Migraine is a chronic neurologic disease that manifests as episodic attacks of headache, which are frequently associated with nausea, phonophobia, and photophobia.1 Migraine causes substantial individual impairment and disability2, 3 and is one of the most disabling diseases worldwide.4 Additionally, individuals with migraine have poor health-related quality of life, including substantial negative effects on family and personal relationships.5, 6 The high prevalence of migraine and the resulting disability make migraine a significant global public health problem.

Esomeprazole magnesium is a commonly used proton pump inhibitor that is available by prescription and also as an over-the-counter (OTC) medication. Prescription esomeprazole magnesium is indicated for the treatment of gastroesophageal reflux disease (GERD), to reduce the risk of nonsteroidal anti-inflammatory drug–associated gastric ulcer, to eradicate Helicobacter pylori to reduce the risk of duodenal ulcer recurrence, and for pathological hypersecretory conditions, including Zollinger-Ellison syndrome.7 OTC esomeprazole magnesium is recommended as a 14-day treatment for frequent heartburn (≥2 days per week).8 Proton pump inhibitors suppress gastric acid secretion by specific inhibition of the enzyme H+–K+-adenosine triphosphatase in gastric parietal cells, blocking the final step in acid production and reducing gastric acidity.9 Esomeprazole is metabolized in the liver by the cytochrome P450 (CYP) isoenzymes 2C19 and 3A4.9

Ubrogepant is an oral, small-molecule calcitonin gene–related peptide (CGRP) receptor antagonist (gepant) that is approved for the acute treatment of migraine with or without aura in adults.10-12 In the pivotal ACHIEVE trials, the proportions of participants reporting pain freedom or absence of the most bothersome migraine symptom at 2 hours were significantly greater for participants receiving ubrogepant 50 or 100 mg than for those receiving placebo.10, 11 In a long-term safety study that followed 813 participants treated intermittently for 1 year, ubrogepant was safe and well tolerated.13

Ubrogepant is metabolized by CYP3A4. The glucuronide conjugates of the oxidative metabolites of ubrogepant are the primary circulating active metabolites, which are cleared from the plasma within 6 hours. Ubrogepant is eliminated mainly via the biliary/fecal route (≈83%); the renal route is responsible for <10% of elimination. Multiple drug-drug interaction studies have been conducted with ubrogepant, and 1 study found that coadministration of mild CYP3A4 inhibitors, including alprazolam, azithromycin, cimetidine, fluvoxamine, isoniazid, and ranitidine, had no impact on ubrogepant clearance. No dose adjustment is necessary with these medications or for differences in sex, race, weight, and age, or for mild/moderate hepatic or renal impairment. Ubrogepant should not be coadministered with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, and clarithromycin. With strong CYP3A4 inducers, ubrogepant exposure is reduced. No clinically significant pharmacokinetic (PK) interactions were observed with oral contraceptives, acetaminophen, naproxen, sumatriptan, or with the CGRP-targeted monoclonal antibodies erenumab and galcanezumab.14-18

With the high prevalence of migraine in the overall population and the common use of prescription and OTC esomeprazole magnesium, ubrogepant and esomeprazole magnesium are likely to be coadministered in some individuals with migraine. Because esomeprazole magnesium increases intragastric pH, there is a possibility that coadministration with ubrogepant could affect the absorption of ubrogepant, a Biopharmaceutics Classification System class IV drug. The objective of this trial was to assess the effect of daily oral doses of esomeprazole magnesium coadministration on the bioavailability of a single dose of ubrogepant in healthy adult participants.

