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Atogepant is a potent, selective, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once‐daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double‐blind, placebo‐controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty‐four participants aged 23–55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well‐tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half‐life of ~ 11 hours, and no evidence of accumulation after once‐daily dosing. Overall, atogepant at a high oral dose is safe and well‐tolerated in healthy participants with no clinically meaningful elevations in ALT. [ABSTRACT FROM AUTHOR]

Study Objective: To evaluate the incidence of hypersensitivity and anaphylaxis after administration of sugammadex.Design: Retrospective analysis.Setting: Sugammadex clinical development program and post-marketing experience.Patients: Surgical patients and healthy volunteers who received sugammadex or placebo/comparator with anesthesia and/or neuromuscular blockade (NMB).Interventions: Sugammadex administered as 2.0 mg/kg at reappearance of the second twitch, 4.0 mg/kg at 1-2 post-tetanic count, or 16.0 mg/kg at 3 min after rocuronium 1.2 mg/kg.Measurements: Three analytical methods were used: 1) automated MedDRA queries; 2) searches of adverse events (AEs) consistent with treatment-related hypersensitivity reactions as diagnosed by the investigator; and 3) a retrospective adjudication of AEs suggestive of hypersensitivity by a blinded, independent adjudication committee (AC). In addition, a search of all post-marketing reports of events of hypersensitivity was performed, and events were retrospectively adjudicated by an independent AC. Anaphylaxis was determined according to Sampson Criterion 1.Main Results: The pooled dataset included 3519 unique subjects who received sugammadex and 544 who received placebo. The automated MedDRA query method showed no apparent increase in hypersensitivity or anaphylaxis with sugammadex as compared to placebo or neostigmine. Similarly, there was a low overall incidence of AEs of treatment-related hypersensitivity (<1%), with no differences between sugammadex and placebo or neostigmine. Finally, the retrospective adjudication of AEs suggestive of hypersensitivity showed a low incidence of hypersensitivity (0.56% and 0.21% for sugammadex 2 mg/kg and 4 mg/kg, respectively), with an incidence similar to subjects who received placebo (0.55%). There were no confirmed cases of anaphylaxis in the pooled studies. During post-marketing use, spontaneous reports of anaphylaxis occurred with approximately 0.01% of sugammadex doses.Conclusions: Subjects who received sugammadex with general anesthesia and/or NMB had a low overall incidence of hypersensitivity, with no apparent increase in hypersensitivity or anaphylaxis with sugammadex as compared to placebo or neostigmine. [ABSTRACT FROM AUTHOR]

Gefapixant, a P2X3 receptor antagonist, has demonstrated efficacy in patients with refractory or unexplained chronic cough. We investigated the effect of renal impairment (RI) on the pharmacokinetics (PK) of gefapixant 50 mg in an open‐label, single‐dose study enrolling participants with moderate (n = 6) or severe (n = 6) RI, end‐stage renal disease (ESRD; n = 6) under hemodialysis (HD) and non‐HD conditions, and healthy matched controls (n = 6). Serial plasma and urine samples for gefapixant concentrations were collected at selected time points over 72 and 48 hours after dosing, respectively. Linear regression analysis predicted a 1.87‐, 2.79‐, and 3.76‐fold higher exposure (area under the plasma concentration–time curve) for participants with mild, moderate, and severe RI, respectively, than that for healthy matched control participants. Categorical analysis exhibited a 2.98‐, 4.43‐, and 4.74‐fold higher exposure for participants with moderate RI, severe RI, and ESRD, respectively, than that for healthy matched control participants. Apparent oral clearance and renal clearance was lower in participants with various degrees of RI, by 66% to 90%, compared with healthy matched control participants, explaining the increased gefapixant exposure with increasing degrees of renal impairment. Gefapixant area under the plasma concentration–time curve and maximum plasma concentration decreased by ≈25% under HD conditions compared to non‐HD conditions. Single‐dose administration of gefapixant was generally well tolerated in this study. The data from this trial informed the enrollment of phase 3 clinical trials that evaluated the efficacy and safety of gefapixant in >2000 participants with refractory or unexplained chronic cough. Those efficacy and safety data, combined with analysis of population pharmacokinetics from across the entire development program, will be used to evaluate the magnitude of the renal impairment effect in the refractory or unexplained chronic cough population and to determine any dose adjustment recommendations. [ABSTRACT FROM AUTHOR]

