Population PK Analyses of Ubrogepant (MK‐1602), a CGRP Receptor Antagonist: Enriching In‐Clinic Plasma PK Sampling With Outpatient Dried Blood Spot Sampling

Abstract

Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene-related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting.

Single Therapeutic and Supratherapeutic Doses of Ubrogepant Do Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized Trial

“…Plasma concentrations of ubrogepant and moxifloxacin were determined using validated liquid chromatography with tandem mass spectrometry methods. 27 Safety was assessed by monitoring adverse events (AEs), clinical laboratory tests, vital signs, safety ECGs, and physical examinations. The safety ECG was a standard 12-lead ECG performed in the supine position to measure the following parameters in lead II or lead III: heart rate, PR interval, QRS duration, QT interval, and QTcF interval.…”

“…The limit of quantitation was 1 ng/mL for ubrogepant and 25 ng/mL for moxifloxacin. Plasma concentrations of ubrogepant and moxifloxacin were determined using validated liquid chromatography with tandem mass spectrometry methods …”

Leveraging Digital Health Technologies and Outpatient Sampling in Clinical Drug Development: A Phase I Exploratory Study

“…Collection of samples in an outpatient setting provides an opportunity to enrich PK/PD information. A prior effort to access PK data in an outpatient setting through DBS samples showed much greater PK variability from outpatient vs. in‐clinic data from the same cohort of patients . This was hypothesized to be partially attributable to inaccurate recording of dosing and sampling times by patients via paper diaries.…”

Harnessing the Potential of Emerging Digital Health and Biological Sampling Technologies for Clinical Drug Development: Promise to Reality

“…38 Further, the use of DBS for PK sampling in an outpatient setting to enhance data available for population PK was also recently reported. 39 The IQ survey suggests a variety of applications of DBS not just for PK but also biomarkers, which is encouraging. To drive acceptance into clinical trials, home sampling approaches will need to be simple to use, be resistant to any cross-contamination, demonstrate integrity and tracking of samples, and will ideally be coupled with date/time-stamps to be useful for PKPD analyses.…”

“…The sampling of alternate matrices such as Dried Saliva Spots to enable home sampling has also been reported . Further, the use of DBS for PK sampling in an outpatient setting to enhance data available for population PK was also recently reported . The IQ survey suggests a variety of applications of DBS not just for PK but also biomarkers, which is encouraging.…”