Dataset Information

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

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

SUBMITTER: Vu T

PROVIDER: S-EPMC5533838 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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

Vu Thuy T Ma Peiming P Chen Jiyun Sunny JS de Hoon Jan J Van Hecken Anne A Yan Lucy L Wu Liviawati Sutjandra LS Hamilton Lisa L Vargas Gabriel G

Pharmaceutical research 20170607 9

<h4>Purpose</h4>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.<h4>Methods</h4>Repeated capsaicin challenges and DBF measurements were performed and se ...[more]

PMID: 28593473

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Project description:Background and objectiveRosuvastatin and ezetimibe are commonly applied in lipid-lowering pharmacotherapy. However, the pharmacokinetic (PK) interaction was not clear by the coadministration of rosuvastatin and ezetimibe. This study investigated the pharmacodynamic (PD) and PK interactions between rosuvastatin and ezetimibe through a crossover clinical trial.Subjects and methodsA randomized, open-label, multiple-dose, two-treatment, two-period, two-sequence crossover study with two treatment parts was conducted in healthy male subjects. Study part A involved rosuvastatin, and study part B involved ezetimibe. A total of 25 subjects in both parts completed the PK and PD evaluations. Rosuvastatin (20 mg) or ezetimibe (10 mg) was administered once daily for 7 days as monotherapy or co-therapy. The plasma concentrations of rosuvastatin, total ezetimibe and free ezetimibe were measured for 72 h after day 7. Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) were investigated for the PD assessments on day 1 (pretreatment) and day 8.ResultsRosuvastatin and ezetimibe presented multiple peaks. The 90% confidence intervals (CIs) of the geometric mean ratios for the peak plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve during the dosing interval at steady state (AUCτ,ss) of rosuvastatin and total ezetimibe were within the range 0.8-1.25. However, the coadministration increased the systemic exposure of free ezetimibe. In the PD assessments, rosuvastatin and ezetimibe monotherapy reduced the LDL-C and TC levels effectively. In addition, the lipid-lowering effects of the coadministration corresponded to an approximate summation of the effects of rosuvastatin and ezetimibe monotherapy. However, no significant changes in HDL-C were observed with rosuvastatin or ezetimibe treatment. No significant safety issue was noted.ConclusionThe coadministration of rosuvastatin and ezetimibe revealed a bioequivalent PK interaction. Additional lipid-lowering effects, including decreased LDL-C and TC, were observed as expected in combination therapy without significant safety concern.

Dataset Information

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

Publications

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

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