Background/Hypothesis: Atogepant, an oral calcitonin gene-related peptide receptor antagonist, is approved for the preventive treatment of migraine in adults. This manuscript characterizes the safety, tolerability, pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of atogepant in healthy males. Methods: Data from two single-ascending dose phase 1 studies of atogepant were utilized to characterize pharmacokinetics and demonstrate proof of activity of atogepant in a capsaicin-induced dermal vasodilatation model and to determine the dosage(s) that results in 90% inhibition of capsaicin-induced dermal vasodilatation (effective concentration, EC90) over 24 hours. Results: Single (0.4−200 mg) doses of atogepant were generally well tolerated by healthy participants with no treatment-related study discontinuations. Atogepant was rapidly absorbed with peak plasma concentrations occurring 1–2 hours post dose and a mean elimination half-life of ∼11 hours. Based on the capsaicin-induced dermal vasodilatation and pharmacokinetic/pharmacodynamic models, atogepant has an estimated EC90 of 13.6 nM which was reached within 30 minutes at therapeutic doses and maintained for 24 hours at dosages of 60 mg once daily and 30 and 60 mg twice daily. Conclusion/Interpretation: Atogepant reached effective concentrations within 0.5 hours which were maintained for 24 hours at dosages of 60 mg once daily and 30 and 60 mg twice daily for the prevention of migraine. Trial Registration: Clinical Trial EudraCT Numbers: 2011-005020-18 (Study 1) and 2012-001192-36 (Study 2). [ABSTRACT FROM AUTHOR]

Gefapixant (MK‐7264) is a first‐in‐class, selective antagonist of the P2X3 purinergic receptor currently being investigated as a therapeutic agent for the treatment of refractory or unexplained chronic cough. In non‐clinical studies, gefapixant was eliminated primarily by renal excretion of the parent drug. The objective of this study was to assess the disposition of gefapixant in humans. The absorption, metabolism, and excretion profiles of gefapixant were assessed after oral administration of a single dose of [14C]gefapixant to six healthy adult males. Following a single‐oral [14C]gefapixant dose to healthy adult males, the mass balance was achieved, with 98.9% of the administered radioactivity recovered in urine and feces. Elimination of gefapixant occurred primarily via renal excretion of the intact drug (64%); metabolism was a minor pathway of elimination of gefapixant (12% and 2% recovered in urine and feces, respectively). Single‐dose administration of [14C]gefapixant 50 mg was generally well tolerated in healthy adult males. The fraction of the anticipated therapeutic oral dose of gefapixant absorbed is estimated to be at least 78%. Gefapixant is expected to be the major circulating drug‐related material in plasma, and the majority of the dosed drug will be excreted unchanged in urine. [ABSTRACT FROM AUTHOR]

Gefapixant (MK‐7264, AF‐219) is a first‐in‐class P2X3 antagonist in development for refractory or unexplained chronic cough. Gefapixant is primarily cleared by renal excretion. To assess the importance of the multidrug and toxin extrusion protein 1 (MATE1) and MATE2K transporters in the elimination of gefapixant, a drug‐drug interaction study was conducted evaluating the effect of coadministration of a single dose of pyrimethamine, a competitive inhibitor of MATE1 and MATE2K, on the single‐dose pharmacokinetics of gefapixant in healthy participants. Safety and tolerability were also assessed. In this open‐label, 2‐period, fixed‐sequence study, a 45‐mg dose of gefapixant was administered to 12 participants in period 1. After a 7‐day washout, a 50‐mg dose of pyrimethamine was administered 3 hours before a 45‐mg dose of gefapixant in period 2. Compared with the administration of gefapixant alone, concomitant dosing of gefapixant with pyrimethamine increased the total gefapixant plasma exposure (area under the plasma concentration–time curve from time 0 to infinity) by 24%, reduced gefapixant renal clearance by 30%, and increased gefapixant mean terminal half‐life from 7.7 to 10.3 hours. The most frequently reported adverse events were dysgeusia, hypogeusia, and dry mouth; all adverse events were considered of mild intensity and resolved by the end of the study. These results support that MATE1 and/or MATE2K contribute to the renal clearance of gefapixant, but the effect of inhibition of these transporters on gefapixant pharmacokinetics is not considered clinically meaningful. [ABSTRACT FROM AUTHOR]

The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene‒related peptide receptor—in development for migraine prevention—is thus likely to be used by women taking oral contraceptives. This phase 1, open‐label, single‐center, 2‐period, fixed‐sequence study examined the effect of multiple‐dose atogepant 60 mg once daily on the single‐dose pharmacokinetics of a combination oral contraceptive, ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg (EE/LNG), in healthy postmenopausal or oophorectomized women. For participants in period 1, a single dose of EE/LNG was followed by a 7‐day washout. In period 2, atogepant was given once daily on days 1‐17; an oral dose of EE/LNG was coadministered with atogepant on day 14. Plasma pharmacokinetic parameters for EE and LNG were assessed following administration with and without atogepant. Twenty‐six participants aged 45‐64 years enrolled; 22 completed the study in accordance with the protocol. The area under the concentration‐time curve extrapolated to infinity (AUC0‐∞) of LNG was increased by 19% when administered with atogepant. Coadministration of atogepant and a single dose of EE/LNG did not substantially alter the pharmacokinetics of EE; the ∼19% increase in plasma AUC0‐∞ of LNG is not anticipated to be clinically significant. Overall, atogepant alone and in combination with EE/LNG was generally well tolerated, with no new safety signals identified. [ABSTRACT FROM AUTHOR]