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A first-in-human oral dose study of mesdopetam (IRL790) to assess its safety, tolerability, and pharmacokinetics in healthy male volunteers.

ABSTRACT: The management of Parkinson's disease (PD) is frequently compromised by complications induced by dopaminergic treatment such as involuntary movements (dyskinesias) and psychosis. Mesdopetam (IRL790) is a novel dopamine D3 receptor antagonist developed for the management of complications of therapy in PD. This study evaluated the safety, tolerability, and pharmacokinetics of escalating single and multiple doses of mesdopetam. We conducted a prospective, single-center, randomized, double-blind, placebo-controlled phase I, and first-in-human (FIH) study with mesdopetam administered to healthy male subjects. Overall, mesdopetam was well-tolerated up to a 120 mg single dose and up to 80 mg upon multiple dosing. Adverse events (AEs) were mainly related to the nervous system and were dose-dependent. No serious adverse events occurred and no AEs led to withdrawal. The results of the single-ascending-dose and multiple-ascending-dose parts indicated dose- and time-independent pharmacokinetics with rapid absorption and maximum plasma levels that were generally reached within 2 h after dosing. No accumulation was observed upon multiple dosing. It is concluded that mesdopetam was safe and well-tolerated in healthy male volunteers. Pharmacokinetic analysis indicated rapid absorption and dose-linear pharmacokinetics of mesdopetam, with a plasma half-life of around 7 h, upon single and repeated dosing. The pharmacokinetics of mesdopetam supports twice-daily use in patients.

SUBMITTER: Sjoberg F

PROVIDER: S-EPMC8137807 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers.

Project description:Venglustat is a small-molecule glucosylceramide synthase (GCS) inhibitor designed to reduce the production of glucosylceramide (GL-1) and thus is expected to substantially reduce formation of glucosylceramide-based glycosphingolipids. Because of its effect on glycosphingolipid formation, GCS inhibition has therapeutic potential across many disorders affecting glycosphingolipid metabolism. Therefore, venglustat is under development for substrate reduction therapy in multiple diseases, including Gaucher disease type 3, Parkinson's disease associated with GBA mutations, Fabry disease, GM2 gangliosidosis, and autosomal dominant polycystic kidney disease. Phase 1 studies were conducted in healthy volunteers to determine venglustat pharmacokinetics, pharmacodynamics, safety, and tolerability and to assess food effects on pharmacokinetics (single-dose and food-effect studies: NCT01674036; repeated-dose study: NCT01710826). Following a single oral dose of venglustat l-malate (2, 5, 15, 25, 50, 100, or 150 mg), venglustat demonstrated linear pharmacokinetics, rapid absorption (median tmax , 3.00-5.50 hours), systemic exposure unaffected by food, low apparent total body clearance (mean CL/F, 5.18-6.43 L/h), and pooled geometric mean t1/2z of 28.9 hours. Following repeated once-daily oral doses of venglustat l-malate (5, 10, or 20 mg) for 14 days, apparent steady state occurred within 5 days of repeated dosing, with pooled accumulation ratios of 2.10 for Cmax and 2.22 for AUC0-24 , and no statistically significant effect of dose or sex on accumulation. The mean fraction of dose excreted unchanged in urine (fe0-24 ) was 26.3% to 33.1%. Plasma GL-1 and GM3 decreased time- and dose-dependently. Venglustat demonstrated a favorable safety and tolerability profile.

| S-EPMC7818513 | biostudies-literature

Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers.

Project description:The pharmacokinetics, safety, and tolerability of intravenous (i.v.) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1-h i.v. infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 h after dosing. The mean pharmacokinetic parameters ± standard deviations of fosfomycin in plasma after 1 g and 8 g i.v., respectively, were the following: maximum clearance of drug in serum (Cmax), 44.3 ± 7.6 and 370 ± 61.9 ?g/ml; time to maximum concentration of drug in serum (Tmax), 1.1 ± 0.05 and 1.08 ± 0.01 h; volume of distribution (V), 29.7 ± 5.7 and 31.5 ± 10.4 liters; clearance (CL), 8.7 ± 1.7 and 7.8 ± 1.4 liters/h; renal clearance (CLR), 6.6 ± 1.9 and 6.3 ± 1.6 liters/h; area under the concentration-time curve from 0 to infinity (AUC0-?), 120 ± 28.5 and 1,060 ± 192 ?g·h/ml; and half-life (t1/2), 2.4 ± 0.4 and 2.8 ± 0.6 h. After oral administration, the parameters were the following: Cmax, 26.8 ± 6.4 ?g/ml; Tmax, 2.25 ± 0.4 h; V/F, 204 ± 70.7 liters; CL/F, 17 ± 4.7 liters/h; CLR, 6.5 ± 1.8 liters/h; AUC0-?, 191 ± 57.6 ?g · h/ml; and t1/2, 9.04 ± 4.5 h. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1-g i.v. dose. Approximately 74% and 80% of the 1-g and 8-g i.v. doses were excreted unchanged in the urine by 48 h compared to 37% after oral administration, with the majority of this excretion occurring by 12 h regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of i.v. fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis.

| S-EPMC5571362 | biostudies-literature

Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers.

