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1.
Clin Pharmacol Drug Dev ; 13(8): 930-937, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38702918

ABSTRACT

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.


Subject(s)
Drug Interactions , Healthy Volunteers , Quinidine , Humans , Quinidine/adverse effects , Quinidine/pharmacokinetics , Quinidine/administration & dosage , Quinidine/pharmacology , Quinidine/analogs & derivatives , Adult , Male , Female , Young Adult , Middle Aged , Area Under Curve , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Cytochrome P-450 CYP2D6 Inhibitors/pharmacology , Cytochrome P-450 CYP2D6 Inhibitors/administration & dosage , Cytochrome P-450 CYP2D6 Inhibitors/adverse effects , Cytochrome P-450 CYP2D6 Inhibitors/pharmacokinetics
2.
Pain Manag ; 13(6): 351-361, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37424270

ABSTRACT

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.


Subject(s)
Esomeprazole , Adult , Humans , Esomeprazole/adverse effects , Esomeprazole/pharmacokinetics , Cross-Over Studies , Area Under Curve , Administration, Oral , Drug Interactions
3.
Clin Pharmacol Drug Dev ; 12(10): 1013-1021, 2023 10.
Article in English | MEDLINE | ID: mdl-37210713

ABSTRACT

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.


Subject(s)
Migraine Disorders , Adult , Humans , Topiramate/adverse effects , Healthy Volunteers , Migraine Disorders/drug therapy , Drug Interactions
4.
Clin Pharmacol Drug Dev ; 10(9): 1099-1107, 2021 09.
Article in English | MEDLINE | ID: mdl-33942560

ABSTRACT

Atogepant is a selective, oral calcitonin gene-related peptide receptor antagonist in development for preventive treatment of migraine. This randomized, double-blind, phase 1 crossover study evaluated the cardiac repolarization effect of a single supratherapeutic (300 mg) atogepant dose vs placebo in healthy adults. Moxifloxacin 400 mg was the open-label active control. The primary end point was a change from baseline in Fridericia-corrected QT intervals (ΔQTcF). Sixty participants were randomized to atogepant 300 mg, placebo, and moxifloxacin; 59 (98.3%) completed all interventions. Assay sensitivity was confirmed: lower 90% confidence interval limit for QTcF interval change from baseline (ΔΔQTcF) for moxifloxacin was >5 millisecond vs placebo at prespecified 2-, 3-, and 4-hour time points. Following single-dose atogepant 300 mg, mean atogepant ΔΔQTcF and upper 90% confidence interval limits were lower than the 10-millisecond threshold at all time points. Atogepant mean peak plasma concentration was 3197 ng/mL, area under the concentration-time curve from time 0 to time t was 16 640 ng • h/mL, area under the concentration-time curve from time 0 to 24 hours was 16 607 ng • h/mL, and median time to peak plasma concentration was 2.1 hours. The incidence of adverse events was low; no serious adverse events or elevations of liver enzymes were reported. Overall, a single supratherapeutic dose of atogepant was safe and did not impact cardiac repolarization in healthy participants.


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists/adverse effects , Long QT Syndrome/chemically induced , Moxifloxacin/adverse effects , Piperidines/adverse effects , Pyridines/adverse effects , Pyrroles/adverse effects , Spiro Compounds/adverse effects , Adolescent , Adult , Area Under Curve , Calcitonin Gene-Related Peptide Receptor Antagonists/administration & dosage , Calcitonin Gene-Related Peptide Receptor Antagonists/pharmacokinetics , Cross-Over Studies , Double-Blind Method , Electrocardiography , Female , Humans , Male , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Pyrroles/administration & dosage , Pyrroles/pharmacokinetics , Spiro Compounds/administration & dosage , Spiro Compounds/pharmacokinetics , Young Adult
5.
Headache ; 61(4): 642-652, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33818780

ABSTRACT

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.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Calcitonin Gene-Related Peptide/administration & dosage , Migraine Disorders/drug therapy , Pyridines/adverse effects , Pyridines/pharmacokinetics , Pyrroles/adverse effects , Pyrroles/pharmacokinetics , Adult , Antibodies, Monoclonal, Humanized/administration & dosage , Drug Interactions , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Pyridines/administration & dosage , Pyrroles/administration & dosage
6.
Clin Pharmacol Drug Dev ; 10(7): 726-733, 2021 07.
Article in English | MEDLINE | ID: mdl-33501783

