0.56589], P < .0001. (B) Slope [95% confidence interval]: 0.35367 [0.22059, 0.48675]; P < .0001. (C) Slope [95% confidence interval]: 0.36708 [0.2429, 0.4912]; P < .0001