Atogepant for the preventive treatment of chronic migraine (PROGRESS): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In this study, we aimed to evaluate the efficacy, safety, and tolerability of atogepant for the preventive treatment of chronic migraine. METHODS: We did this randomised, double-blind, placebo-controlled, phase 3 trial at 142 clinical research sites across the USA, the UK, Canada, China, Czech Republic, Denmark, France, Germany, Italy, Japan, South Korea, Poland, Russia, Spain, Sweden, and Taiwan. Adults aged 18-80 years with a 1-year or longer history of chronic migraine were randomly assigned (1:1:1) to receive oral atogepant 30 mg twice a day, oral atogepant 60 mg once a day, or placebo. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) across the 12-week treatment period. The primary analysis was done in the modified intent-to-treat population and included all randomly assigned participants who received at least one dose of study intervention, had an evaluable baseline period of electronic diary (eDiary) data, and had at least one evaluable post-baseline 4-week period (weeks 1-4, 5-8, and 9-12) of eDiary data during the double-blind period. The safety population consisted of all participants who received at least one dose of study intervention. This trial is registered with ClinicalTrials.gov (NCT03855137). FINDINGS: Between March 11, 2019 and Jan 20, 2022, 1489 participants were assessed for eligibility. 711 were excluded, and 778 participants were randomly assigned to atogepant 30 mg twice a day (n=257), atogepant 60 mg once a day (n=262), or placebo (n=259). Participants in the safety population were aged 18-74 years (mean 42·1 years). 459 (59%) of 773 patients were White, 677 (88%) patients were female, and 96 (12%) were male. 84 participants discontinued treatment during the trial, and 755 comprised the modified intent-to-treat population (atogepant 30 mg twice a day n=253, atogepant 60 mg once a day n=256, and placebo n=246). Baseline mean number of MMDs were 18·6 (SE 5·1) with atogepant 30 mg twice a day, 19·2 (5·3) with atogepant 60 mg once a day, and 18·9 (4·8) with placebo. Change from baseline in mean MMDs across 12 weeks was -7·5 (SE 0·4) with atogepant 30 mg twice a day, -6·9 (0·4) with atogepant 60 mg once a day, and -5·1 (0·4) with placebo. Least squares mean difference from placebo was -2·4 with atogepant 30 mg twice a day (95% CI -3·5 to -1·3; adjusted p<0·0001) and -1·8 with atogepant 60 mg once a day (-2·9 to -0·8; adjusted p=0·0009). Most common adverse events for atogepant were constipation (30 mg twice a day 28 [10·9%]; 60 mg once a day 26 [10%]; and placebo 8 [3%]) and nausea (30 mg twice a day 20 [8%]; 60 mg once a day 25 [10%]; and placebo 9 [4%]). Potentially clinically significant weight decrease (≥7% reduction at any time post-baseline) was observed in each treatment group (atogepant 30 mg twice a day 14 [6%]; atogepant 60 mg once a day 15 [6%]; and placebo 5 [2%]). INTERPRETATION: Atogepant 30 mg twice a day and 60 mg once a day showed clinically relevant reductions in MMDs across 12 weeks in chronic migraine patients. Both atogepant doses were well tolerated, consistent with the known safety profile of atogepant. FUNDING: Allergan (now AbbVie).

Linaclotide Reduced Response Time for Irritable Bowel Syndrome With Constipation Symptoms: Analysis of 4 Randomized Controlled Trials.

INTRODUCTION: These post hoc analyses provide clinically relevant data concerning time to response for individual irritable bowel syndrome with constipation (IBS-C) symptoms after linaclotide use. METHODS: Time-to-response data were pooled from 4 randomized controlled trials. Response time for abdominal symptoms (pain, discomfort, and bloating) and complete spontaneous bowel movements (CSBMs) were analyzed using the Kaplan-Meier method; patients were categorized as early responders (≤4 weeks), late responders (>4-12 weeks), or nonresponders. RESULTS: Among 2,350 patients (1,172 placebo and 1,178 linaclotide 290 µg), >50% of patients with IBS-C who initiated linaclotide treatment experienced a decrease of ≥30% in abdominal pain, discomfort, or bloating within 3-4 weeks (median). The median time to achieving ≥3 CSBMs was 4 weeks. Although not all linaclotide-treated patients responded within 12 weeks, a late response occurred between 4 and 12 weeks in 1 in 6 patients for abdominal pain and in approximately 1 in 10 patients for CSBM frequency. Comparisons of early responders, late responders, and nonresponders for both response definitions indicated that women, Whites, and patients with less severe baseline abdominal symptoms were more likely to respond early. DISCUSSION: Although treatment responses with linaclotide occurred in >50% of patients with IBS-C within 4 weeks of treatment initiation, benefits for individual abdominal symptoms and/or CSBM frequency can still occur between 4 and 12 weeks. A lack of improvement in one symptom does not negate the possibility of response for others, highlighting the importance of discussing all symptoms with patients and not assuming treatment futility at 4 weeks.

