Pharmacokinetics and Safety of Coadministered Atogepant and Topiramate in Healthy Participants: A Phase 1, Open‐Label, Drug–Drug Interaction Study

Atogepant, an oral calcitonin gene‐related peptide receptor antagonist, and topiramate, a commonly used oral antiepileptic, are approved as preventive migraine treatments. Given the distinct mechanisms of action of these treatments, it is possible that they may be coprescribed for migraine. This open‐label, single‐center, 2‐cohort, phase 1 trial evaluated the potential pharmacokinetic (PK) 2‐way drug–drug interactions (DDIs), safety, and tolerability of atogepant and topiramate in healthy adults. Participants received atogepant 60 mg once daily and topiramate 100 mg twice daily. Cohort 1 (N = 28) evaluated the effect of topiramate on the PK of atogepant; cohort 2 (N = 25) evaluated the effect of atogepant on the PK of topiramate. Potential DDIs were assessed using geometric mean ratios and 90% confidence intervals calculated for maximum plasma drug concentration at steady state (Cmax,ss) and area under the plasma concentration–time curve during the dosing interval at steady state (AUC0−tau,ss). Additional PK parameters were assessed. Atogepant AUC0−tau,ss and Cmax,ss decreased by 25% and 24%, respectively, with topiramate coadministration. Topiramate AUC0−tau,ss and Cmax,ss decreased by 5% and 6%, respectively, with atogepant coadministration. The 25% reduction in atogepant exposure when coadministered with topiramate is not considered to be clinically relevant and would not require dose adjustments.

Migraine is a chronic neurologic disease characterized by headache attacks with associated symptoms such as photophobia, phonophobia, nausea, and vomiting. 1,2igraine attacks can vary in frequency, severity, and their impact on an individual's quality of life. 1 Migraine treatment can include acute or preventive strategies, and individuals with frequent and severe headaches may require both approaches. 1 The goals for the preventive treatment of migraine include reducing attack frequency, severity, duration, and disability, as well as improving responsiveness to acute medications.2 Effective preventive treatment may require a combination of ≥2 preventive options, preferably with different mechanisms of action. 2 Particularly, individuals with severe migraine attacks who are unable to achieve migraine freedom with the use of a single preventive medication may require coadministration of multiple preventives.2,3 Non-migraine-specific medications, such as antiepileptics, beta-blockers, and antide-pressants, have historically been recommended as preventive treatments for migraine.4 Calcitonin gene-related peptide (CGRP) and its receptor have become targets in the preventive treatment of migraine attacks.5,6 Several monoclonal antibodies targeting CGRP or the receptor are indicated for the preventive treatment of migraine, including erenumab, 7 galcanezumab, 8 fremanezumab, 9 and eptinezumab.10 Atogepant, an oral CGRP receptor antagonist, is indicated for the preventive treatment of episodic migraine in adults.ADVANCE and PROGRESS were 12-week, randomized, double-blind, phase 3 trials that found that atogepant significantly reduced the number of monthly migraine days compared with placebo in people with episodic and chronic migraine, respectively.2,11 In a 52-week, randomized, open-label trial, atogepant was found to be safe, well tolerated, and efficacious as a preventive treatment for episodic migraine. Iaddition, a randomized study of healthy participants demonstrated that a single dose of atogepant 300 mg did not alter cardiac repolarization.12 Given the positive safety and tolerability profile of atogepant, it is likely to be used in combination with other preventive treatments in select patients, such as those with severe and/or high-frequency migraine attacks.Consequently, it is important to consider the potential for drug-drug interactions (DDIs) between atogepant and other preventive medications for migraine. Topiramate is a commonly prescribed oral antiepileptic approved for the preventive treatment of migraine (100 mg/day administered in 2 divided doses) in individuals of at least 12 years of age.[15][16][17] Topiramate is a mild inducer of CYP3A4 activity, 18 with a long elimination half-life of ≈24 hours at the most commonly used doses (100-200 mg/day), 19 whereas atogepant is extensively metabolized predominantly by CYP3A4 with a minor contribution from CYP2D6, and has an elimination half-life of ≈11 hours.20,21 The potential for a DDI between atogepant and topiramate has yet to be characterized.Although its exact mechanism of action in the treatment of migraine is unknown, topiramate blocks voltage-dependent sodium channels, inhibits carbonic anhydrase, blocks αamino-3-hydroxy-5-methylisoxazole-4-propionic acid, and enhances gamma-aminobutyric acid-mediated inhibition.17 Since atogepant has a different mechanism of action, there is a possibility that topiramate and atogepant may be used together for preventive treatment of migraine.Therefore, the primary objective of this study was to evaluate the potential for a pharmacokinetic (PK) DDI between atogepant and topiramate, and to secondarily evaluate the safety and tolerability profiles of both medications coadministered versus administered alone.