ABSTRACT

Atogepant is a selective oral calcitonin gene-related peptide receptor antagonist in development for migraine prevention. Here, we report the pharmacokinetics (PK) and safety of single-dose 60 mg atogepant in participants with severe, moderate, or mild hepatic impairment and matched participants with normal hepatic function from an open-label, parallel-group, single-dose phase 1 trial. Thirty-two participants aged 45 to 72 years were enrolled, which included 8 each with severe, moderate, mild, or no hepatic impairment. All participants completed the study. Atogepant was rapidly absorbed (median time to maximum plasma concentration, ∼2 hours) with an apparent terminal elimination half-life of ∼11 hours. Compared with participants with normal hepatic function, the change in maximum plasma concentrations of atogepant were -4%, -12%, and +9% in participants with severe, moderate, or mild hepatic impairment, respectively. Overall systemic exposures to atogepant were 15% to 38% higher in participants with hepatic impairment compared with those with normal hepatic function, but these differences are not expected to be clinically relevant given the established safety profile of atogepant. Only 1 adverse event was reported: mild rhinorrhea in a participant with moderate hepatic impairment. Overall, atogepant was safe and not associated with any clinically relevant change in PK in participants with severe, moderate, or mild hepatic impairment.


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists/pharmacokinetics , Liver Diseases/physiopathology , Piperidines/pharmacokinetics , Pyridines/pharmacokinetics , Pyrroles/pharmacokinetics , Spiro Compounds/pharmacokinetics , Administration, Oral , Aged , Calcitonin Gene-Related Peptide Receptor Antagonists/adverse effects , Female , Half-Life , Humans , Male , Middle Aged , Piperidines/adverse effects , Pyridines/adverse effects , Pyrroles/adverse effects , Severity of Illness Index , Spiro Compounds/adverse effects
7.
J Ocul Pharmacol Ther ; 27(2): 173-8, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21351868

ABSTRACT

PURPOSE: Anti-inflammatory activity of topical nonsteroidal anti-inflammatory drugs is mediated by suppression of cyclooxygenase (COX) isoenzymes. This study compared ocular penetration and inflammation suppression of topical ketorolac 0.45% and bromfenac 0.09% ophthalmic solutions in a rabbit model. METHODS: At hour 0, 36 rabbits received ketorolac 0.45%, bromfenac 0.09%, or an artificial tear 3 times once every 20 min. Half of the rabbits in each group then received intravenous injections of lipopolysaccharide (LPS) and fluorescein isothiocyanate (FITC)-dextran at hour 1, and the other half at hour 10. Aqueous and iris-ciliary body (ICB) samples were collected in the former group at hour 2 (peak) and in the latter group at hour 11 (trough) An additional group of 6 animals received only FITC-dextran, and samples were collected 1 h later. Peak and trough nonsteroidal anti-inflammatory drug concentrations were compared with previously determined half-maximal inhibitory concentrations (IC(50)) for COX isoenzymes. RESULTS: Peak and trough aqueous and ICB concentrations of ketorolac were at least 7-fold or greater than those of bromfenac. At peak levels, both ketorolac 0.45% and bromfenac 0.09% significantly inhibited LPS-induced aqueous prostaglandin E(2) and FITC-dextran elevation (P < 0.01). At trough, both study drugs significantly inhibited LPS-induced aqueous prostaglandin E(2) elevation (P < 0.05), but only ketorolac 0.45% significantly reduced LPS-induced aqueous FITC-dextran elevation (P < 0.01). Aqueous and ICB ketorolac concentrations exceeded its IC(50) for COX-1 and COX-2 at peak and trough. Aqueous and ICB bromfenac levels exceeded its IC(50) for COX-2 at peak and trough, but not for COX-1 at trough aqueous levels and peak and trough ICB levels. CONCLUSIONS: Both ketorolac 0.45% and bromfenac 0.09% effectively suppressed inflammation at peak. At trough, only ketorolac 0.45% effectively suppressed inflammation as measured by FITC-dextran leakage. The difference in inflammation suppression may be due to differences in tissue concentrations and/or greater COX-1 suppression by ketorolac 0.45%.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzophenones/pharmacology , Bromobenzenes/pharmacology , Endophthalmitis/drug therapy , Eye/metabolism , Ketorolac/pharmacology , Animals , Aqueous Humor/drug effects , Aqueous Humor/metabolism , Benzophenones/pharmacokinetics , Bromobenzenes/pharmacokinetics , Dextrans/metabolism , Dinoprostone/analysis , Female , Fluorescein-5-isothiocyanate/analogs & derivatives , Fluorescein-5-isothiocyanate/metabolism , Ketorolac/pharmacokinetics , Lipopolysaccharides , Prostaglandin-Endoperoxide Synthases/metabolism , Rabbits
8.
Clin Ophthalmol ; 4: 1403-8, 2010 Dec 01.
Article in English | MEDLINE | ID: mdl-21179226