Materials and Methods Study Design

This open-label, 2-treatment, 2-period, single-sequence, nonrandomized, crossover, drug-drug interaction phase 1 trial was conducted at a single study site (PPD Development LP, Austin, Texas). The study treatment was administered at the study center on the appropriate days under the direct supervision of study center personnel. Participants received a single oral dose of ubrogepant 100 mg on day 1, which was followed by an 8-day washout. Participants received once-daily oral doses of esomeprazole magnesium 40 mg on days 9 to 13. On day 14, participants received a single oral dose of ubrogepant 100 mg coadministered with a single oral dose of esomeprazole magnesium 40 mg. Participants had an end-of-study evaluation on or within 7 days of day 15 or at early termination, and a final follow-up visit on day 44 (±2 days).

This study was conducted in accordance with the principles of the Declaration of Helsinki and with the International Council for Harmonisation E6 guideline for Good Clinical Practice. The study protocol was approved by IntegReview Institutional Review Board (Austin, Texas). All participants provided written informed consent before initiation of any study-specific procedures.

Participants

Eligible participants were healthy men or women aged 18 to 45 years with a sitting pulse rate between 50 and 100 beats per minute and body mass index between 18 and 30 kg/m2. Participants were current nonsmokers and had not smoked within the previous 2 years. Participants were excluded from the trial if they had sitting systolic blood pressure ≥140 or ≤90 mm Hg or sitting diastolic blood pressure ≥90 or ≤50 mm Hg; abnormal electrocardiogram (ECG) results thought to be potentially clinically significant or QT prolongation (Fridericia-corrected QT interval ≥450 milliseconds for males or ≥470 milliseconds for females, or uncorrected QT interval ≥500 milliseconds); a clinically significant disease state; known hypersensitivity to ubrogepant, other CGRP receptor antagonists or esomeprazole magnesium; positive test results for antibodies to HIV-1, HIV-2, hepatitis B virus, or hepatitis C virus; abnormal or clinically significant results on physical examination; history of substance abuse within the previous 5 years; or a clinical condition or previous surgery that could affect the absorption, distribution, biotransformation, or excretion of ubrogepant or esomeprazole magnesium.

Study Procedures

Participants could not have taken or consumed caffeine- or xanthine-containing foods or drinks within 48 hours; alcohol within 72 hours; any concomitant prescription or OTC medications, dietary supplements, or other foods or beverages that could affect drug-metabolizing enzymes and transporters, vegetables from the mustard green family, or charbroiled meats within 2 weeks; hormonal drug products within 30 days; or herbal preparations containing St. John's wort within 4 weeks before the first dose. Participants received all interventions under fasted conditions and remained fasted and seated upright and awake for 4 hours after dosing. Blood samples for PK testing were collected at 0 (before dosing), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 14, and 24 hours after ubrogepant dosing on days 1 and 14, and before administration of esomeprazole magnesium on days 13 and 14. Ubrogepant and esomeprazole concentrations in plasma were determined using validated liquid chromatography with tandem mass spectrometry detection methodology. Bioanalytical testing was conducted by Algorithme Pharma (an Altasciences Company, Laval, Quebec, Canada).

Study Outcomes

The primary outcome was PK parameters derived from plasma concentrations of ubrogepant. PK parameters included peak plasma concentration (Cmax), area under the plasma concentration–time curve (AUC) from time 0 to time t (AUC0-t) or from time 0 to infinity (AUC0-∞), time to peak plasma concentration (tmax), terminal elimination half-life (t1/2), and the apparent total body clearance of drug from plasma after extravascular administration. Safety was assessed at every visit and included evaluations of treatment-emergent adverse events (TEAEs), physical examinations, clinical laboratory determinations, vital signs, and 12-lead ECGs.

Pharmacokinetic Analysis

The PK population comprised all participants who received a dose of study medication and had evaluable PK results. The PK parameters calculated for ubrogepant were AUC0-t, AUC0-∞, Cmax, tmax, terminal elimination rate constant (λz), t1/2, and apparent total body clearance, and were derived from plasma concentrations using noncompartmental analysis with Phoenix WinNonlin version 6.3 software (Certara, Princeton, New Jersey). Plasma concentrations below the limit of quantification were treated as 0 for all PK calculations. Descriptive statistics are reported for the plasma concentrations of ubrogepant alone and in combination with esomeprazole magnesium at each nominal time point for all participants by treatment in the PK population.

