CGRP receptor ( IC50 = 0.081 nM )
Ubrogepant is a Calcitonin Gene-related Peptide Receptor Antagonist. The mechanism of action of ubrogepant is as a Calcitonin Gene-related Peptide Receptor Antagonist.

Ubrogepant is a small molecule inhibitor of the calcitonin gene-related peptide (CGRP) receptor that blocks the action of CGRP, a potent vasodilator believed to play a role in migraine headaches.
Ubrogepant (MK-1602) is a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist. [1]

Ubrogepant is a Calcitonin Gene-related Peptide Receptor Antagonist. The mechanism of action of ubrogepant is as a Calcitonin Gene-related Peptide Receptor Antagonist.

Ubrogepant is a small molecule inhibitor of the calcitonin gene-related peptide (CGRP) receptor that blocks the action of CGRP, a potent vasodilator believed to play a role in migraine headaches.

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The average in vitro blood-to-plasma ratio of ubrogepant was 0.8 and was consistent across the concentration range of 1–100 μM. [1]
The average fraction unbound in human plasma was 12.7% and was consistent across the concentration range of 0.1 to 10 μM. [1]

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The average in vitro blood-to-plasma ratio of ubrogepant was 0.8 and was consistent across the concentration range of 1–100 μM. [1]
The average fraction unbound in human plasma was 12.7% and was consistent across the concentration range of 0.1 to 10 μM. [1]

Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene-related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting.[1]

Absorption, Distribution and Excretion
Following oral administration, Tmax ranges from 0.7 to 1.5 hours. When taken with a high-fat meal, Tmax is delayed by approximately 2 hours, Cmax decreases by 22%, and AUC remains unchanged. Ubregapan exhibits dose-proportional pharmacokinetic characteristics within its recommended dose range. The primary route of excretion is fecal/biliary excretion, with relatively low renal excretion—in healthy subjects, approximately 42% of the dose is excreted unchanged in feces and 6% unchanged in urine after a single oral dose. The apparent central volume of distribution after oral administration is approximately 350 liters. The apparent oral clearance of ubrogpan is approximately 87 liters/hour. Metabolism/Metabolites Ubregapan is primarily eliminated through metabolism, with most metabolism mediated by CYP3A4. In human plasma, the two circulating glucuronide conjugates and the unchanged drug are the most abundant circulating components. It has been reported that the glucuronide metabolite has 6,000 times less activity on CGRP receptors than the original drug and is therefore considered to have no pharmacological activity.

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Biological half-life
The elimination half-life of ubrogipan is 5-7 hours.

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Absorption: Population pharmacokinetic models describe the absorption process of ubrogipan, which is first infused into the absorption storage chamber in a zero-order sequence and then absorbed into the central chamber in a lag first-order sequence. [1]
Distribution: The in vitro plasma ratio is approximately 0.8. Population pharmacokinetic models estimate the plasma ratio (slope parameter, SLP) to be 0.732. [1] Metabolism/excretion: Key pharmacokinetic parameters estimated by population pharmacokinetic models include apparent clearance (CL/F), apparent central chamber volume (Vc/F), apparent intercompartmental clearance (Q/F), and apparent peripheral chamber volume (Vp/F). Specific values for clearance, volume, or half-life are not provided in this paper. [1] Bioavailability: Migraine attacks were identified as a significant covariate affecting the bioavailability (F1) of ubrogpan, with absorption reduced by approximately 30% in migraine patients compared to healthy subjects. [1] Analytical methods: Bioanalytical methods for the quantitative analysis of ubrogpan in plasma and dried blood spot (DBS) samples have been developed and validated. DBS detection methods involve extraction of the drug directly from 3.2 mm discs punched from DBS cards, followed by liquid-liquid extraction with methyl tert-butyl ether, separation by reversed-phase high-performance liquid chromatography, and detection by tandem mass spectrometry (MS/MS). The limit of quantitation (LLOQ) for DBS detection is 0.36 nM (supporting study PN007) or 0.91 nM (supporting study PN005). [1] Stability: Ubrogepant is stable in DBS for at least 10 weeks at room temperature and at high temperature (40°C/75% relative humidity) for at least 5 weeks. In human plasma, it is stable for at least 14 weeks at -20°C or -70°C. [1]

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Absorption: Population pharmacokinetic models describe the absorption process of ubrogepant, which is characterized by the drug being first infused into the absorption storage chamber in zero order, followed by absorption into the central chamber in a lag first order. [1]
Distribution: The in vitro plasma ratio is approximately 0.8. The plasma ratio (slope parameter, SLP) estimated by the population pharmacokinetic model is 0.732. [1]
Metabolism/Excretion: Key pharmacokinetic parameters estimated by the population model include apparent clearance (CL/F), apparent central chamber volume (Vc/F), apparent intercompartment clearance (Q/F), and apparent peripheral chamber volume (Vp/F). Specific values for clearance, volume, or half-life are not provided in this paper. [1]
Bioavailability: Migraine attacks were identified as an important covariate affecting ubrogepant bioavailability (F1), with migraine sufferers showing approximately 30% lower absorption compared to healthy subjects. [1]
Analytical methods: Bioanalytical methods for quantifying ubrogepant in plasma and dried blood spot (DBS) samples were developed and validated. DBS detection involved punching a 3.2 mm diameter disc from a DBS card, followed by liquid-liquid extraction with methyl tert-butyl ether, separation by reversed-phase high-performance liquid chromatography (HPLC), and detection by tandem mass spectrometry (MS/MS). The limit of quantitation (LLOQ) for DBS detection was 0.36 nM (supporting study PN007) or 0.91 nM (supporting study PN005). [1]
Stability: Ubrrogpan is stable for at least 10 weeks in dried blood spots at room temperature and for at least 5 weeks at high temperature (40°C/75% relative humidity). In human plasma, it is stable for at least 14 weeks at -20°C or -70°C. [1]

