Dataset Information

Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects.

ABSTRACT: Activation of the brain dopamine D1 receptor has attracted attention because of its promising role in neuropsychiatric diseases. Although efforts to develop D1 agonists have been challenging, a positive allosteric modulator (PAM), represents an attractive approach with potential better drug-like properties. Phase 1 single-ascending-dose (SAD; NCT03616795) and multiple-ascending-dose (MAD; NCT02562768) studies with the D1PAM mevidalen (LY3154207) were conducted with healthy subjects. There were no treatment-related serious adverse events (AEs) in these studies. In the SAD study, 25-200 mg administered orally showed dose-proportional pharmacokinetics (PK) and acute dose-related increases in systolic blood pressure (SBP) and diastolic blood pressure DBP) and pulse rate at doses ≥ 75 mg. AE related to central activation were seen at doses ≥ 75 mg. At 25 and 75 mg, central penetration of mevidalen was confirmed by measurement of mevidalen in cerebrospinal fluid. In the MAD study, once-daily doses of mevidalen at 15-150 mg for 14 days showed dose-proportional PK. Acute dose-dependent increases in SBP, DBP, and PR were observed on initial administration, but with repeated dosing the effects diminished and returned toward baseline levels. Overall, these findings support further investigation of mevidalen as a potential treatment for a range of neuropsychiatric disorders.

SUBMITTER: Wilbraham D

PROVIDER: S-EPMC8048550 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects.

Wilbraham Darren D Biglan Kevin M KM Svensson Kjell A KA Tsai Max M Kielbasa William W

Clinical pharmacology in drug development 20201007 4

Activation of the brain dopamine D1 receptor has attracted attention because of its promising role in neuropsychiatric diseases. Although efforts to develop D1 agonists have been challenging, a positive allosteric modulator (PAM), represents an attractive approach with potential better drug-like properties. Phase 1 single-ascending-dose (SAD; NCT03616795) and multiple-ascending-dose (MAD; NCT02562768) studies with the D1PAM mevidalen (LY3154207) were conducted with healthy subjects. There were n ...[more]

PMID: 33029934

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Project description:BackgroundMigraine is one of the most common headache disorders that greatly affect the quality of life. Selective serotonin (5-HT) receptor agonists such as triptamine-based drugs called triptans are used for treatment of migraine.PurposeThis study aimed to evaluate the pharmacokinetic (PK) and tolerability profiles of eletriptan hydrobromide (eletriptan HBr), a selective 5-hydroxytryptamine (also known as serotonin) 1B/1D receptor agonist, in Koreans and compare the results to those observed in non-Koreans in a previously published study.Patients and methodsA randomized, open-label, single, and repeated-dose study was conducted in 16 healthy Korean male subjects using a four-treatment, four-period, and four-sequence crossover design (NCT01139515). The subjects received one of the following four treatments in each period: a single dose of 20, 40, 80 mg eletriptan HBr or a repeated oral dose of 40 mg 2 h apart. Blood samples were collected before and up to 26 h after dosing for quantification of plasma eletriptan concentration by high-performance liquid chromatography tandem-mass spectrometry. The PK parameters were estimated using noncompartmental methods. Ethnicity differences between Korean and non-Korean subjects were identified using geometric mean ratios and 90% confidence intervals (CIs) of dose-normalized maximum plasma concentration (Cmax) and dose-normalized area under the plasma concentration versus time curve from 0 h to the last measurable concentration (AUC0-t).ResultsAfter single-dose administration of eletriptan HBr to Korean subjects, the mean Cmax and AUC0-t increased linearly with dose. Comparable total systemic exposures were observed in the 2 h apart 40 mg repeated and single 80 mg dose. The geometric mean ratios (90% CIs) of the dose-normalized Cmax and AUC0-t of Korean subjects were similar to those of non-Korean subjects reported in the literature. The adverse events observed were transient and mild in severity.ConclusionEletriptan HBr showed linear PK and was well tolerated in Korean subjects. The PK and tolerability of eletriptan HBr did not differ between Korean and non-Korean subjects.

Project description:BackgroundActivation of the sympathetic nervous system is an important feature in hypertension and congestive heart failure. A strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of norepinephrine (noradrenaline) via inhibition of dopamine-β-hydroxylase (DβH).ObjectiveTo assess the safety, tolerability, and pharmacokinetics of etamicastat (BIA 5-453), a new DβH inhibitor, following repeated dosing.MethodsA double-blind, randomized, placebo-controlled study was conducted in healthy young male volunteers. Participants received once-daily doses of placebo or etamicastat 25, 50, 100, 200, 400, or 600 mg, for 10 days.ResultsEtamicastat underwent N-acetylation to its metabolite BIA 5-961. Etamicastat and BIA 5-961 maximum concentrations were achieved at 1-3 and 2-4 hours, respectively, after dosing. Elimination half-lives ranged from 18.1 to 25.7 hours for etamicastat and 6.7 to 22.5 hours for BIA 5-961. Both etamicastat and BIA 5-961 followed linear pharmacokinetics. The extent of systemic exposure to etamicastat and BIA 5-961 increased in an approximately dose-proportional manner, and steady-state plasma concentrations were attained up to 9 days of dosing. Etamicastat accumulated in plasma following repeated administration. The mean observed accumulation ratio was 1.3-1.9 for etamicastat and 1.3-1.6 for BIA 5-961. Approximately 40% of the etamicastat dose was recovered in urine in the form of parent compound and BIA 5-961. There was a high variability in pharmacokinetic parameters, attributable to different N-acetyltransferase-2 (NAT2) phenotype. Urinary excretion of norepinephrine decreased following repeated administration of etamicastat. Etamicastat was generally well tolerated. There was no serious adverse event or clinically significant abnormality in clinical laboratory tests, vital signs, or ECG parameters.ConclusionEtamicastat was well tolerated. Etamicastat undergoes N-acetylation, which is markedly influenced by NAT2 phenotype. NAT2 genotyping could be a step toward personalized medicine for etamicastat.Trial registrationEudraCT No. 2007-004142-33.

Dataset Information

Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects.

Publications

Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects.

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