Ubrogepant

Limits on what this shows

• Key negative findings: The study authors explicitly caution that the in vitro concentration-response parameters "may not be active at the predicted liver concentration range for the compound," and the integrated DILIsym systems-toxicology model, which combines this and other in vitro signals with actual human exposure data, predicted that all four next-generation gepants, ubrogepant included, would be significantly less likely to cause drug-induced liver injury than telcagepant. No hepatotoxicity or mitochondrial-injury signal has been reported in ubrogepant's FDA label or pivotal trial data.
• At-risk subgroups: None established at approved clinical dosing; this is a preclinical, mechanistic-tier signal only. Severe hepatic impairment already carries a labeled reduced-dose recommendation for unrelated pharmacokinetic-clearance reasons.

Regulatory status

Not addressed in the FDA label as a mitochondrial-toxicity finding; the label carries no hepatotoxicity warning and no boxed warning of any kind.

Population evidence

Tier B. In vitro study, HepG2 human hepatocyte cell line, ubrogepant tested by name alongside three other next-generation gepants (rimegepant, atogepant, zavegepant), contrasted with the first-generation gepant telcagepant, which failed clinical development for hepatotoxicity. Oxygen consumption rate versus LC/MS/MS-confirmed intracellular ubrogepant concentration, after 24-hour incubation, was fit with MITOsym modeling software; ubrogepant, like telcagepant, rimegepant, and atogepant, inhibited the electron transport chain, while zavegepant instead acted as a mild uncoupler of the mitochondrial proton gradient. Woodhead JL, Siler SQ, Howell BA, Watkins PB, Conway C. Toxicological Sciences, 2022;188(1):108-116. PMID 35556143, DOI 10.1093/toxsci/kfac051.

Mechanism

Named: electron transport chain inhibition in hepatocytes, detected via oxygen-consumption-rate modeling at the in vitro concentrations tested. Not established as an active mechanism at approved clinical exposure; see framing caution.

Counter-evidence held on record

This is a supratherapeutic in vitro liver-toxicology screening result, generated specifically to compare next-generation gepants against the hepatotoxic telcagepant, not a demonstrated clinical mitochondrial-injury or nutrient-depletion effect. Do not present as an established human mitochondrial-toxicity risk. No mitochondrial-support supplementation (coenzyme Q10, carnitine, alpha-lipoic acid, or similar) is indicated on this basis. Migraine itself, independent of any drug, has a separate literature associating the disease state with impaired oxidative energy metabolism, the rationale for riboflavin and coenzyme Q10 as migraine-prevention supplements; that disease-level association is not evidence that ubrogepant causes or worsens it, and is out of scope for this drug-specific finding.

Limits on what this shows

• Key negative findings: The same authors' caveat regarding predicted liver concentration range applies here, and the same DILIsym conclusion, that ubrogepant carries significantly lower predicted drug-induced liver injury risk than telcagepant despite this in vitro signal, applies as well. No oxidative-stress-related finding is documented in ubrogepant's FDA label.
• At-risk subgroups: None established clinically; preclinical screening signal only.

Regulatory status

Not addressed in the FDA label; no oxidative-stress-related adverse effect appears in the labeled adverse reactions.

Population evidence

Tier B, same source as Mitochondrial burden (Woodhead et al, Toxicological Sciences, 2022, PMID 35556143, see Overlap map). Reactive oxygen species formation assayed by dihydroethidium (DHE) fluorescence in HepG2 cells over 6- and 24-hour incubations, three independent studies in triplicate. Telcagepant, rimegepant, atogepant, and ubrogepant all showed increased ROS; zavegepant, tested at a top concentration at least 10-fold higher than the others, did not.

Mechanism

Named: reactive oxygen species induction in hepatocytes at the in vitro concentrations assayed, part of the same toxicology-screening battery used to model hepatotoxicity risk.