Phase Ib, open-label, fixed-sequence, drug-drug interaction, safety, and tolerability study between atogepant and ubrogepant in participants with a history of migraine.

OBJECTIVE: To evaluate potential drug-drug interactions of ubrogepant and atogepant. BACKGROUND: Ubrogepant and atogepant, calcitonin gene-related peptide (CGRP) receptor antagonists, are recently approved drugs for acute and preventive treatment of migraine, respectively. For patients with migraine who are prescribed atogepant for the preventive treatment of migraine, health care providers could prescribe ubrogepant for the acute treatment of breakthrough migraine attacks. METHODS: A phase Ib, multi-center, open-label, fixed-sequence study was conducted in participants diagnosed with migraine for at least 1 year. To assess the primary objective of pharmacokinetic interactions in this phase I trial, the highest United States Food and Drug Administration-approved individual dose strengths of atogepant (60 mg once daily) and ubrogepant (100 mg) were utilized, with ubrogepant being administered on a fixed-dose schedule every 3 days, regardless of whether a participant was experiencing a migraine attack. Secondary endpoints included safety and tolerability. Clinical safety measurements were monitored throughout the study. RESULTS: Of the 31 participants enrolled, 26 completed the study. A single dose of ubrogepant had no statistically significant effect on atogepant pharmacokinetics. Co-administration of ubrogepant with atogepant resulted in a 19% increase (geometric mean ratio 118.80, 90% confidence interval [CI] 108.69-129.84) in the ubrogepant area under the plasma concentration-time curve and a 26% increase (geometric mean ratio 125.63, 90% CI 105.58-149.48) in the ubrogepant maximum plasma concentration. These statistically significant changes in ubrogepant exposure were not clinically meaningful, and no new safety concerns were identified for the combination. CONCLUSION: The combination use of atogepant and ubrogepant was safe and well tolerated in adult participants with a history of migraine enrolled in the study. Pharmacokinetic changes during co-administration were not clinically meaningful.

Safety and Efficacy of Eluxadoline in Patients with Irritable Bowel Syndrome-Diarrhea With or Without Bile Acid Diarrhea: Open-Label Study.

BACKGROUND: Eluxadoline, a peripherally acting, mixed µ- and κ-opioid receptor (OR) agonist and δ-OR antagonist, is approved for treatment of adults with irritable bowel syndrome-diarrhea (IBS-D). About a third of IBS-D patients has bile acid diarrhea (BAD); opioids may stimulate TGR5 (bile acid) receptors. AIM: To evaluate eluxadoline's efficacy on altered bowel functions and safety in IBS-D patients with or without BAD. METHODS: In a single-center, phase 4, parallel-group, open-label study, patients with IBS-D (cohort 1) and patients with BAD were treated with eluxadoline, 100 mg tablets BID, with food for 4 weeks. Patients recorded bowel functions by electronic daily diary. BAD was based on fasting serum 7αC4 (> 52.5 ng/mL) or concurrent criteria of increased total or primary fecal BAs excreted in 48 h. We assessed efficacy on treatment compared to baseline in the two cohorts. Primary outcome measures were changes from baseline in average stool consistency Bristol Stool Form Scale (BSFS) score (range 1-7) and safety. RESULTS: Mean changes from baseline in cohorts 1 and 2 (data presented in this order) were similar for: BSFS score averaged over 4 weeks' treatment (- 1.25 and - 1.09); daily bowel movement frequency (- 1.48 and - 0.79); daily urgent bowel movements (- 0.52 and - 0.80); IBS-QoL (5.9 and 13.6); serum 7αC4 (- 5.59 and - 8.78 ng/mL). There were no deaths, serious treatment-emergent adverse events, or discontinuations due to adverse events during the study. CONCLUSION: Eluxadoline is similarly efficacious in the treatment of IBS-D and BAD, and it appears to be safe and efficacious as documented in large clinical trials.