Hepatotoxicity
In pre-registration controlled trials of ubrogepant involving thousands of patients, only a small number (1% to 2%) experienced mild to moderate elevations in serum transaminases, with an overall incidence not significantly different from the placebo group. No clinically significant liver injury caused by ubrogepant has been reported in these controlled trials or in subsequent routine use. In contrast, telcagepant, an oral CGRP receptor antagonist initially developed for migraine treatment, was abandoned during development due to clinically significant liver injury in multiple patients. These liver injuries were characterized by significantly elevated serum transaminase levels and symptoms such as fatigue, nausea, and abdominal discomfort appearing within 2 to 4 weeks of starting treatment, which rapidly resolved upon timely discontinuation of the drug. No similar events have been reported with ubrogepant. Probability Score: E (Unlikely to be the cause of clinically significant acute liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no published experience regarding the use of ubrogepant during lactation. Ubrogepant has a protein binding rate of 87%, so the drug concentration in breast milk may be very low. If a mother of an older infant needs to take ubrogpant, this is not a reason to stop breastfeeding, but until more data is available, alternative medications may be preferred, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding Ubrogepant has an in vitro protein binding rate of 87%, but the specific proteins that ubrogpant binds to have not been determined.

[1]. Population PK Analyses of Ubrogepant (MK-1602), a CGRP Receptor Antagonist: Enriching In-Clinic Plasma PK Sampling With Outpatient Dried Blood Spot Sampling. J Clin Pharmacol. 2017 Nov 14. doi: 10.1002/jcph.1021.

Pharmacodynamics
Ubrigadipam treats migraine acutely by blocking the activity of key neurotransmitters involved in the pathogenesis of migraine. Ubrigadipam exposure may be significantly increased in patients with severe hepatic or renal impairment—these patients require dose adjustment to avoid overexposure, and ubrogipam is not recommended for patients with end-stage renal disease. Ubrigadipam is being developed for the acute treatment of migraine. [1] This article highlights the use of dried blood spot (DBS) sampling in an outpatient setting for population pharmacokinetic (PK) modeling of ubrogipam. DBS sampling allows for the collection of samples at home before and after spontaneous migraine attacks, enriching the PK dataset, which is difficult to achieve with traditional in-office plasma sampling. [1]
This strategy includes in vitro feasibility studies, bridging studies in healthy subjects (PN005) and migraine patients (PN007) to establish the relationship between blood (dried blood spots) and plasma concentrations, and extensive training for research centers and subjects. [1]
A population pharmacokinetic model was developed using pooled data from multiple studies. The model identified formulation, health status, sex, and migraine onset as important covariates. [1]
Analysis of residual variability showed that dried blood spot sampling was accurate in a controlled clinical setting, but variability increased significantly when subjects collected samples at home, which may be due to operational compliance or recording errors rather than problems with the test itself. [1]

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Ubrrogipam is being developed for the acute treatment of migraine. [1]
This article highlights population pharmacokinetic (PK) modeling of ubrogipam using dried blood spot (DBS) sampling in an outpatient setting. DBS sampling was used to enrich pharmacokinetic (PK) datasets, allowing subjects to collect samples at home before and after spontaneous migraine attacks, which is difficult to achieve with traditional clinical plasma sampling. [1]
This strategy included in vitro feasibility studies, bridging studies in healthy subjects (PN005) and migraine patients (PN007) to establish the relationship between blood (DBS) and plasma concentrations, and extensive training for research centers and subjects. [1]
A population pharmacokinetic model was developed using pooled data from multiple studies. The model identified formulation, health status, sex, and migraine attacks as important covariates. [1]
Analysis of residual variability showed that DBS sampling had high accuracy in a controlled clinical setting, but variability increased significantly when subjects collected samples at home, which may be due to operational compliance or recording errors rather than problems with the test itself. [1]

C29H26F3N5O3

549.54364

549.199

C, 63.38; H, 4.77; F, 10.37; N, 12.74; O, 8.73

1374248-77-7

68748835

White to off-white solid powder

1.45±0.1 g/cm3(Predicted)

729.4±60.0 °C(Predicted)

4.128

2

8

4

40

1000

4

O=C(C1=CN=C2C(C[C@@]3(C4=CC=CN=C4NC3=O)C2)=C1)N[C@@H]5C(N(CC(F)(F)F)[C@H](C)[C@H](C6=CC=CC=C6)C5)=O

DDOOFTLHJSMHLN-ZQHRPCGSSA-N

InChI=1S/C29H26F3N5O3/c1-16-20(17-6-3-2-4-7-17)11-22(26(39)37(16)15-29(30,31)32)35-25(38)19-10-18-12-28(13-23(18)34-14-19)21-8-5-9-33-24(21)36-27(28)40/h2-10,14,16,20,22H,11-13,15H2,1H3,(H,35,38)(H,33,36,40)/t16-,20-,22+,28+/m1/s1

(3S)-N-[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide

Ubrogepant; MK1602; MK-1602; 1374248-77-7; Ubrelvy; Ubrogepant anhydrous; UNII-AD0O8X2QJR; AD0O8X2QJR; DTXSID00160178;MK1602; trade name: Ubrelvy

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100~250 mg/mL (182~454.9 mM)
Ethanol: ~50 mg/mL

Solubility in Formulation 1: ≥ 6.25 mg/mL (11.37 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 6.25 mg/mL (11.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly.

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Solubility in Formulation 3: ≥ 5 mg/mL (9.10 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 4: 5%DMSO + 40%PEG300 + 5%Tween 80 + 50%ddH2O: 5.0mg/ml (9.10mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)