Study Design
This open-label, single-center, multiple-dose, 2-cohort, phase 1 trial was designed to assess the potential of a PK DDI between atogepant and topiramate in healthy adult participants.The trial was conducted at a single site (Spaulding Clinical, LLC, West Bend, Wisconsin) in the United States.Eligible participants were enrolled either in cohort 1 to evaluate the effect of topiramate 100 mg twice daily on the PK of atogepant 60 mg once daily or in cohort 2 to evaluate the effect of atogepant 60 mg once daily on the PK of topiramate 100 mg twice daily (Figure 1).Participants in cohort 1 received atogepant alone on days 1-7 and atogepant plus topiramate on days 8-17, and participants in cohort 2 received topiramate alone on days 1-10 and topiramate plus atogepant on days 11-17.The duration of the study was 25 days (±2 days), which included day −1 through the follow-up visit and excluded the screening period.The screening period was up to 21 days before day 1, and the intervention period was a total of 19 days, at which point the end-of-dosing visit was conducted.Cerebrospinal fluid (CSF) samples for measurement of atogepant concentration were collected via lumbar puncture in a subset of consenting participants in cohort 1. CSF samples were collected once from individual participants in the CSF collection subset at 2 or 6 hours after the morning dose on day 6 for cohort 1. CSF data will be used in a future analysis.Clinical laboratory tests were performed at the followup visit, which was conducted on day 24 (7 [±2] days after the last dose of study medication).
The study protocol and other relevant documents were approved by the Advarra Institutional Review Board at Spaulding Clinical, LLC (West Bend, WI), and all participants provided written informed consent prior to enrollment.The study was conducted according to the principles of the Declaration of Helsinki and the International Council for Harmonization E6 guideline for Good Clinical Practice.All authors had full access to all study data.

Participants
Eligible participants were healthy adults aged 18-45 years who were nonsmokers and had a body mass index between ≥18 and ≤30 kg/m 2 and a sitting pulse rate between ≥45 and ≤100 beats per minute.Participants were excluded if they had clinically significant abnormal electrocardiogram (ECG) results or QT prolongation (Fridericia corrected QT ≥450 milliseconds for men, ≥470 milliseconds for women), or any clinical condition or previous surgery that may affect the absorption, distribution, biotransformation, or excretion of atogepant or topiramate.