Efficacy of Linaclotide in Reducing Abdominal Symptoms of Bloating, Discomfort, and Pain: A Phase 3B Trial Using a Novel Abdominal Scoring System.

INTRODUCTION: Linaclotide improves abdominal pain and constipation in patients with constipation-predominant irritable bowel syndrome (IBS-C). Patients report additional bothersome abdominal symptoms of bloating and discomfort. The intention of this study was to evaluate linaclotide's efficacy in relieving IBS-C-related abdominal symptoms (bloating, discomfort, and pain) using a novel multi-item Abdominal Score (AS). METHODS: Patients with IBS-C with abdominal pain ≥3 (0-10 scale) were randomized to linaclotide 290 µg or placebo daily for 12 weeks. The AS, derived from the Diary for IBS Symptoms-Constipation, is the average of abdominal bloating, discomfort, and pain at their worst (0 = none, 10 = worst possible). The primary end point was overall change from baseline (CFB) in AS. Secondary end points included CFB in 12-week AS evaluated using cumulative distribution function and 6-week/12-week AS responder (AS improvement ≥2 points for ≥6-week/12-week). RESULTS: Overall, 614 patients (mean age 46.7 years; 81% female) were randomized. All prespecified end points showed significant benefit of linaclotide vs placebo. The mean overall CFB AS reduction for linaclotide was -1.9 vs -1.2 for placebo (P < 0.0001); the 6-week/12-week AS responder rate was 40.5% for linaclotide vs 23.4% for placebo (odds ratio = 2.2 [95% confidence interval, 1.55-3.12; P < 0.0001]). Diarrhea was the most common treatment-emergent adverse event (linaclotide = 4.6%, placebo = 1.6%). DISCUSSION: Linaclotide significantly reduced multiple abdominal symptoms important to patients with IBS-C (bloating, discomfort, and pain) compared with placebo, as measured by a novel multi-item AS. The AS, derived from the Diary for IBS Symptoms-Constipation, should be considered for use in future IBS-C clinical studies to measure clinically meaningful improvements beyond traditional end points.

Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation.

INTRODUCTION: Immediate-release (IR) formulation of linaclotide 290 µg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects. METHODS: This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 µg; MD-7246 30, 100, or 300 µg; or IR 290 µg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate. RESULTS: Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo. DISCUSSION: Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.

Pharmacokinetics and safety of ubrogepant when coadministered with calcitonin gene-related peptide-targeted monoclonal antibody migraine preventives in participants with migraine: A randomized phase 1b drug-drug interaction study.

OBJECTIVE: To evaluate the impact of two calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies (mAbs), erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant. BACKGROUND: People taking CGRP-targeted mAbs for migraine prevention sometimes take ubrogepant, an oral small-molecule CGRP receptor antagonist, for acute treatment of breakthrough migraine attacks. DESIGN: In this two-arm, multicenter, open-label, phase 1b trial, adults with migraine were randomized to arm 1 (ubrogepant ± erenumab) or arm 2 (ubrogepant ± galcanezumab). The PK profile of ubrogepant was characterized for administration before and 4 days after CGRP-targeted mAb injection. Participants received single-dose ubrogepant 100 mg on day 1, subcutaneous erenumab 140 mg (arm 1) or galcanezumab 240 mg (arm 2) on day 8, and ubrogepant 100 mg once daily on days 12-15. In each study arm, serial blood samples were drawn on days 1 and 12 for measurement of plasma ubrogepant concentrations. The primary outcomes were area under the plasma ubrogepant concentration-time curve (AUC) from time 0 to t post-dose (AUC0- t ) and from time 0 to infinity (AUC0-inf ), and maximum plasma concentration (Cmax ) of ubrogepant when ubrogepant was administered before or after a single dose of erenumab or galcanezumab. Vital signs and laboratory parameters were monitored. RESULTS: Forty participants enrolled (20 per arm; mean [standard deviation] ages, 32.2 [8.9] and 38.4 [8.8] years; 50% [10/20] and 60% [12/20] female in arms 1 and 2, respectively). There were no significant differences in ubrogepant Cmax after versus before erenumab administration (geometric least-squares mean [LSM] ratio, 1.04 [90% CI, 0.93-1.16]), and no significant differences in AUC0- t (1.06 [0.96-1.16]) or AUC0-inf (1.05 [0.96-1.15]). Similarly, ubrogepant Cmax (1.00 [90% CI, 0.82-1.20]), AUC0- t (1.05 [0.90-1.23]), and AUC0-inf (1.05 [0.90-1.22]) geometric LSM ratios were statistically equivalent after galcanezumab versus ubrogepant alone. Treatment-emergent adverse events (TEAEs) were similar to those reported with each treatment alone. No serious TEAEs, TEAEs leading to discontinuation, or clinically relevant changes in laboratory parameters or vital signs were reported. CONCLUSIONS: The PK profile of ubrogepant was not significantly changed and no safety concerns were identified when ubrogepant was coadministered with erenumab or galcanezumab.