Analytic Methods

A validated bioanalytical method was used for determining ubrogepant plasma concentrations. Sample pretreatment involved protein precipitation extraction of ubrogepant from 0.100 mL of plasma and ubrogepant-D3 was used as the internal standard. The compounds were identified and quantified using reversed-phase high-performance liquid chromatography with triple quadrupole mass spectrometry detection over a theoretical concentration range of 0.100 to 150 ng/mL for ubrogepant. A concentrated solution of the compound to be tested was first prepared and, using mobile phase, the compound solution was infused by postcolumn infusion using a tee mixer while running the mobile phase into the liquid chromatography–mass spectrometer (without column). The Q1 scan was acquired on a mass range corresponding to the compound mass (typically ±10 amu), using the appropriate ionization mode (ie, positive mode or negative mode; the compound may ionize in a different mode than the parent compound). Mobile phase A consisted of 0.02% CH3COOH in H2O and mobile phase B consisted of acetonitrile.

Multiple stock solutions of ubrogepant were prepared and compared to verify the accuracy of reference standard weighing. Stock solutions were deemed acceptable if the percent difference between mean response ratios of at least 2 stock solutions was ≤5%.

Solutions of esomeprazole were also prepared; however, this compound was used qualitatively only because quality control (QC) samples better represent study samples. Stock solutions of ubrogepant and ubrogepant-D3 were screened for potential interference at the retention times and mass transitions of ubrogepant and ubrogepant-D3 and were free of significant interference. The stock solution used for calibrants was a different lot number than the stock solution used for QC samples. An API 5000 quadrupole mass spectrometer (AB Sciex, Framingham, Massachusetts) using a Turbo V ion source with ES probe operating in positive ion mode was used for the detection of ubrogepant. Assay sensitivity was assessed at the lower limit of quantitation (LOQ) QC concentration of 0.100 ng/mL for ubrogepant. The LOQ signals were >5 times the height of the baseline noise. Precision and accuracy of ubrogepant in plasma were determined at LOQ, low, medium, and high QC sample concentrations. For each precision and accuracy batch, each QC concentration level was assayed within a single batch. To evaluate method ruggedness, at least 1 within-run precision and accuracy batch represented the expected batch size during subject sample analysis. At least 2 within-run precision and accuracy batches were extracted by 2 different analysts, on 2 different days, and were injected on 2 different chromatographic systems, employing different analytical columns (ie, same phase, dimensions, manufacturer, etc, but different column identification number). Within-run precision and accuracy for ubrogepant in plasma were determined at LOQ, low, medium, and high QC sample concentrations.

Statistical Analysis

A sample size of 30 participants was estimated to ensure 90% power that the 90% confidence interval (CI) of the geometric mean ratios (GMRs) of PK parameters Cmax and AUC for ubrogepant coadministered with esomeprazole magnesium versus ubrogepant alone would be within the limits of 80% to 125%. In a previous study, the within-participant coefficients of variation for the ubrogepant Cmax and AUC parameters were ≈8% to 16% in the evaluation of the effects of verapamil (a moderate CYP3A4 inhibitor) and 33% to 39% in the evaluation of the effects of ketoconazole (a strong CYP3A4 inhibitor) on ubrogepant PK. The power analysis for this study was based on an assumption that within-participant coefficient of variation would be 25% in this study and geometric mean ratio for Cmax and AUC would be 1.0.

