Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects.
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ABSTRACT:
SUBMITTER: Wilbraham D
PROVIDER: S-EPMC8048550 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Migraine 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.This 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.A 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).After 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.Eletriptan 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.
| S-EPMC5823072 | biostudies-literature
Project description:Metabotropic glutamate receptor 5 (mGlu5) has been shown to modulate nociception in animals, but no mGlu5 antagonists have been developed commercially as analgesics. The mGlu5 antagonist fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was originally evaluated for development as a nonbenzodiazepine anxiolytic. Fenobam is analgesic in numerous mouse pain models, acting exclusively through mGlu5 blockade. Furthermore, fenobam showed no signs of analgesic tolerance with up to 2 weeks of daily dosing in mice. Analgesic effects of fenobam in humans have not been reported. The purpose of this investigation was to evaluate fenobam pharmacokinetics and analgesic effects in humans. We first evaluated single-dose oral fenobam disposition in a parallel-group dose-escalation study in healthy volunteers. A second investigation tested the analgesic effects of fenobam in an established experimental human pain model of cutaneous sensitization using capsaicin cream and heat, in a double-blind placebo-controlled study. The primary outcome measure was the area of hyperalgesia and allodynia around the area applied with heat/capsaicin. Secondary outcome measures included nociception, measured as pain rating on a visual analog scale, heat pain detection threshold, and effects on cognition and mood. Fenobam plasma exposures showed considerable interindividual variability and were not linear with dose. Fenobam reduced sensitization vs placebo at a single timepoint (peak plasma concentration); we found no other difference between fenobam and placebo. Our results suggest highly variable fenobam disposition and minimal analgesic effects at the dose tested. We suggest that future studies testing analgesic effects of mGlu5 blockade are warranted, but such studies should use molecules with improved pharmacokinetic profiles.
| S-EPMC6923598 | biostudies-literature
Project description:GLPG1205 is a modulator of GPR84, a G-protein-coupled receptor reported to be associated with several diseases. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1205 in healthy subjects were evaluated in 2 randomized, double-blind, placebo-controlled, single-site, phase 1 studies. In study 1, 16 (aged 21-48 years) and 24 (24-50 years) healthy men received single doses of GLPG1205 10 to 800 mg, and GLPG1205 50, 100, or 200 mg once daily for 14 days, respectively, or placebo. Study 2 evaluated the effect of aging on GLPG1205 pharmacokinetics: 24 healthy men (aged 37-83 years), weight-matched into 3 age cohorts (65-74, ≥75, and 18-50 years), received GLPG1205 50 mg or placebo once daily for 14 days; an open-label part of this study evaluated a GLPG1205 250-mg loading dose followed by 50 mg once daily for 13 days in 8 healthy men (aged 68-74 years). Single (up to 800 mg) and multiple (maximum tolerated dose 100 mg once daily) GLPG1205 doses had favorable safety and tolerability profiles. After single administration of GLPG1205, median time to occurrence of maximum observed plasma concentration and arithmetic mean apparent terminal half-life ranged from 2.0 to 4.0 and from 30.1 to 140 hours, respectively. Age did not affect GLPG1205 exposure. GPR84 receptor occupancy with GLPG1205 vs placebo confirmed target engagement. These results support further clinical development of GLPG1205.
| S-EPMC8453901 | biostudies-literature
Project description:Dupilumab is a fully human monoclonal antibody directed against the interleukin (IL)-4 receptor ? subunit (IL-4R?) of IL-4 heterodimeric type I and type II receptors that mediate IL-4/IL-13 signaling through this pathway. Blockade of these receptors broadly suppresses type 2 inflammation associated with atopic/allergic diseases, including atopic dermatitis and asthma. Six phase 1 studies investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of dupilumab in healthy subjects. Two randomized, double-blind, placebo-controlled, sequential studies assessed safety and tolerability of single escalating dupilumab doses administered intravenously or subcutaneously (one included various racial groups, and one included exclusively Japanese subjects); 3 randomized, parallel-group, single-dose studies compared the pharmacokinetic profiles of different dupilumab products and formulations after single subcutaneous doses; and one study assessed dupilumab administered as fast versus slow subcutaneous injections. Dupilumab concentrations in serum were measured in all studies, and total immunoglobulin E (IgE) and thymus- and activation-regulated chemokine (TARC) concentrations were measured in 2 studies as pharmacodynamic markers. Across the phase 1 studies, dupilumab exhibited target-mediated pharmacokinetics consisting of parallel linear and nonlinear elimination, with the target-mediated phase highly dominated by nonlinearity at lower drug concentrations. Systemic exposure and tolerability of dupilumab were consistent irrespective of differences in product, formulation, or racial background. Dupilumab reduced circulating concentrations of total IgE and TARC, indicating blockade of IL-4R?-mediated signaling. Dupilumab had a favorable safety profile across the wide range of doses administered. Together, these findings support the continued development and use of dupilumab in treatment of type 2 diseases.
| S-EPMC7496261 | biostudies-literature
Project description:AimsTAK-071 is a muscarinic M1 receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first-in-human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK-071.MethodsTAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers alone and in combination with donepezil. Laboratory, electrocardiogram (ECG) and electroencephalogram (EEG) evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate the pharmacokinetics (PK), relative bioavailability and food effect.ResultsTAK-071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK-071 demonstrated a long mean (% coefficient of variation) half-life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Coadministration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK-071 40-80 mg increased power in the 7-9 Hz range in the posterior electrode group with eyes open and 120-160 mg doses increased power in the 16-18 Hz range and reduced power in the 2-4 Hz range in central-posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK-071 at high doses and was enhanced with coadministration of donepezil under the eyes-closed condition.ConclusionsPK and safety profiles of TAK-071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK-071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK-071 is warranted.