Intestinal Guanylate Cyclase-C mRNA Expression in Duodenum and Colon of Children.

OBJECTIVES: Guanylate cyclase-C (GC-C) agonists, which increase intestinal secretion and accelerate transit, are used to treat chronic constipation and constipation-predominant irritable bowel syndrome and are being evaluated for pediatric use. Prior studies suggest GC-C receptor density may be higher in young children, potentially amplifying GC-C agonism with treatment implications. We aimed to quantitate duodenal and colonic GC-C mRNA expression in children. METHODS: Mucosal biopsies were obtained from subjects aged 6 months to 18 years during clinically indicated upper, that is, esophago-gastro-duodenal, and/or colonic endoscopy. Tissue samples without histologic abnormalities were grouped by subject age (<24 months, 24 months to <6 years, 6 to <12 years, and 12 to <18 years) and analyzed for GC-C mRNA expression by qPCR. The relationship between GC-C mRNA levels and age was modeled using regression analyses. RESULTS: Ninety-nine subjects underwent upper endoscopy/colonoscopy; 93 had evaluable samples. Mean relative GC-C mRNA expression was 2.36 (range 2.21-2.46) for duodenal samples and 1.56 (range 1.22-1.91) for colonic samples. Predicted and observed normalized GC-C mRNA expression in each region were comparable among age groups. Pooled expression by region demonstrated lower expression in colonic versus duodenal samples. CONCLUSIONS: Uniform levels of GC-C mRNA expression were detected in children aged >6 months in the duodenum and >12 months in the colon. Higher expression was observed in all age groups in duodenal versus colonic samples, indicating regional variability in GC-C receptor density. These data are reassuring for further studies of GC-C agonists in children.

Evaluation of the Pharmacokinetic Interaction of Ubrogepant Coadministered With Sumatriptan and of the Safety of Ubrogepant With Triptans.