ABSTRACT

PURPOSE: A new carboxymethylcellulose (CMC)-containing ophthalmic formulation of 0.45% ketorolac, pH 6.8 (Acuvail(®)) was recently developed for treatment of inflammation and pain after cataract surgery. This study compared pharmacokinetics of the new formulation with that of a prior formulation, 0.4% ketorolac, pH 7.4 (Acular LS(®)). METHODS: Ketorolac formulations were administered bilaterally (35 µL) to female New Zealand White rabbits. Samples from aqueous humor and iris-ciliary body were collected at multiple time points, and ketorolac was quantified using liquid chromatography-tandem mass spectrometry. RESULTS: In aqueous humor, the peak concentration (C(max)) and area under the concentration-time curve (AUC(0-τ)) of ketorolac were, respectively, 389 ng/mL and 939 ng·h/mL following administration of the CMC-containing 0.45% ketorolac, pH 6.8, and 211 ng/mL and 465 ng·hr/mL following administration of the 0.4% ketorolac, pH 7.4. In iris-ciliary body, C(max) and AUC(0-τ) of ketorolac were, respectively 450 ng/g and 2040 ng·h/g after administration of the CMC-containing 0.45% ketorolac, pH 6.8, and 216 ng/g and 699 ng·h/g after administration of the 0.4% ketorolac, pH 7.4. PK simulations predicted an AUC(0-τ) of 2910 ng·h/g for twice daily, CMC-containing 0.45% ketorolac, pH 6.8, compared to 725 ng·h/g for 4 times daily, 0.4% ketorolac, pH 7.4. CONCLUSIONS: The CMC-containing formulation of 0.45% ketorolac, pH 6.8, increased ketorolac bioavailability by 2-fold in aqueous humor and by 3-fold in iris-ciliary body in comparison to the 0.4% ketorolac, pH 7.4, allowing a reduced dosing schedule from 4 times daily to twice daily.

9.
Pharm Res ; 25(7): 1572-82, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18299965

ABSTRACT

PURPOSE: To evaluate the sensitivity requirement for LC-MS/MS as an analytical tool to support human microdosing study with sub-pharmacological dose, investigate proportionality of pharmacokinetics from the microdose to therapeutic human equivalent doses in rats and characterize circulating metabolites in rats administered with the microdose. MATERIALS AND METHODS: Five drugs of antipyrine, metoprolol, carbamazepine, digoxin and atenolol were administered orally to male Sprague-Dawley rats at 0.167, 1.67, 16.7, 167 and 1,670 microg/kg doses. Plasma samples were extracted using either solid phase extraction or liquid-liquid extraction, and analyzed using LC-MS/MS. RESULTS: Using 100 microl of plasma sample, the lower limit of quantitation for antipyrine (10 pg/ml), carbamazepine (1 pg/ml), metoprolol (5 pg/ml), atenolol (20 pg/ml), and digoxin (5 pg/ml) were achieved using an API 5000. Proportional pharmacokinetics were observed from 0.167 microg/kg to 1,670 microg/kg for antipyrine and carbamazepine and from 1.67 to 1,670 microg/kg for atenolol and digoxin, while metoprolol exhibited a non-proportional pharmacokinetics relationship. Several metabolites of carbamazepine were characterized in plasma from rats dosed at 1.67 mug/kg using LC-MS/MS. CONCLUSIONS: This study has shown the promise of sensitive LC-MS/MS method to support microdose pharmacokinetics and drug metabolism studies in human.


Subject(s)
Pharmaceutical Preparations/metabolism , Pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Biological Availability , Biopharmaceutics , Calibration , Chemical Phenomena , Chemistry, Physical , Chromatography, Liquid , In Vitro Techniques , Indicators and Reagents , Male , Microsomes, Liver/metabolism , NADP/metabolism , Quality Control , Rats , Rats, Sprague-Dawley , Reference Standards , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry
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