Counter-evidence held on record

Preclinical and mechanistic only, from a toxicology-screening assay, not a demonstrated clinical oxidative-stress or antioxidant-depletion problem at approved dosing. No antioxidant supplementation is indicated on this basis. This entry shares its entire evidence base with Mitochondrial burden and, more cautiously, ATP production (see Overlap map); treat the three as one preclinical finding viewed from three required-category angles, not three independent confirmations.

Limits on what this shows

• Why no grade: Both Step 7 conditions are met: no Tier B or C evidence and no circulating claim, across both the original session's queries and this repair pass's fresh, successful queries to DailyMed, Crossref, and Europe PMC. Assessment: a genuine, now twice-confirmed gap, with a residual tooling-limited component on the channels still blocked this session (Semantic Scholar, OpenAlex, eutils, Unpaywall, WebSearch). Mechanistically, ubrogepant's absorption is not documented as chelation- or transporter-mediated, and its primary elimination is biliary/fecal plus CYP3A4 metabolism, not a copper-dependent pathway, which further reduces prior plausibility for this category.

Channels tried

Repair-pass search conducted 2026-09-29, in addition to the original session's queries. FDA prescribing information, most recent supplement (S-012, approved 2025-06-05), fetched directly as a full-text PDF and searched for "copper," "ceruloplasmin," and "mineral": zero matches. DailyMed's current record for UBRELVY (last updated 2025-06-05) fetched directly and confirmed consistent with the FDA PDF. PubMed search-listing, query "ubrogepant copper OR iron" returned 10 displayed results, all general iron/copper biochemistry reviews (e.g. Auerbach et al, "Iron Deficiency in Adults," 2025; Nemeth and Ganz, "Hepcidin and Iron in Health and Disease," 2022), none mentioning ubrogepant or any gepant. Crossref API, two bibliographic queries, "ubrogepant copper iron ceruloplasmin" (10 results, ubrogepant synthesis-chemistry papers and unrelated copper/cuproptosis biomarker literature) and "CGRP receptor antagonist gepant copper ceruloplasmin" (15 results, gepant synthesis-chemistry and clinical-overview papers, none addressing copper), neither returning a copper-specific finding for any gepant. Europe PMC REST API, broad query "ubrogepant" (25 results reviewed by title, none copper-related).

Channels blocked

This session: the Semantic Scholar and OpenAlex APIs returned HTTP 429 on every query attempted; NCBI's eutils service was disallowed by its own robots.txt; Unpaywall's search endpoint returned HTTP 422 on every query attempted; several PubMed and Crossref follow-up fetches were rejected by the fetch proxy with HTTP 429 ("do not fetch this page again"); WebSearch had already exhausted its full session budget (200 of 200 calls) before this repair pass began. This differs from the original session, in which DailyMed, Europe PMC, and Crossref were blocked outright (HTTP 403) and could not be reached at all; this pass reached all three successfully at least once.

Circulating claim

None found; see Fails verification for the consumer drug-interaction database check (267 listed interactions for ubrogepant, zero nutrient-related).

Limits on what this shows

• Why no grade: No Tier B or C evidence and no circulating claim, across both the original session and this repair pass's fresh, successful queries to DailyMed, Crossref, and Europe PMC. Assessment: a genuine, now twice-confirmed gap, with a residual tooling-limited component on the channels still blocked this session. Ubrogepant's renal elimination is minor (6% recovered unchanged in urine), and no tubular or absorptive mechanism plausibly touching iron status is documented in the label.

Channels tried

Repair-pass search conducted 2026-09-29, in addition to the original session's queries. FDA prescribing information, most recent supplement (S-012, approved 2025-06-05), fetched directly as a full-text PDF and searched for "iron," "ferritin," "hemoglobin," "hematocrit," and "anemia": zero matches on any term. DailyMed's current record fetched and confirmed consistent. PubMed search-listing, same combined query used for Copper ("ubrogepant copper OR iron", 10 displayed results, all general iron-biochemistry reviews, none ubrogepant- or gepant-specific). Crossref API, same two combined queries used for Copper ("ubrogepant copper iron ceruloplasmin" and "CGRP receptor antagonist gepant copper ceruloplasmin"), neither surfacing an iron- or hemoglobin-specific finding for any gepant. Europe PMC REST API, broad query "ubrogepant" (25 results reviewed by title, none iron- or hematologic-related).