OBJECTIVE: To evaluate the potential for pharmacokinetic interaction and the safety and tolerability when ubrogepant and sumatriptan are coadministered in a Phase 1 study in healthy participants, and to inform the safety and tolerability of ubrogepant alone and in combination with triptans in Phase 3 trials in participants with migraine. BACKGROUND: Calcitonin gene-related peptide is a potent vasodilatory neurotransmitter believed to play a key role in the pathophysiology of migraine. Ubrogepant (UBRELVY™) is a potent and selective antagonist of the human calcitonin gene-related peptide receptor approved for the acute treatment of migraine. Sumatriptan is a serotonin receptor agonist and the most commonly used triptan for the acute treatment of migraine. Ubrogepant could be prescribed with triptans. DESIGN: The Phase 1 study was a single-center, open-label, randomized, 3-way crossover, single-dose, pharmacokinetic interaction study, where participants received each of 3 oral treatments with a 7-day washout period between treatments: single dose of ubrogepant 100 mg, single dose of sumatriptan 100 mg, and ubrogepant 100 mg plus sumatriptan 100 mg. Pharmacokinetic parameters were calculated using a model-independent approach. The ACHIEVE I and II trials were 2 multicenter, single-attack, randomized, Phase 3 trials in adults with a history of migraine with or without aura. Participants had the option to take a second dose of study medication or rescue medication to treat a nonresponding migraine or a migraine recurrence from 2 to 48 hours after the initial dose of study medication. Rescue medication options included acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, anti-emetics, or triptans. Treatment-emergent adverse events were evaluated up to 30 days after the last dose in the Phase 1 and Phase 3 studies. RESULTS: Ubrogepant median time to maximum plasma concentration was delayed (3 hours [range: 1-5 hours] vs 1.5 hours [range: 1-4 hours]), mean maximum plasma concentration was reduced by 24% (coefficient of variation: 37.4%) when ubrogepant was coadministered with sumatriptan (n = 29) compared with ubrogepant administered alone (N = 30). No significant effect was observed on the area under the plasma concentration-time curve of ubrogepant. Sumatriptan area under the curve and maximum plasma concentration showed no significant change when sumatriptan was coadministered with ubrogepant (n = 29), but the sumatriptan time to maximum plasma concentration was delayed (1 hour [range: 0.5-5 hours] vs 3 hours [range: 0.5-6 hours]. No treatment-emergent adverse events were reported with the coadministration of ubrogepant 100 mg and sumatriptan 100 mg in the Phase 1 study. The pooled safety data from ACHIEVE trials (N = 1938) showed similar rates of treatment-related treatment-emergent adverse events between participants who took ubrogepant alone and participants who took ubrogepant and a triptan as a rescue medication (14.9% [53/355] vs 12.8% [5/39] in the ubrogepant 100 mg treatment group, respectively). CONCLUSIONS: Although there were slight alterations in ubrogepant pharmacokinetic parameters when coadministered with sumatriptan, such changes are expected to have minimal clinical relevance, especially because no changes were seen in sumatriptan area under the curve and maximum plasma concentration when coadministered with ubrogepant. Coadministration of ubrogepant with sumatriptan was well tolerated in healthy participants in the Phase 1 study, and coadministration of ubrogepant with triptans was well tolerated in participants with migraine in the Phase 3 trials. No new safety concerns for ubrogepant were identified across all trials.

Pharmacokinetics and Safety of Vilazodone in Hepatic Impairment.

Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder, is extensively hepatically metabolized. The pharmacokinetics, tolerability, and safety of vilazodone were investigated in 2 trials comparing participants with hepatic impairment with healthy controls. In these phase 1, open-label, parallel-group, single-dose pharmacokinetic studies, vilazodone (20 mg) was administered to participants with mild, moderate, or severe hepatic impairment or individually matched healthy controls. Vilazodone and M17 (the major metabolite) concentrations in plasma were analyzed using validated liquid chromatography with tandem mass spectrometry. Forty-eight participants (8 each in mild, moderate, and severe hepatic impairment groups with matched healthy controls) were evaluated for pharmacokinetic analyses. All pharmacokinetic parameters in participants with mild and moderate hepatic impairment were similar to those in healthy controls. Mean Cmax and AUC0-∞ were approximately 29% and 17% lower in participants with severe hepatic impairment compared with healthy participants; values for Tmax, and t1/2 were similar between groups. Diarrhea was experienced by more participants with hepatic impairment than controls (10 vs. 5, respectively), and vomiting (4 participants) occurred only in participants with severe hepatic impairment; other adverse events were roughly equivalent between groups. Following a single, 20-mg oral dose of vilazodone, pharmacokinetics were similar in participants with mild, moderate, or severe hepatic impairment and healthy controls. No dose adjustment is needed for patients with major depressive disorder who have mild, moderate, or severe hepatic impairment.

Pharmacokinetics of Ubrogepant in Healthy Japanese and White Adults.

Ubrogepant is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults. The objectives of this study were to evaluate (1) single-dose pharmacokinetics (PK) and dose proportionality of ubrogepant in Japanese participants, (2) the safety and tolerability of ubrogepant in healthy Japanese and White participants, and (3) to compare the PK of ubrogepant in Japanese versus White participants. A total of 48 participants were enrolled into 4 cohorts (N = 12 [9 active + 3 placebo] per cohort). A single dose was administered on Day 1 following an overnight fast to assess the PK of ubrogepant at 3 dose levels and test dose proportionality between 25 and 100 mg in Japanese participants. White participants were randomly assigned to ubrogepant (100 mg) or placebo. Dose proportionality was observed in the dose range of 25-100 mg in Japanese participants. Systemic exposure was 20% lower in Japanese participants as compared with White participants, but this difference is unlikely to be clinically relevant. Single doses of ubrogepant (25-100 mg) had a safety profile similar to placebo, and no differences in the safety profile of ubrogepant 100 mg were observed between Japanese versus White participants.