End Points
The primary end points were area under the plasma concentration-time curve (AUC) during the dosing interval at steady state (AUC 0−tau,ss ) and maximum plasma drug concentration at steady state (C max,ss ) of atogepant and topiramate when coadministered and when administered alone.Additional PK parameters included time to maximum plasma drug concentration at steady state (t max,ss ), average plasma drug concentration at steady state, and minimum plasma drug concentration at steady state of topiramate and atogepant when coadministered and when administered alone.Safety and tolerability of atogepant, topiramate, and their combination were monitored throughout the study by clinical assessment of adverse events, measurement of vital signs, evaluation of 12-lead electrocardiograms, and clinical laboratory tests (hematology, clinical chemistry, coagulation, and urinalysis) at specified time points.
Drug concentrations in plasma samples were analyzed by Altasciences (Laval, Quebec, Canada).Concentrations of atogepant in plasma were determined using a validated liquid chromatographytandem mass spectrometry assay.Atogepant was extracted from plasma samples using protein precipitation.Chromatographic separation was achieved by gradient elution of acetonitrile and acetic acid solution using a C18 column.Mass spectrometric detection was conducted in positive electrospray ionization with the mass-to-charge (m/z) ion pairs of 604 → 264 and 608 → 268 for atogepant and deuterium-labeled (d4) internal standard, respectively.The assay was linear over the range of 1-1000 ng/mL and met current regulatory standards of precision and accuracy within 15%.Concentrations of topiramate in plasma were determined using a validated liquid chromatography-tandem mass spectrometry assay.Topiramate was extracted from plasma samples using protein precipitation.Chromatographic separation was achieved by isocratic elution of acetonitrile/methanol and ammonium acetate solution using a C8 column.Mass spectrometric detection was conducted in negative electrospray ionization with m/z ion pairs of 338 → 78 and 350 → 78 for topiramate and deuterium-labeled (d12) internal standard, respectively.The assay was linear over the range of 0.1-6 μg/mL and met current regulatory standards of precision and accuracy within 15%.

Statistical Analyses
A sample size of 22 participants was estimated to provide at least 80% power to show that the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for mean PK parameters of C max,ss and AUC 0−tau,ss of atogepant with and without coadministration of topiramate would be within 80%-125%.The withinparticipant coefficient of variation of topiramate for C max and AUC parameters was assumed to be ≤25%.Based on the assumption that the true ratio of test to reference geometric means was ≈1, this sample size was estimated to ensure a power of at least 80% to show that the 90%CIs for the GMRs for mean PK parameters of C max,ss and AUC 0−tau,ss of topiramate with and without atogepant would be within 80%-125%.With an assumption of a 10% dropout rate, a sample size of 25 participants per cohort (50 participants total) was planned.
All standard PK parameters (AUC 0−tau,ss , C max,ss , t max,ss , minimum plasma drug concentration at steady state, and average plasma drug concentration at steady state) were calculated using Phoenix WinNonlin Version 8.0 (Certara, Princeton, NJ).Plasma concentrations of atogepant and topiramate below the limit of quantification were treated as zero for all PK calculations.A linear mixed-effects model was used to compare log-transformed PK parameters (C max,ss and AUC 0−tau,ss ) of atogepant and topiramate in cohorts 1 and 2, respectively.In this model, the study intervention was a fixed effect, and the participant was a random effect.In both cohorts, the 2-sided 90%CI for the least-square GMRs of C max,ss and AUC 0−tau,ss between the test (atogepant and topiramate coadministered) and reference (atogepant or topiramate administered alone) study interventions was constructed; the difference in median t max,ss for the test and reference study interventions was provided.No interaction was concluded if the 90%CIs for the GMRs of the PK parameter values between coadministered medications versus atogepant or topiramate alone were within 80%-125%.

Participants
This trial was conducted between August 19, 2020, and January 22, 2021.The safety population included 28 participants in cohort 1 (28 received atogepant alone and 26 received atogepant plus topiramate; 24 participants were included in the CSF collection subset) and 25 participants in cohort 2 (25 received topiramate alone, and 24 received topiramate plus atogepant) (Figure S1).The PK analysis populations for atogepant alone and atogepant plus topiramate included 25 and 21 participants, respectively.The PK analysis populations for topiramate alone and topiramate plus atogepant included 24 and 22 participants, respectively.A total of 21 participants in cohort 1 and 22 participants in cohort 2 completed the trial.Ten participants discontinued the trial: 8 participants due to adverse events, 1 participant due to noncompliance with study drug, and 1 participant due to other reasons (noncompliance with study investigators).Baseline demographics were similar between the 2 cohort populations (Table S2).

