130: PBPK Model Development & Simulations to Predict Drug-Drug Interactions of Atogepant

Statement of Purpose: Migraine is a common neurological disorder that is known to affect 18% of women and 6% of men in the US. Calcitonin gene-related peptide (CGRP) is a neuropeptide implicated in the pathophysiology of migraine. Atogepant is a CGRP receptor antagonist approved at doses of 10, 30, and 60 mg for the preventive treatment of episodic migraine in adults. Atogepant is primarily metabolized by cytochrome P450 (CYP) 3A4 enzyme in the liver and gut. Based on in vitro studies, it is a substrate for uptake transporters - organic anion transporting polypeptide (OATP)1B1/1B3 and efflux transporters - P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Atogepant is also an inhibitor of OATP1B1/1B3, OCT1 (organic cation transporter 1), MATE-1 (multidrug and toxin extrusion 1) and a weak inhibitor of OCT2, P-gp and BCRP in vitro. A physiologically-based pharmacokinetic (PBPK) model for atogepant was developed and utilized to assess potential drug-drug interactions (DDI) with atogepant.

Description of Methods & Materials: Nonclinical and clinical data of atogepant were utilized to develop a PBPK model for atogepant using Simcyp® V17. In vitro transport data were modeled in SIVA® V3 in order to define model inputs for passive permeability and active transport alongside enzymatic conversion rates for atogepant measured in vitro. The model was verified for accurate prediction of DDIs with itraconazole (strong CYP3A and P-gp inhibitor) and rifampin (OATP inhibitor and strong CYP3A inducer). The model was then applied to predict the extent of DDI during co-administration of atogepant with weak (cimetidine) and moderate (fluconazole) CYP3A4 inhibitors, moderate CYP3A inducers, inhibitors of P-gp and BCRP, and the effect of atogepant on the exposure of concomitantly administered substrates of OATP1B1/1B3, OCT1, MATE-1, OCT2, P-gp and BCRP.

Data & Results: The PBPK model predicted plasma PK of atogepant and fecal elimination of unchanged atogepant were in agreement with observed clinical data within 25% prediction error. Model predictions of the effect of itraconazole and rifampin (both single and multiple doses) on atogepant were within 25% of the observed clinical data. Simulation results for the DDI with fluconazole and cimetidine suggested a weak interaction and no interaction, respectively. A moderate CYP3A inducer, efavirenz, reduced atogepant exposure by 30%. Completely ‘knocking out’ P-gp or BCRP transporters caused a 1.20- and 1.18-fold increase in the area under the concentration profile of atogepant, respectively. Based on model predictions, the effect of atogepant on the exposure of tested substrates of OATP1B1/1B3, OCT1, and MATE-1 transporters, was found to be minimal.

Interpretation, Conclusion or Significance: In conclusion, a PBPK model of atogepant was developed, verified, and applied to predict the DDI for potential atogepant combinations that were not tested clinically. Along with the clinical DDI studies, PBPK modeling was used to elucidate relative contributions of enzyme and transporters to the disposition of atogepant. The results suggest no dose adjustment requirements for atogepant when administered with moderate and weak CYP3A inhibitors, weak CYP3A inducers, inhibitors of P-gp and BCRP, or for concomitantly administered substrates of OATP1B1/1B3, OCT1, and MATE-1 transporters. Higher atogepant doses should be considered when co-administered with strong and moderate CYP3A inducers.

Disclosures: AbbVie funded this study. AbbVie and Certara contributed to the research, and interpretation of data, writing, reviewing, and approving the publication. DM and RB are AbbVie employees and may hold AbbVie stocks or options. HB, LA, and KRY are Certara employees and may hold Certara stocks or options.