Ubrogepant PK parameters of Cmax, AUC0-t, and AUC0-∞ following administration with or without esomeprazole magnesium were compared using a linear mixed-effects model with treatment as fixed effect and participant as random effect. Statistical inference was based on log-transformed values. The 2-sided 90% CI was constructed for the ratio of geometric least squares means of Cmax, AUC0-t, and AUC0-∞ of ubrogepant coadministered with esomeprazole magnesium (test) versus ubrogepant alone (reference). No significant effect of esomeprazole magnesium on ubrogepant PK was concluded if the 90% CI for the test-to-reference ratio was within 80% to 125%. All statistical analyses were calculated using SAS version 9.3 software (SAS Institute Inc., Cary, North Carolina).

TEAEs were coded based on the Medical Dictionary for Regulatory Activities version 20.0. The safety analysis was performed on the basis of the safety population, which included all participants who received at least 1 dose of the study medication. Descriptive statistics (n, mean, median, standard deviation [SD], minimum, and maximum) were presented for continuous variables. Frequency distributions (counts and percentages) were presented for categorical variables.

Results Participants

This study was conducted between March 26, 2017, and June 10, 2017. A total of 30 participants were enrolled; of these, 29 (96.7%) completed the trial. One participant withdrew consent after receiving a single dose of ubrogepant. The mean age was 31.7 years (range, 19–43 years) and slightly more than half (16/30; 53.3%) were men (Table 1). All 30 participants were included in the safety population and all 30 were evaluated for ubrogepant PK administered alone; 29 participants were included in the analysis of ubrogepant PK parameters when coadministered with esomeprazole magnesium.

Table 1. Demographic Characteristics (Safety Population) Characteristic All Participants (N = 30) Age, y, mean (SD) 31.7 (7.3) Sex, male, n (%) 16 (53.3) Race/Ethnicity, n (%) White 22 (73.3) Black/African American 8 (26.7) Hispanic/Latino 13 (43.3) BMI, kg/m2, mean (SD) 25.3 (3.3) BMI, body mass index; SD, standard deviation. Effect of Esomeprazole Magnesium on Ubrogepant PK

Mean (SD) trough plasma concentrations of esomeprazole on days 13 and 14 were 0.26 (1.01) and 0.24 (0.92) ng/mL, respectively. The mean (SD) plasma concentrations when ubrogepant 100 mg was administered alone or coadministered with esomeprazole magnesium 40 mg are shown in Figure 1. The median tmax (1.5 hours) for ubrogepant was delayed by 1.5 hours with esomeprazole magnesium coadministration (Table 2). The mean apparent terminal t1/2 was similar when ubrogepant was administered alone or coadministered with esomeprazole magnesium, suggesting no impact of esomeprazole magnesium on ubrogepant elimination. Compared with ubrogepant 100 mg administered alone, ubrogepant Cmax was 23% lower, AUC0-t was 9% lower, and AUC0-∞ was 10% lower when ubrogepant 100 mg was coadministered with esomeprazole magnesium 40 mg (Table 3). The 90% CI for the ratio of Cmax was not contained within the equivalence limits of 80% to 125%, but the decrease was not considered to be clinically meaningful.

Mean (SD) plasma ubrogepant concentrations when administered alone or coadministered with esomeprazole magnesium. Concentrations of ubrogepant administered alone (red circles) or coadministered with esomeprazole magnesium (green triangles) are shown on (A) linear and (B) semilogarithmic scales. SD, standard deviation.

Table 2. Mean (SD) Ubrogepant PK Parameters When Administered Alone or Coadministered With Esomeprazole Magnesium (PK Population) PK Parameter Ubrogepant 100 mg (n = 30) Ubrogepant 100 mg + Esomeprazole Magnesium 40 mg (n = 29) Cmax, ng/mL 378.8 (200.6) 275.5 (124.1) AUC0-t, ng·h/mL 1601.3 (775.4) 1440.7 (668.6) AUC0-∞, ng·h/mL 1647.3 (776.2) 1448.1 (679.8) tmax, ha 1.5 (0.5-4.2) 3.0 (0.6-5.0) t1/2, h 6.1 (2.3) 5.4 (1.0) CL/F, L/h 74.3 (33.3) 83.0 (38.0) AUC0-∞, area under the plasma concentration–time curve from time 0 to infinity; AUC0-t, area under the plasma concentration–time curve from time 0 to time t; CL/F, apparent total body clearance of drug from plasma after extravascular administration; Cmax, peak plasma concentration; PK, pharmacokinetic; SD, standard deviation; t1/2, terminal elimination half-life; tmax, time to peak plasma concentration. a Median (range). Table 3. Statistical Analysis of Ubrogepant PK Parameters for Ubrogepant Coadministered With Esomeprazole Magnesium vs Ubrogepant Administered Alone (PK Population) PK Parameter