Ubrogepant: Mechanism of action, clinical and translational science.

In recent years, the treatment of migraine has experienced a breakthrough in the development of drugs that target the calcitonin gene-related peptide (CGRP) signaling pathway. Monoclonal antibodies against the receptor or ligand have been developed for the preventive treatment of migraine; whereas, orally administered small molecule CGRP receptor antagonists, called gepants, have been developed for both acute and/or preventive treatment. Both modalities have demonstrated safe and effective treatment of migraine, reducing the number of migraine days for patients as well as reducing symptoms and improving patient function and overall quality of life. Here, we provide an abridged review of ubrogepant, an oral CGRP receptor antagonist, approved for the acute treatment of migraine. We briefly summarize the role of CGRP in migraine pathophysiology, describing the mechanism of action of ubrogepant in the context of this pathway, the clinical pharmacology properties and the clinical development and outcomes, including safety, efficacy, pharmacokinetics, and pharmacodynamics, that supported ubrogepant's approval.

Pharmacokinetics and Safety of Atogepant Co-administered with Quinidine Gluconate in Healthy Participants: A Phase 1, Open-Label, Drug-Drug Interaction Study.

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, is approved for the preventive treatment of migraine. Atogepant is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein, organic anion transporting polypeptide transporters, and cytochrome P450 (CYP)3A4 and 2D6. Quinidine is a strong P-gp and CYP2D6 inhibitor. A phase 1 open-label study evaluated the effect of P-gp and CYP2D6 inhibition by quinidine on the pharmacokinetics of atogepant, and the safety and tolerability of atogepant and quinidine gluconate (QG) when co-administered and when given alone in 33 healthy adults. There was no significant change in the atogepant maximum plasma concentration with QG co-administration. The overall systemic exposure, the area under the plasma concentration-time curve (from time 0 to time t or to infinity), of atogepant increased by 25% when co-administered with QG. However, such an increase was not considered clinically relevant. Atogepant did not alter the mean plasma concentration of quinidine at steady state. The incidence of treatment-emergent adverse events (TEAEs) was highest when QG was administered alone (42.4%), which was primarily due to QT prolongation. Most TEAEs reported were mild in severity and resolved within 1-2 days. Co-administration of atogepant with QG did not result in any unexpected tolerability findings in this phase 1 study in healthy participants. The increase in atogepant exposure during QG co-administration could be due to inhibition of CYP2D6 (a minor contributor to atogepant clearance) as well as inhibition of P-gp.

Effect of a High-Fat Meal on the Pharmacokinetics of an Immediate Release Atogepant Tablet.

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, is approved for the preventive treatment of migraine. A phase 1, open-label, single-dose, 2-period crossover study evaluated the effect of a high-fat meal on the pharmacokinetics and safety of atogepant in 20 healthy adults. Administration of atogepant 60 mg immediate-release (IR) tablets under fed conditions reduced the area under the plasma concentration-time curve (AUC) from 0 to time t and from 0 to time infinity by approximately 18% and reduced the maximum plasma concentration (Cmax) by 22%. The 90% confidence intervals for the geometric mean ratios of Cmax and AUC were not contained within the bioequivalence limits of 80%-125%. There was no change in the median time to maximum plasma concentration in the fed versus fasted state. The incidence of treatment-emergent adverse events (TEAEs) was similar between fed and fasted conditions. Four TEAEs were considered related to study intervention and were reported after participants received atogepant under fasted conditions (3 participants). A single-dose atogepant 60 mg IR tablet was safe and tolerated under both fed and fasted states. Due to the wide effective dose range of 10-60 mg/day for atogepant for the preventive treatment of migraine, the food effect on its pharmacokinetics is not considered clinically relevant.

Atogepant: Mechanism of action, clinical and translational science.

Since the discovery of calcitonin gene-related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine-specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP-mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant.

Vilazodone lacks proarrhythmogenic potential in healthy participants: a thorough ECG study.

