Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects

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Abstract

Purpose

Capsaicin-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.

Methods

Repeated 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.

Results

Two-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.

Conclusions

Our results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF.

Electronic supplementary material

The online version of this article (doi:10.1007/s11095-017-2183-6) contains supplementary material, which is available to authorized users.

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Most cited references 14

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Prevalence and burden of migraine in the United States: data from the American Migraine Study II.

R Lipton, W F Stewart, Herbert Diamond … (2015)

To describe the prevalence, sociodemographic profile, and the burden of migraine in the United States in 1999 and to compare results with the original American Migraine Study, a 1989 population-based study employing identical methods. A validated, self-administered questionnaire was mailed to a sample of 20 000 households in the United States. Each household member with severe headache was asked to respond to questions about symptoms, frequency, and severity of headaches and about headache-related disability. Diagnostic criteria for migraine were based on those of the International Headache Society. This report is restricted to individuals 12 years and older. Of the 43 527 age-eligible individuals, 29 727 responded to the questionnaire for a 68.3% response rate. The prevalence of migraine was 18.2% among females and 6.5% among males. Approximately 23% of households contained at least one member suffering from migraine. Migraine prevalence was higher in whites than in blacks and was inversely related to household income. Prevalence increased from aged 12 years to about aged 40 years and declined thereafter in both sexes. Fifty-three percent of respondents reported that their severe headaches caused substantial impairment in activities or required bed rest. Approximately 31% missed at least 1 day of work or school in the previous 3 months because of migraine; 51% reported that work or school productivity was reduced by at least 50%. Two methodologically identical national surveys in the United States conducted 10 years apart show that the prevalence and distribution of migraine have remained stable over the last decade. Migraine-associated disability remains substantial and pervasive. The number of migraineurs has increased from 23.6 million in 1989 to 27.9 million in 1999 commensurate with the growth of the population. Migraine is an important target for public health interventions because it is highly prevalent and disabling.

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Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial.

Jae Hong Sun, David W Dodick, Stephen D. Silberstein … (2016)

The calcitonin gene-related peptide (CGRP) pathway is a promising target for preventive therapies in patients with migraine. We assessed the safety and efficacy of AMG 334, a fully human monoclonal antibody against the CGRP receptor, for migraine prevention.

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Population pharmacokinetics of therapeutic monoclonal antibodies.

Bernd Meibohm, Kim Dirks (2010)

A growing number of population pharmacokinetic analyses of therapeutic monoclonal antibodies (mAbs) have been published in the scientific literature. The aims of this article are to summarize the findings from these studies and to relate the findings to the general pharmacokinetic and structural characteristics of therapeutic mAbs. A two-compartment model was used in the majority of the population analyses to describe the disposition of the mAb. Population estimates of the volumes of distribution in the central (V(1)) and peripheral (V(2)) compartments were typically small, with median (range) values of 3.1 (2.4-5.5) L and 2.8 (1.3-6.8) L, respectively. The estimated between-subject variability in the V(1) was usually moderate, with a median (range) coefficient of variation (CV) of 26% (12-84%). Between-subject variability in other distribution-related parameters such as the V(2) and intercompartmental clearance were often not estimated. Although the pharmacokinetic models used most frequently in the population analyses were models with linear clearance, other models with nonlinear, or parallel linear and nonlinear clearance pathways were also applied, as many therapeutic mAbs are eliminated via saturable target-mediated mechanisms. Population estimates of the maximum elimination rate (V(max)) and the mAb concentration at which elimination was at half maximum for Michaelis-Menten-type elimination pathways varied considerably among the different therapeutic mAbs. However, estimates of the total clearance (CL) of mAbs with linear clearance characteristics and of the clearance of mAbs via the linear clearance pathway (CL(L)) with parallel linear and nonlinear clearance were quite similar for the different mAbs and typically ranged from 0.2 to 0.5 L/day, which is relatively close to the estimated clearance of endogenous IgG of 0.21 L/day. The between-subject variability in the V(max), CL and CL(L) was moderate to high, with estimated CVs ranging from 15% to 65%. Measures of body size were the covariates most commonly identified as influencing the pharmacokinetics of therapeutic mAbs. In summary, many features of the population pharmacokinetics of currently used therapeutic mAbs are similar, despite differences in their pharmacological targets and studied patient populations.

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Author and article information

Contributors

Thuy Vu: (805) 447-4276 , thuy@amgen.com

Journal

Journal ID (nlm-ta): Pharm Res

Journal ID (iso-abbrev): Pharm. Res

Title: Pharmaceutical Research

Publisher: Springer US (New York )

ISSN (Print): 0724-8741

ISSN (Electronic): 1573-904X

Publication date (Electronic): 7 June 2017

Publication date PMC-release: 7 June 2017

Publication date (Print): 2017

Volume: 34

Issue: 9

Pages: 1784-1795

Affiliations

[1 ]Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California, 91320-1799 USA

[2 ]Clinical Pharmacology, GSK R&D, Shanghai, China

[3 ]Medivation, San Francisco, California, USA

[4 ]ISNI 0000 0004 0626 3338, GRID grid.410569.f, Center for Clinical Pharmacology, , University Hospitals of Leuven, ; Leuven, Belgium

[5 ]Global Biostatistical Sciences, Amgen Limited, Uxbridge, England UK

Article

Publisher ID: 2183

DOI: 10.1007/s11095-017-2183-6

PMC ID: 5533838

PubMed ID: 28593473

SO-VID: 9f87f49d-3e54-4d43-8002-05d4e356770f

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 6 January 2017

Date accepted : 15 May 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100002429, Amgen;

Custom metadata

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: anti-cgrp receptor,dermal blood flow,migraine,pharmacokinetics-pharmacodynamics,vasodilation

Data availability:

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: anti-cgrp receptor, dermal blood flow, migraine, pharmacokinetics-pharmacodynamics, vasodilation

Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects

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Abstract

Purpose

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Dermal Microdialysis in Pharmacokinetics

Most cited references 14

Prevalence and burden of migraine in the United States: data from the American Migraine Study II.

Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial.

Population pharmacokinetics of therapeutic monoclonal antibodies.

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