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

In the setting of breast cancer screening, 5-9% of needle core biopsies are diagnosed as lesions of uncertain malignant potential (B3). The management of these lesions is potentially problematic as the data on their outcome remains limited. In our study, we aim to assess the outcome of screen-detected lesions diagnosed as B3 in a large series to validate previous studies and to characterize the malignant lesions detected after a B3 diagnosis. Therefore, the results of 1,025 needle core biopsies of women screened over a 7-year period (1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006) in two different regions in the UK with B3 diagnoses who underwent surgical excision were reviewed and compared to the final excision histology. Final histology showed that 25% of cases were malignant (17% ductal carcinoma in situ and 8% invasive). Predictors of malignancy included calcification on imaging and epithelial atypia on needle core biopsy particularly atypical ductal hyperplasia [positive predictive value 50%]. Pure flat epithelial atypia showed the lowest positive predictive value amongst all epithelial atypia groups (21%). The positive predictive value was low for complex sclerosing lesions (9%) and papillary lesions (13%) without epithelial atypia. Malignant tumors detected after B3 diagnosis showed favorable histological features, the majority were in situ, and most belonged to the low grade breast neoplasia family that is associated with indolent behavior. The underlying radiological abnormality was calcification in 44% of cases and the imaging classification was malignant/suspicious in 38%. In conclusion, our results further emphasize the heterogeneity of B3 lesions and that the likelihood of malignancy varies substantially between different histological subtypes. Malignancy is particularly associated with epithelial atypia suggesting the use of two categories of with and without epithelial atypia. Radiological findings provided useful information regarding the nature and outcome of B3 lesions.

Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase I studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in >75% inhibition of capsaicin-induced dermal blood flow, with no apparent dose-dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with an acceptable safety profile, supporting further clinical development of erenumab for migraine prevention.

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The study has found a decrease in the PPV for a B3 diagnosis and suggests possible explanations.