Effect of Topiramate on Atogepant Pharmacokinetics
The mean (standard deviation [SD]) steady-state plasma concentrations of atogepant following administration alone and in combination with topiramate are shown in Figure 2.These data demonstrate marginally lower atogepant plasma concentrations when atogepant was coadministered with topiramate compared with administration of atogepant alone.For participants in cohort 1, mean steady-state predose atogepant plasma concentrations (following once-daily administration of atogepant either alone or in the presence of steady-state topiramate) and mean steady-state predose topiramate plasma concentrations (following twice-daily administration in the presence of steady-state atogepant) are shown in Figure S2.Trough  steady state by day 15 when coadministered with atogepant.Table 1 summarizes the PK parameters of atogepant alone and in combination with topiramate.Coadministration of atogepant and topiramate reduced atogepant C max,ss compared with atogepant administered alone, while there was no change in the median t max,ss .The analysis of GMRs showed that atogepant AUC 0−tau,ss and C max,ss were reduced by 25% and 24%, respectively, when atogepant was coadministered with topiramate (Table 2).The GMR and the lower 90%CI for both AUC 0−tau,ss and C max,ss were <0.80, suggesting a statistically significant reduction of atogepant exposure when coadministered with topiramate.

Effect of Atogepant on Topiramate PK
The mean (SD) steady-state plasma concentrations of topiramate following administration alone and in combination with atogepant are shown in Figure 3. Topiramate plasma concentrations were marginally lower when coadministered with atogepant compared with topiramate alone.For participants in cohort 2, mean steady-state predose plasma topiramate concentrations (following twice-daily administration either alone or in the presence of steady-state atogepant) and mean steady-state predose atogepant plasma concentrations (following once-daily administration in the presence of steady-state topiramate) are shown in Figure S3.with and without coadministration of atogepant; however, the median t max,ss of topiramate was delayed by 0.5 hours when coadministered with atogepant.The analysis of GMRs showed that topiramate AUC 0−tau,ss and C max,ss were reduced by 5% and 6%, respectively, with atogepant coadministration (Table 4).The GMRs and their 90%CIs for the C max and AUC values were contained within the range of 0.80-1.25,indicating no DDI.
The most commonly reported TEAEs were nausea and constipation.Nausea was reported by 6 participants receiving atogepant alone, 2 participants receiving coadministered atogepant and topiramate in cohort 1, and 3 participants receiving topiramate alone in cohort 2. Constipation was reported by 3 participants receiving atogepant alone in cohort 1, 2 participants receiving topiramate alone, and 2 participants receiving coadministered topiramate and atogepant in cohort 2.

Discussion
The use of ≥2 preventive medications with different mechanisms of action may be of interest in individuals with severe and/or high-frequency migraine attacks or for individuals who are unable to meet treatment goals with a single preventive alone. 2,3The favorable tolerability profile of atogepant allows for the potential to combine with other preventive treatments for migraine.The results of this trial do not suggest that there would be clinically significant PK interactions when atogepant and the commonly used preventive treatment topiramate are coadministered.Although the AUC 0−tau,ss for atogepant was reduced by 25% and C max,ss was reduced by 24%, these statistically significant reductions are unlikely to be clinically relevant given that atogepant showed significant efficacy across a wide range of 10-, 30-, and 60-mg doses. 2 Administration of atogepant with a high-fat meal reduced AUC and C max by ≈18% and 22%, respectively, with no effect on median time to atogepant C max .Atogepant was administered without regard to food in clinical efficacy studies and was demonstrated to be effective at all doses tested.Based on this, the 25% reduction in atogepant exposure when coadministered with topiramate (or other weak CYP3A4 inducers) is not considered clinically relevant, and no dose adjustment is recommended when atogepant is administered with weak CYP3A4 inducers.
Atogepant 60 mg is the highest approved once-daily dose of atogepant and was selected for evaluation in this trial. 20The highest recommended dose of topiramate for the preventive treatment of migraine in individuals aged ≥12 years is 100 mg/day 17 ; however, a dose of 200 mg/day may be of benefit in some individuals.this trial, a maintenance dose of topiramate was titrated to 100 mg twice daily to test the highest recommended dose.Atogepant is metabolized mainly by CYP3A4, 20,21 and potential DDIs may occur with medications that share the same pathway.In a previous trial, coadministration of atogepant with ethinyl estradiol/levonorgestrel oral contraceptive, which is metabolized by CYP3A4, did not demonstrate significant PK DDIs. 22Administration of atogepant with itraconazole, a strong CYP3A4 inhibitor, was associated with a significant increase in atogepant exposure. 21onsequently, the recommended daily dose of atogepant is 10 mg when coadministered with a strong CYP3A4 inhibitor. 23Coadministration of atogepant and rifampin, a strong CYP3A4 inducer, was associated with a significant decrease in atogepant exposure. 20,21lthough PK DDIs for atogepant appear to be minimal with the coadministration of mild CYP3A4 inducers and atogepant and a dose adjustment is not likely to be necessary, clinicians should be aware that the use of moderate and strong CYP3A4 inducers may require a dosage modification.The use of atogepant 30 or 60 mg is recommended when concomitant drug use includes a strong or moderate CYP3A4 inducer. 23 potential limitation of this study was the relatively small sample size; however, this is common with phase 1 DDI PK studies.This trial enrolled healthy adults, whereas atogepant is approved for the preventive treatment of episodic migraine and the results may not be generalizable to the target patient population.Use of the sequential crossover design may lead to carryover effects; however, this design was also a strength of the trial, as it reduced the need for a larger sample size and allowed participants to serve as their own controls.In addition, the use of 2 separate cohorts allowed the impact of each medication on the PK of the other medication to be evaluated.This reduced the potential for any speculation as to the cause of the change in PK.

