Effects of CYP3A4 Inhibition/Induction and OATP Inhibition on the Pharmacokinetics of Atogepant in Healthy Adults

Abstract

Aim: Atogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is a substrate of OATP and metabolized by CYP3A4. Effect of multiple-dose itraconazole (strong CYP3A4 inhibitor), single-dose rifampin (strong OATP inhibitor) and multiple-dose rifampin (strong CYP3A4 inducer) on single-dose pharmacokinetics (PK) and safety of atogepant were assessed. Methods: Two phase I, open-label, single-center, crossover trials enrolled healthy adults. Results: C_max and area under the curve of atogepant increased when co-administered with itraconazole. Atogepant systemic exposure increased following co-administration with single-dose rifampin. Atogepant systemic exposure decreased with co-administration of multiple-dose rifampin. Treatment emergent adverse events (TEAEs) were predominantly mild or moderate, and included constipation, dizziness, headache and nauseas. Conclusion: Systemic exposure of atogepant increased significantly when co-administered with a strong CYP3A4 or OATP inhibitor and decreased significantly when co-administered with a strong CYP3A4 inducer.

Plain language summary

Calcitonin gene-related peptide (CGRP) is involved in migraines, a neurological disorder with severe headache and sensory disturbances. A medication called atogepant is a CGRP receptor antagonist that can block the effect of CGRP and is approved by the US FDA for the preventive treatment of migraines. If you take a drug, such as itraconazole, a strong inhibitor of an enzyme called CYP3A4, that metabolizes atogepant, at the same time as atogepant, it can increase the amount of atogepant in your body. OATPs are membrane transport proteins that facilitate liver uptake of atogepant. If you take a drug that is an OATP inhibitor with atogepant, it can increase the amount of atogepant in your body. However, if you take a CYP3A4 inducer such as rifampin, which increases the activity of CYP3A4, it can decrease the amount of atogepant in your body. Your doctor may adjust the dose of atogepant accordingly.

Keywords::

• atogepant
• CGRP receptor antagonist
• CYP3A4
• drug interaction
• migraine prophylaxis
• OATP
• pharmacokinetics

Acknowledgments

The authors thank the study investigators, participants and clinical sites for their contributions to various aspects of the studies.

Financial & competing interests disclosure

This work was supported by AbbVie. AbbVie participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review and approval of the publication. R Boinpally, D McGeeney and JM Trugman are employees of AbbVie Inc. and may hold AbbVie stock or stock options. W Chen is a former employee of AbbVie Inc. and may hold AbbVie stock or stock options. This work was previously presented at the 2022 American Headache Society Annual Scientific Meeting. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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Additional information

Funding

This work was supported by AbbVie. AbbVie participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review and approval of the publication. R Boinpally, D McGeeney and JM Trugman are employees of AbbVie Inc. and may hold AbbVie stock or stock options. W Chen is a former employee of AbbVie Inc. and may hold AbbVie stock or stock options. This work was previously presented at the 2022 American Headache Society Annual Scientific Meeting. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.