Channels blocked

Same as Copper this session: Semantic Scholar and OpenAlex APIs returned HTTP 429 on every attempt; NCBI eutils disallowed by robots.txt; Unpaywall's search endpoint returned HTTP 422 on every query; several PubMed and Crossref follow-up fetches rejected by the fetch proxy (HTTP 429); WebSearch budget already exhausted (200 of 200) before this pass began. DailyMed, Europe PMC, and Crossref, blocked outright in the original session, were each reached successfully at least once this pass.

Circulating claim

None found; see Fails verification for the consumer-database check.

Limits on what this shows

• Why no grade: No confirmed Tier B or C evidence and no circulating claim. The Johnson/Li/Li 2020 abstract is a real study of a gepant-class member (telcagepant) on a mechanistically relevant endpoint (GI transit time), which would ordinarily support a class-extrapolation yellow grade per Step 7, but its result cannot be confirmed from the title and aim alone, and grading a category on an unverified finding would fail the self-audit test that every claim survive a pharmacist reading the cited source. This entry therefore stays ungraded rather than assigning yellow to an unconfirmed result; it should be the first channel re-checked on any future revision, ideally via direct access to the Neurology supplement or a search for a subsequent full-length publication. Oral tablets do transit the gastrointestinal tract, and ubrogepant's acute, intermittent dosing pattern (maximum 8 treatment days per 30 days) further limits plausibility of a sustained microbiome effect compared with a chronic daily medication, even if the telcagepant lead is eventually confirmed.

Channels tried

Original session: PubMed search-listing, query "ubrogepant microbiome OR ubrogepant gut" (0 results, page explicitly stated no results found); Crossref API, query combining ubrogepant with gut microbiome and intestinal terms (8 results returned, none involving ubrogepant or any CGRP receptor antagonist). Repair pass, 2026-09-29: FDA prescribing information, most recent supplement (S-012, approved 2025-06-05), fetched directly and searched for "gut microbiome," "intestinal flora," and "gastrointestinal flora": zero matches. DailyMed's current record fetched and consistent. Europe PMC REST API, broad query "ubrogepant" (25 results reviewed by title; one disease-level, non-drug-specific result, "A review on gut microbiota and migraine severity: a complex relationship," was noted but its full text could not be retrieved this session to confirm whether it discusses any gepant drug, so it is not used as evidence). Crossref API, bibliographic query pairing "CGRP receptor antagonist gepant" with gastrointestinal/hemoglobin terms surfaced a real, class-adjacent lead: Johnson KW, Li X, Li B. "Characterization of Transit Times in the Large Intestine of Mice Following Treatment with a CGRP Antibody, CGRP Receptor Antibody and a Small Molecule CGRP Receptor Antagonist." Neurology. 2020;94(15 Suppl):1791 (American Academy of Neurology conference abstract, Eli Lilly authors). Its OpenAlex record confirms the small-molecule antagonist tested was telcagepant, a first-generation gepant, in a mouse gastrointestinal-transit-time model, a mechanism (altered transit time) plausibly relevant to microbiome composition. The actual measured result (direction, magnitude, or statistical significance of any transit-time change) could not be retrieved: the Neurology journal's abstract page returned an HTTP 403 error, and a follow-up Crossref search for any full peer-reviewed publication arising from this abstract was rejected by rate limiting (HTTP 429) before it could complete.

Channels blocked

Semantic Scholar and OpenAlex search endpoints returned HTTP 429 on every further query attempted this session; NCBI eutils disallowed by robots.txt; Unpaywall's search endpoint returned HTTP 422 on every query; the Neurology journal site returned HTTP 403 on direct fetch; WebSearch budget already exhausted (200 of 200) before this pass began.

Circulating claim

None found; see Fails verification for the consumer-database check.