Ubrogepant 100 mg + Esomeprazole Magnesium 40 mg (Test) Geometric LSM

Ubrogepant 100 mg (Reference)

Geometric LSM

GMR (Test/Reference)

90% CI Lower Limit 90% CI Upper Limit Cmax, ng/mL 254.6 331.0 0.8 0.7 0.9 AUC0-t, ng·h/mL 1317.6 1451.9 0.9 0.8 1.0 AUC0-∞, ng·h/mL 1359.2 1501.9 0.9 0.8 1.0 AUC0-∞, area under the plasma concentration–time curve from time 0 to infinity; AUC0-t, area under the plasma concentration–time curve from time 0 to time t; Cmax, peak plasma concentration; GMR, geometric mean ratio; LSM, least squares mean; PK, pharmacokinetic. Safety

Eight (26.7%) participants experienced a TEAE during the study (Table 4). Compared with the administration of ubrogepant alone, the coadministration of esomeprazole magnesium with ubrogepant did not lead to an increase in the incidence rate of TEAEs (3.4% for coadministration vs 13.3% for ubrogepant alone). No serious TEAEs or deaths occurred, and no participant discontinued the study because of a TEAE. Only 1 TEAE occurred in more than 1 participant: presyncope was reported for 2 participants following ubrogepant administered alone. In addition to the presyncope events, 1 participant had viral upper respiratory tract infection, and 1 had contact dermatitis with ubrogepant administered alone. During treatment with esomeprazole magnesium, 4 participants had TEAEs of seasonal allergy, skin abrasion, headache, pruritus, and influenza-like illness, and following coadministration of ubrogepant and esomeprazole magnesium, 1 participant had a TEAE of dizziness. The TEAEs of contact dermatitis and dizziness and 1 event of presyncope were considered to be treatment related. All TEAEs were mild in intensity except for 1 event of presyncope, which was assessed as moderate. No participant met the criteria for potential Hy's law (alanine aminotransferase or aspartate aminotransferase ≥3 times the upper limit of normal [ULN], total bilirubin ≥2 times the ULN, and alkaline phosphatase <2 times ULN) or had concurrent elevations of liver laboratory parameters during the intervention period.13, 19 No clinically relevant findings from physical examinations, vital sign evaluations, or ECG assessments were observed.

Table 4. Overall Summary of TEAEs (Safety Population) n (%) Ubrogepant 100 mg (n = 30) Esomeprazole Magnesium 40 mg (n = 29) Ubrogepant 100 mg + Esomeprazole Magnesium 40 mg (n = 29) Totala (N = 30) Any TEAEb 4 (13.3) 4 (13.8) 1 (3.4) 8 (26.7) Treatment-related TEAEb 2 (6.7) 0 1 (3.4) 3 (10.0) SAEc 0 0 0 0 TEAE leading to discontinuationd 0 0 0 0 Severe TEAE 0 0 0 0 Deathc 0 0 0 0 SAE, serious adverse event; TEAE, treatment-emergent adverse event. aTotal represents all participants who received investigational product; each participant is counted once. TEAEs were attributed to the last intervention received. bEvents that began or worsened on or after the intervention start date and within 30 days of the intervention end date. cEvents that occurred on or after the intervention start date and within 30 days of the intervention end date. dEvents that occurred within the intervention period plus 30 days after the intervention end date. Discussion