Project description:The purpose of this study was to establish safety and tolerability of a single intravenous (IV) infusion of a p38 mitogen-activated protein kinase inhibitor, losmapimod, to obtain therapeutic levels rapidly for a potential acute coronary syndrome indication. Pharmacokinetics (PK) following IV dosing were characterized, and pharmacokinetic/pharmacodynamic (PK/PD) relationships between losmapimod and phosphorylated heat shock protein?27 (pHSP27) and high-sensitivity C-reactive protein were explored.Healthy volunteers received 1?mg losmapimod IV over 15?min (n = 4) or 3?mg IV over 15?min followed by a washout period and then 15?mg orally (PO; n = 12). Pharmacokinetic parameters were calculated by noncompartmental methods. The PK/PD relationships were explored using modelling and simulation.There were no deaths, nonfatal serious adverse events or adverse events leading to withdrawal. Headache was the only adverse event reported more than once (n = 3 following oral dosing). Following 3?mg IV and 15?mg PO, Cmax was 59.4 and 45.9??g?l(-1) and AUC0-? was 171.1 and 528.0??g?h?l(-1) , respectively. Absolute oral bioavailability was 0.62 [90% confidence interval (CI) 0.56, 0.68]. Following 3?mg IV and 15?mg PO, maximal reductions in pHSP27 were 44% (95% CI 38%, 50%) and 55% (95% CI 50%, 59%) occurring at 30?min and 4?h, respectively. There was a 17% decrease (95% CI 9%, 24%) in high-sensitivity C-reactive protein 24?h following oral dosing. A direct-link maximal inhibitory effect model related plasma concentrations to pHSP27 concentrations.A single IV infusion of losmapimod in healthy volunteers was safe and well tolerated, and may potentially serve as an initial loading dose in acute coronary syndrome as rapid exposure is achieved.

| S-EPMC3703232 | biostudies-literature

Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Volunteers: a Randomized, Placebo-Controlled First-in-Human Single-Dose Escalation Study.

Project description:Cysticercosis is a parasitic disease that frequently involves the human central nervous system (CNS), and current treatment options are limited. Oxfendazole, a veterinary medicine belonging to the benzimidazole family of anthelmintic drugs, has demonstrated substantial activity against the tissue stages of Taenia solium and has potential to be developed as an effective therapy for neurocysticercosis. To accelerate the transition of oxfendazole from veterinary to human use, the pharmacokinetics, safety, and tolerability of oxfendazole were evaluated in healthy volunteers in this phase 1 first-in-human (FIH) study. Seventy subjects were randomly assigned to receive a single oral dose of oxfendazole (0.5, 1, 3, 7.5, 15, 30, or 60?mg oxfendazole/kg body weight) or placebo and were followed for 14?days. Blood and urine samples were collected, and the concentrations of oxfendazole were measured using a validated ultraperformance liquid chromatography mass spectrometry method. The pharmacokinetic parameters of oxfendazole were estimated using noncompartmental analysis. Oxfendazole was rapidly absorbed with a mean plasma half-life ranging from 8.5 to 11?h. The renal excretion of oxfendazole was minimal. Oxfendazole exhibited significant nonlinear pharmacokinetics with less than dose-proportional increases in exposure after single oral doses of 0.5?mg/kg to 60?mg/kg. This nonlinearity of oxfendazole is likely due to the dose-dependent decrease in bioavailability that is caused by its low solubility. Oxfendazole was found to be well tolerated in this study at different escalating doses without any serious adverse events (AEs) or deaths. There were no significant differences in the distributions of hematology, biochemistry, or urine parameters between oxfendazole and placebo recipients. (This study has been registered at ClinicalTrials.gov under identifier NCT02234570.).

| S-EPMC6437481 | biostudies-literature

A First-in-Human Safety, Tolerability, and Pharmacokinetics Study of Benapenem in Healthy Chinese Volunteers.