Limits on what this shows

• Key negative findings: No cardiovascular adverse-event signal above placebo appears in ubrogepant's FDA label; the telcagepant coronary-artery study found no vasoconstriction; ubrogepant's elimination half-life of 5 to 7 hours combined with its acute, intermittent dosing cap (maximum 8 treatment days per 30 days) limits sustained systemic exposure compared with a chronic daily medication.
• At-risk subgroups: Patients with underlying ischemic or vasospastic coronary disease represent a theoretical class-level concern per the mechanism above; the ubrogepant label itself does not single out this subgroup.

Regulatory status

The FDA label documents no cardiovascular warning, no blood-pressure precaution, and no vasospastic-disease contraindication; the only cardiac-specific label finding is that ubrogepant does not meaningfully prolong the QT interval at twice the maximum recommended dose.

Population evidence

Tier B, established pharmacology, not ubrogepant-specific: CGRP is a potent, physiologically important vasodilator, and CGRP-receptor blockade is mechanistically capable of blunting a protective vasodilatory response during ischemia. A human isolated coronary artery study of telcagepant, an earlier-generation gepant, not ubrogepant (Chan KY et al, J Pharmacol Exp Ther, 2010), found no coronary vasoconstriction, supporting general class tolerability relative to the triptans, which carry labeled coronary vasospasm warnings. Two further items were identified by title only through PubMed search-listing pages and could not be independently verified this session: a 2025 case report (Jeon and Cho, BMC Neurology) describing variant angina associated with "a CGRP receptor antagonist," and a 2020 mouse study (Mulder et al, Annals of Neurology) on CGRP-receptor antagonists and cerebral ischemic outcome. In both cases the full record was inaccessible (reCAPTCHA verification page for the case report; blank/inaccessible content for the mouse study), so the specific compound(s) involved, and whether ubrogepant was among them, could not be confirmed. Both are disclosed here for completeness and are not used as supporting evidence for this grade.

Mechanism

Named at the class level only: CGRP-receptor antagonism blocking a vasodilatory rescue pathway during ischemia. Not confirmed for ubrogepant specifically. This is a mechanism/class consideration, not a nutrient-mediated oxygen-delivery deficiency, and it must not be filed as one.

Counter-evidence held on record

This is the drug class's own pharmacologic action on CGRP signaling, described here as a theoretical mechanism, not a demonstrated ubrogepant-specific cardiovascular event, and not anemia or any other nutrient-mediated oxygen-delivery deficiency. No iron, B12, or other hematologic supplementation is indicated by this finding. Any cardiovascular concern belongs with the prescriber, not with a nutrient intervention.

Limits on what this shows

• Key negative findings: Same as Mitochondrial burden: the authors' concentration-relevance caveat and the DILIsym model's low predicted clinical liver-injury risk for ubrogepant both argue against a clinically meaningful energy-metabolism effect at approved dosing.
• At-risk subgroups: None established clinically.

Regulatory status

Not addressed in the label.

Population evidence

Same Woodhead et al 2022 source as Mitochondrial burden and Oxidative stress (PMID 35556143, see Overlap map). The oxygen-consumption-rate assay used to detect electron transport chain inhibition is mechanistically linked to oxidative-phosphorylation capacity, but the study reports electron transport chain inhibition and mitochondrial uncoupling as its endpoints, not a directly measured ATP production rate or ATP-to-oxygen ratio.

Mechanism

Inferred, not directly measured: electron transport chain inhibition mechanistically implies reduced oxidative-phosphorylation capacity and therefore reduced maximal ATP synthesis capacity, at the in vitro concentrations tested. Not demonstrated as a clinical energy-metabolism deficit.

Counter-evidence held on record

Graded yellow because a Tier B source touches this category, per protocol, but the underlying evidence is the same in vitro hepatocyte dataset already described under Mitochondrial burden and Oxidative stress (see Overlap map); treat all three entries as one preclinical finding viewed from three required-category angles, not three independent confirmations. No energy-support supplementation (coenzyme Q10, carnitine, creatine, or similar) is indicated on this basis, and ubrogepant's acute, intermittent dosing pattern further limits any cumulative bioenergetic burden compared with a chronic daily medication.