Conclusion
Atogepant was demonstrated to be safe and effective across a dose range of 10 mg once daily to 60 mg twice daily in pivotal trials, suggesting a wide therapeutic window.Administration of atogepant with a high-fat meal reduced AUC and C max by ≈18% and 22%, respectively, with no effect on median time to maximum atogepant plasma concentration.Atogepant was administered without regard to food in clinical studies and was demonstrated to be effective at all doses tested.Based on these data, the 25% reduction in atogepant exposure when coadministered with topiramate (or other weak CYP3A4 inducers) is not considered to be clinically relevant, and no dose adjustment is recommended when atogepant is administered with weak CYP3A4 inducers.

Figure 1 .
Figure 1.Study design and dosing schedule for cohort 1 and cohort 2. AM, morning; BID, twice daily; PM, evening; QD, once daily.

Table 1 .
atogepant concentrations reached steady state by day 5 when administered alone and by day 15 when coadministered with topiramate.Trough topiramate plasma concentrations reached Mean (±SD) PK Parameters of Atogepant Alone (Day 7) and in Combination With Topiramate (Day 17) AUC 0−tau,ss , area under the plasma concentration-time curve during the dosing interval at steady state; C avg,ss , average plasma drug concentration at steady state; C max,ss , maximum plasma drug concentration at steady state; C min,ss , minimum plasma drug concentration at steady state; PK, pharmacokinetic; SD, standard deviation; t max,ss , time to maximum plasma drug concentration at steady state.a Median (minimum-maximum).

Table 2 .
Statistical Analysis of PK Parameters: Comparison of Plasma Atogepant Alone and Coadministered With Topiramate AUC 0−tau,ss , area under the plasma concentration-time curve during the dosing interval at steady state; C max,ss , maximum plasma drug concentration at steady state; CI, confidence interval; GMR, geometric mean ratio; LSM, least-square mean; PK, pharmacokinetic.

Table 3 .
Trough topiramate concentrations reached steady state by day 8 when administered alone and by day 15 when coadministered with atogepant.Trough atogepant plasma concentrations reached steady state by day 15 when coadministered with topiramate.Topiramate PK parameters are summarized in Table 3. Overall, topiramate PK parameters were generally similar Mean (±SD) steady-state plasma topiramate concentrations when administered alone and in combination with atogepant.SD, standard deviation.Mean (±SD) PK Parameters of Topiramate Alone (Day 10) and When Coadministered With Atogepant (Day 17) a Median (minimum-maximum).

Table 4 .
Statistical Analysis of PK Parameters: Comparison of Plasma Topiramate Alone and Coadministered With Atogepant