Dataset Information

Evaluation of the Pharmacokinetic Interaction and Safety of Atogepant Co-Administered with Acetaminophen or Naproxen in Healthy Participants: A Randomized Trial.

ABSTRACT:

Background

Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for preventive treatment of migraine.

Objective

To evaluate potential pharmacokinetic drug-drug interactions (DDIs), safety and tolerability of atogepant co-administered with acetaminophen or naproxen in healthy participants.

Methods

This open-label, randomized, five-way crossover, single-center, phase 1 DDI trial randomized healthy adult participants to one of ten intervention sequences to receive single-dose 60 mg atogepant, 1000 mg acetaminophen, 500 mg naproxen, or co-administrations of atogepant with acetaminophen or naproxen, with 7-day washout periods between interventions. Potential DDIs were assessed using geometric mean ratios and 90% confidence intervals (CIs) calculated from maximum plasma drug concentrations (C_max) and area under the plasma drug concentration-time curves (AUCs) for co-administered medications versus medications administered alone. Secondary pharmacokinetic parameters [time to C_max (t_max), terminal elimination half-life (t_1/2), volume of distribution during terminal phase (V_Z/F), total body clearance (CL/F)], and safety were evaluated.

Results

Forty participants enrolled; 35 (87.5%) completed the trial. Atogepant C_max was unchanged, AUC_0-t and AUC_0-∞ both increased 13%, and t_max and t_1/2 were unchanged when co-administered with acetaminophen; and acetaminophen C_max decreased 11%, AUC_0-t and AUC_0-∞ both decreased 6%, and t_max and t_1/2 were unchanged when co-administered with atogepant. Atogepant mean (SD) V_z/F and CL/F were 369.45 (255.68) L and 18.88 (9.28) L/h, respectively, when administered alone and 297.56 (196.01) L and 16.33 (6.11) L/h when co-administered with acetaminophen. Atogepant C_max was unchanged, AUC_0-t and AUC_0-∞ both decreased 1%, and t_max and t_1/2 were unchanged when co-administered with naproxen; and naproxen C_max decreased 6%, AUC_0-t and AUC_0-∞ both decreased 2%, and t_max and t_1/2 were unchanged when co-administered with atogepant. Atogepant mean (SD) V_z/F and CL/F were 359.61 (247.99) L and 18.80 (7.78) L/h, respectively, when co-administered with naproxen. Treatment-emergent adverse events (TEAEs) occurred at rates of 5.6-21.1% across interventions. The most commonly reported TEAEs were oropharyngeal pain (n = 2, with atogepant; not treatment related) and nausea (n = 2, with atogepant/acetaminophen; treatment related).

Conclusion

Co-administration of 60 mg atogepant with 1000 mg acetaminophen or 500 mg naproxen was safe and well tolerated in healthy participants, and no DDIs were observed.

SUBMITTER: Boinpally R

PROVIDER: S-EPMC8195918 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundGolidocitinib is an orally available, potent and highly selective JAK (Janus kinase)-1 inhibitor of JAK/STAT3 signaling under clinical development for the treatment of cancer and autoimmune diseases. The objectives of the two reported studies were to investigate the pharmacokinetics (PK), safety, and tolerability of golidocitinib in healthy Chinese participants as compared to those healthy Western participants, as well as the food effect exploration.MethodsTwo phase I studies (JACKPOT2 and JACKPOT3) were conducted in USA and China, respectively. In JACKPOT2 study, participants were randomized into placebo or golidocitinib arm in single-ascending dose cohorts (5 - 150 mg) and multiple-ascending dose cohorts (25 - 100 mg, once daily) for 14 days. In the food effect cohort, golidocitinib (50 mg) was administrated shortly after a high-fat meal (fed conditions) as compared to under fasting conditions. In JACKPOT3 study conducted in China, participants were randomized to placebo or golidocitinib arm in single-ascending dose cohorts (25 - 150 mg).ResultsExposure of golidocitinib generally increased in a dose-proportional manner across a dose range of 5 mg to 150 mg (single dose) and 25 mg to 100 mg (once daily). High-fat food did not alter the PK of golidocitinib with statistical significance. Low plasma clearance and extensive volume of distribution characterizes PK of golidoctinib, and long half-life across the dose levels supported once daily dosing. The inter-ethnic difference in primary PK parameters was evaluated. The result suggested slightly higher peak plasma concentrations (Cmax) but comparable area under the plasma concentration-time curve (AUC) was observed in Asian (Chinese) subjects as compared to Caucasian and/or Black subjects, while it was not considered clinically relevant. Golidocitinib was well tolerated without Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher drug-related treatment emergent adverse events (TEAE) reported.ConclusionNo noticeable inter-ethnic difference was observed among Asian, Black, and Caucasian healthy subjects in anticipation of the favorable PK properties of golidocitinib. The effect of food on the bioavailability of golidocitinib was minor following a single oral administration of 50 mg. These data guided to use the same dose and regimen for multinational clinical development.Clinical trial registrationshttps://clinicaltrials.gov/ct2/show/NCT03728023?term=NCT03728023&draw=2&rank=1, identifier (NCT03728023); http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier (CTR20191011).