Many individuals with migraine have gastrointestinal conditions that are commonly treated with prescription or OTC esomeprazole magnesium; these include GERD, acid reflux, and dyspepsia. In population-based studies, dyspepsia was found to be 2 times higher in individuals with migraine compared with those without migraine in Finland,20 and the prevalence of dyspepsia was 41% among individuals with migraine in Iran.21 Rates of GERD were 1.8 times higher among individuals with migraine vs those without in the Finland study.20 Gastrointestinal disorders have also been addressed in recent surveys of individuals with migraine. In a cross-sectional, web-based survey based on the National Health and Wellness Survey of individuals with physician-diagnosed migraine, 22% of respondents had physician-diagnosed GERD, 12% had diagnosed heartburn, and 49% had been diagnosed with GERD or heartburn or had experienced symptoms of these conditions within the previous year.22 In the Chronic Migraine Epidemiology and Outcomes (CaMEO) study, 11% of survey respondents with migraine self-reported physician-diagnosed GERD.23 These results suggest that many individuals with migraine are likely to use esomeprazole magnesium or other gastric acid–reducing agents for gastrointestinal conditions.

Repeated, once-daily administration of esomeprazole magnesium 40 mg has been shown to increase gastric pH.24 This increase in gastric pH affected the rate of absorption of ubrogepant, as demonstrated by the delay in tmax by 1.5 hours and a 23% decrease in Cmax. There was no significant change in the extent of absorption of ubrogepant upon coadministration with esomeprazole magnesium. The minor changes in overall PK of ubrogepant when coadministered with esomeprazole magnesium were not considered to be clinically meaningful. Ubrogepant has been associated with a flat exposure-response relationship observed between the 50- and 100-mg ubrogepant doses in the pivotal efficacy/safety studies.10, 11 Additionally, based on a human capsaicin-induced dermal vasodilation model, the potential pharmacologically active concentration (EC90) of ubrogepant was 13 ng/mL (23 nM).25, 26 The 23% lower ubrogepant Cmax when coadministered with esomeprazole magnesium would still be well above this threshold. Although ubrogepant and esomeprazole magnesium are both metabolized by CYP3A4,9, 14 neither drug is a CYP3A4 inducer or inhibitor, and ubrogepant exposure was not changed based on shared CYP3A4 metabolism.

A limitation of this study was the relatively small sample size, which is common with PK studies because of the intensive blood sampling. This study was conducted in healthy adult participants, whereas ubrogepant is indicated for the acute treatment of migraine attacks. A strength of this study was the use of the crossover design, allowing participants to serve as their own controls, reducing the need for a larger sample size, and improving the precision of the estimated treatment differences.

Conclusions

Coadministration of ubrogepant and esomeprazole magnesium caused a reduction in the rate of ubrogepant absorption, as evidenced by the longer tmax, but had minimal impact on the extent of ubrogepant systemic exposure. The 23% reduction in Cmax is not expected to be clinically meaningful. Overall, ubrogepant 100 mg administered alone or coadministered with esomeprazole magnesium 40 mg was safe and well tolerated in healthy adult participants.

Acknowledgments

The authors thank Abhijeet Jakate and Chris Stein for their assistance with this research and thank the trial participants and site staff. Writing and editorial assistance was provided to the authors by Peloton Advantage, LLC, an OPEN Health company, Parsippany, New Jersey, and was funded by AbbVie. The opinions expressed in this article are those of the authors. The authors received no honorarium/fee or other form of financial support related to the development of this article.

Conflicts of Interest

Ramesh Boinpally, PhD, and Kaifeng Lu, PhD, are employees of AbbVie and may hold AbbVie stock.

Funding

This study was supported by Allergan (before its acquisition by AbbVie).