OBJECTIVE: Vilazodone is a potent serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder (MDD) in adults. The effect of clinical and supratherapeutic doses of vilazodone on cardiac repolarization was determined in healthy volunteers. METHODS: In this Phase 1, randomized, doubleblind, placebo- and active-controlled, 3-arm, parallel, single-center study, healthy subjects received placebo; moxifloxacin 400 mg; or vilazodone (sequentially escalated every 3 days) 10, 20, 40, 60, and 80 mg/day. The primary endpoint was the time-matched change from baseline in the QT interval corrected for heart rate (QTc) using an individual correction method (QTcI). RESULTS: Placebo-corrected time-matched analysis of the QTcI duration for the vilazodone treatment effect indicated that no vilazodone dose had an upper bound that approached or exceeded 10 ms, demonstrating no signal for a significant vilazodone effect on cardiac repolarization. Vilazodone had no significant effect on heart rate, PR, or QRS interval duration. The pharmacokinetic/pharmacodynamic model showed that the QTcI slope for vilazodone was not different from 0.0 and that the predicted increase from baseline in the QTc at Cmax for the highest therapeutic dose (156 ng/ml after 40 mg/day) was < 1 ms. The incidence of adverse events (AEs) was higher in the vilazodone group (57.6%) than in the moxifloxacin (37.0%) and placebo (35.6%) groups, though AEs were generally mild to moderate in severity and resulted in few discontinuations. CONCLUSIONS: Vilazodone had no significant effect on cardiac repolarization, heart rate, PR or QRS interval duration, or ECG morphology in healthy adult participants.

Single-dose Pharmacokinetics of Eluxadoline in Healthy Participants With Normal Renal Function and Participants With Renal Impairment.

Eluxadoline is approved for the treatment of diarrhea-predominant irritable bowel syndrome in the United States. The impact of renal impairment on the pharmacokinetic (PK) parameters of eluxadoline is currently unknown. This phase 1, open-label, parallel-group study evaluated the PK and safety profile of eluxadoline in 8 participants with renal impairment and 8 matched healthy controls. Of the participants with renal impairment, 2 had severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 ) and 6 had end-stage renal disease while not yet on dialysis (eGFR <15 mL/min/1.73 m2 ). The primary objective was to assess plasma and urine PKs, and plasma protein binding of eluxadoline. In participants with renal impairment, mean plasma concentrations of eluxadoline were consistently higher compared with matched healthy controls: 1.4-fold higher for mean maximum plasma concentration (Cmax ) and 2.2-fold higher for mean area under the plasma concentration-time curve from time 0 to time t. The median time to Cmax was 2.5 hours in both groups. Although eluxadoline is a locally acting drug with low oral bioavailability, because of the increased systemic exposure in participants with renal impairment as a cautionary measure the lower approved dose of 75 mg twice daily is recommended for individuals with severe renal impairment and end-stage renal disease while not yet on dialysis. Eluxadoline 100 mg single dose was well tolerated in participants with renal impairment and matched healthy controls.

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.

Effects of CYP3A4 inhibition/induction and OATP inhibition on the pharmacokinetics of atogepant in healthy adults.

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: Cmax and AUC 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.

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 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.

Evaluation of the pharmacokinetic interactions and safety of atogepant coadministered with esomeprazole.

Aim: To investigate potential pharmacokinetic interactions between atogepant and esomeprazole. Methods: Atogepant, esomeprazole, or both were administered to 32 healthy adults in an open-label, nonrandomized, crossover study. Systemic exposure (area under the plasma concentration-time curve [AUC] and peak plasma concentration [Cmax]) for atogepant administered in combination versus alone were compared using a linear mixed effects model. Results: Coadministration with esomeprazole delayed atogepant time to Cmax by ∼1.5 h and reduced Cmax by ∼23% with no statistically significant change in AUC compared with atogepant alone. Administration of atogepant 60 mg alone or in combination with esomeprazole 40 mg was well tolerated in healthy adults. Conclusion: Esomeprazole had no clinically meaningful effect on atogepant pharmacokinetics. Clinical Trial Registration: unregistered phase I study.

A clinical study was conducted in 32 healthy adults to evaluate the possibility of interactions between atogepant, a new drug for the prevention of migraine, and esomeprazole, a drug used to reduce stomach acid. The participants of the study were given each drug alone and together to understand the effect they had on the body's ability to absorb, distribute, and excrete each drug alone and together. The results of this study show that there are no clinically important changes in how atogepant is processed by the body when administered with esomeprazole, and they can be safely taken together.