Project description:The objective of this trial was to investigate the safety, tolerability, and pharmacokinetics (PK) of benapenem administered by single or multiple intravenous infusions in healthy Chinese volunteers. The trial was divided into 3 parts. In part A, 94 subjects were enrolled in a double-blind, placebo-controlled, sequential-ascending-single-dose study. The subjects were randomly assigned to groups receiving placebo or benapenem for injection at doses of 62.5, 125, 250, 500, 1,000, 2,000, or 3,000 mg. The effects of intravenous infusion time on the subjects of 250-, 500-, and 1,000-mg groups were explored. In part B, 12 subjects were enrolled in a single-dose PK study under fasting conditions and received 250, 500, or 1,000 mg of benapenem for injection. In part C, 36 subjects were given 250, 500, and 1,000 mg of benapenem for injection once daily for 7 consecutive days. The results showed that benapenem for injection was well tolerated during the studies. The major observed adverse events were mild, and all were resolved spontaneously without any medical intervention. Benapenem was mainly excreted through the kidneys in the form of parent molecule and metabolites. The PK and safety profiles of benapenem in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (Part A, part B, and part C have been registered at ClinicalTrials.gov under identifiers NCT03588156, NCT03578588, and NCT03570970, respectively.).

| S-EPMC6395932 | biostudies-literature

Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers.

Project description:Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT2A receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease.ObjectiveThis study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 μg, 10 μg, and 20 μg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response.MethodsThis was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 μg, 10 μg, 20 μg LSD, and placebo), and received their assigned dose on six occasions (i.e., every 4 days).ResultsForty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 μg (n = 12), 10 μg (n = 12), or 20 μg (n = 12) LSD. LSD plasma levels were undetectable for the 5 μg group and peak blood plasma levels for the 10 μg and 20 μg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment.ConclusionsOur results suggest safety and tolerability of orally administered 5 μg, 10 μg, and 20 μg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer's disease (AD).

| S-EPMC7036065 | biostudies-literature

Napabucasin Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers.

Project description:Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.

| S-EPMC8453567 | biostudies-literature

Safety, tolerability, and pharmacokinetics of intravenous nemonoxacin in healthy chinese volunteers.

Project description:Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (Cmax) values were 4.826 μg/ml, 7.152 μg/ml, and 11.029 μg/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC0-72 h) were 17.05 μg · h/ml, 39.30 μg · h/ml, and 61.98 μg · h/ml. The mean elimination half-life (t1/2) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. Volunteers treated with 250 to 750 mg nemonoxacin exhibited a linear dose-response relationship between the AUC0-72 h and AUC0-∞. These findings provide further support for the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

| S-EPMC4187916 | biostudies-literature

Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.

Project description:AimsTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans.MethodsTwo double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600?mg) in 44 healthy volunteers (36 men and eight postmenopausal women).ResultsAdverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6?h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ?40-80?h. The area under the curve0-24 hours (AUC(0-24?h)), concentration at 24 hours (C(24?h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600?mg. Administration of ODN with a high-fat meal led to ?100% increases in AUC(0-24?h), C(max,day1), C(max,overall) and C(24?h) relative to the fasted state, while administration with a low-fat meal led to a ?30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24?h for doses ?5?mg and at 168?h postdose for ?10?mg. In postmenopausal women administered 50?mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24?h. At 168?h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8?nM and ?80% maximal reduction.ConclusionsOdanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.

| S-EPMC3635595 | biostudies-literature

Single- and Multiple-Dose Trials to Determine the Pharmacokinetics, Safety, Tolerability, and Sex Effect of Oral Ginsenoside Compound K in Healthy Chinese Volunteers.

Project description:Background and objectives: Ginsenoside compound K (CK) is a candidate drug for rheumatoid arthritis therapy. The objective of this study was to investigate the pharmacokinetic properties, safety and tolerability of CK. Methods: In randomized, double-blind trials, 76 healthy Chinese subjects received 1 of 7 single oral doses (25, 50, 100, 200, 400, 600, 800 mg) of CK or placebo under fasting condition, and another 36 subjects received repeated oral doses (100, 200, or 400 mg) of CK or placebo for up to 9 days a week after a corresponding single dose, after breakfast. Both sexes were equally represented in the two trials. Pharmacokinetic parameters of CK and its metabolite 20(S)-protopanaxadiol (PPD) were calculated and statistically analyzed according to the plasma concentration data. Tolerability was evaluated by adverse events (AEs) and laboratory examinations. Results: The range of time to maximum concentration (Tmax) was 1.5-6.0 h, with a linear increase in the exposure of CK over the dose range of 100-400 mg. Steady state was reached after the 7th administration, and the accumulation index range was 2.60-2.78. Sex differences were characterized by a higher exposure in females than males with the single administration after breakfast. In addition, no severe AEs were observed. Conclusion: CK was safe and well-tolerated over the treatment period. The sex- and food-related impacts on CK pharmacokinetics need further investigations to be validated. (Registration number: ChiCTR-TRC-14004824 and ChiCTR-IPR-15006107, http://www.chictr.org.cn/index.aspx).

| S-EPMC5769417 | biostudies-literature

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