| S-EPMC9291057 | biostudies-literature
Project description:This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL-335 800 mg once daily (QD) (days 1-3, 11-13, and 21-23), simeprevir 150 mg QD (days 4-23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15-23). Group 2 (n = 16) received the same AL-335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5-23) and simeprevir 150 mg QD (days 14-23). Blood samples were collected to determine plasma concentrations of AL-335 (prodrug) and its metabolites, ALS-022399 (monophosphate precursor) and ALS-022227 (parent nucleoside), odalasvir, and simeprevir. Thirty-two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL-335 area under plasma concentration-time curve over 24 hours (AUC 0-24 h) 3-, 4-, and 7- to 8-fold, respectively; ALS-022399 AUC 0-24 h increased 2-, 2-, and 3-fold, respectively. Simeprevir had no effect on ALS-022227 AUC 0-24 h, whereas odalasvir with/without simeprevir increased ALS-022227 AUC 0-24 h 1.5-fold. AL-335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0-24 h increased 1.5- to 2-fold for both drugs when coadministered irrespective of AL-335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL-335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.
| S-EPMC5927802 | biostudies-literature
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.
| S-EPMC3585840 | biostudies-literature
Project description:Three phase 1 pharmacokinetic (PK)/pharmacodynamics (PD) studies were conducted in healthy men and women to further characterize the safety, tolerability, and PK/PD of mirogabalin administration with or without food and to guide the dose selection and regimen for phase 2 and 3 clinical development. The 3 studies included 2 randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose studies, and 1 open-label, crossover study to evaluate the PK of mirogabalin administered under fasting and fed (high-fat meal) conditions. Forty-eight and 47 healthy volunteers completed the single- and multiple-dose studies, respectively. Thirty subjects were enrolled and completed the food effect study. Mirogabalin was well tolerated in the fed and fasted states. The most frequent treatment-emergent adverse events (TEAEs)-dizziness and somnolence-were expected based on mirogabalin's mechanism of action. Subjects receiving the highest mirogabalin doses (50 and 75 mg single dose) showed greater dizziness and sedation and higher rates of TEAEs than subjects receiving 3-30 mg. After oral administration, mirogabalin was rapidly absorbed (time to maximum concentration, ?1 hour) and eliminated through urine unchanged (61%-72% urinary excretion). Exposure increased in a dose-proportional manner after single or multiple mirogabalin doses. No significant accumulation occurred with multiple doses over 14 days. After single doses of mirogabalin (15 mg), the bioavailability was considered equivalent in the fed and fasted states, indicating that mirogabalin can be taken without food restrictions. Based on these data, mirogabalin 15 mg twice daily was selected as the highest target dose for further clinical development.
| S-EPMC6106189 | biostudies-literature
Project description:Background and objectivesRotigotine is a dopamine receptor agonist with activity across the D1 through to D5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson's disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with rotigotine transdermal patch in Japanese and Caucasian subjects.MethodsIn this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration-time curve from time zero to last quantifiable concentration [AUClast], maximum plasma concentration [Cmax], and body weight- and dose-normalized values).ResultsThe pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of rotigotine was 2.0±0.5 mg for Japanese subjects and 2.08±0.58 mg for Caucasians. Plasma concentration-time profiles of unconjugated rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, Cmax, time to Cmax (tmax), and AUClast, for unconjugated rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total rotigotine concentrations (total rotigotine=unconjugated rotigotine+conjugated rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total rotigotine were 8.6 h and 9.6 h. Less than 0.1% of the apparent dose was renally excreted as the parent compound. Renal elimination of total rotigotine covers 11.7% of absorbed dose in Japanese subjects and 10.8% of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl rotigotine was 8.2 and 7.1%, respectively. The corresponding values for total desthienylethyl rotigotine were 3.5% in Japanese subjects and 4.2% Caucasians. Most adverse events were mild in intensity and typical for dopamine agonists or for transdermal therapeutics.ConclusionAdministration of a single patch delivering 2 mg/24 h rotigotine resulted in comparable pharmacokinetic profiles in Japanese and Caucasian subjects. The rotigotine transdermal patch was generally well-tolerated. Our findings suggest similar dose requirements for Japanese and Caucasian populations.
| S-EPMC3899448 | biostudies-literature
Project description:IntroductionLC350189 is a novel selective xanthine oxidase inhibitor under clinical development for the management of hyperuricemia in gout patients. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of the drug in healthy subjects.MethodsA dose-block randomized, double-blind, active and placebo-controlled, single- and multiple-dosing study was conducted. A single ascending dose (SAD) study (10-600 mg) and a multiple ascending dose (MAD) study with once-daily doses (100-800 mg) for 7 days were conducted. Serial samples of blood and urine for pharmacokinetics/pharmacodynamics analysis were collected, and tolerability and adverse events were assessed throughout the study.ResultsSixty-seven and 58 subjects were enrolled in the SAD and MAD studies, respectively. The mean Cmax and AUClast values increased with increasing doses, and exposure to LC350189 was dose proportional. The 24-hour mean serum uric acid (Cmean,24) decreased by 8.7%-31.7% (day 1) and 53.5%-91.2% (day 7) from baseline in the SAD and MAD studies, respectively, and the percentage decrease in Cmean,24 increased with higher doses.ConclusionLC350189 was well tolerated in the dose range of 10-800 mg. It lowered the serum and urine uric acid levels substantially in this dose range; the extent of the decrease in the serum uric acid level in the 200 mg dose group was similar or higher compared to that of febuxostat 80 mg group in the MAD study. It is expected that LC350189 could be safely administered once daily to patients with hyperuricemia or gout, leading to a sufficient decrease in uric acid levels.
| S-EPMC4560520 | biostudies-literature