Navafenterol (AZD8871) in healthy volunteers: safety, tolerability and pharmacokinetics of multiple ascending doses of this novel inhaled, long-acting, dual-pharmacology bronchodilator, in two phase I, randomised, single-blind, placebo-controlled studies.
ABSTRACT: BACKGROUND:Navafenterol (AZD8871) is a novel, long-acting, dual-pharmacology (muscarinic receptor antagonist and ?2-adrenoceptor agonist) molecule in development for chronic obstructive pulmonary disease and asthma. METHODS:These two phase I, randomised, single-blind, multiple-ascending-dose studies evaluated inhaled navafenterol and placebo (3:1 ratio) in healthy, male, non-Japanese (study A; NCT02814656) and Japanese (study B; NCT03159442) volunteers. In each study, volunteers were dosed in three cohorts, allowing gradual dose escalation from 300??g to 600??g to 900??g. The primary objective was to investigate the safety and tolerability of navafenterol at steady state. Pharmacokinetics were also assessed. RESULTS:Twenty-four volunteers completed each study (navafenterol, n?=?6; placebo, n?=?2 in each cohort). There were no deaths, serious adverse events (AEs) or treatment-emergent AEs (TEAEs) leading to discontinuation of navafenterol. The most frequent TEAEs were vessel puncture-site bruise (placebo, n?=?2; navafenterol 900??g; n?=?3) in study A and diarrhoea (placebo, n?=?1; navafenterol 300??g, n?=?2; navafenterol 900??g, n?=?3) in study B. No dose-response relationship was observed for TEAEs. There was a dose-dependent increase in mean heart rate on day 16 in both studies. The pharmacokinetics of navafenterol were similar between non-Japanese and Japanese volunteers. CONCLUSIONS:Multiple ascending doses of navafenterol were well-tolerated and the safety and pharmacokinetics of navafenterol were similar in non-Japanese and Japanese volunteers. The findings support navafenterol clinical development. TRIAL REGISTRATION:ClinicalTrials.gov ; Nos.: NCT02814656 and NCT03159442; URL: www.clinicaltrials.gov .
Project description:Preclinical work suggests that the metabotropic glutamate receptor subtype 5 (mGlu5) may represent a novel target to treat neuropsychiatric disorders, including alcohol use disorder and obesity. The goal of this first-in-man study was to evaluate the safety, tolerability and pharmacokinetics (PK) of GET 73 (PubChem SID: 329974174), a novel mGluR5 negative allosteric modulator. This was a double-blind, placebo-controlled, ascending dose, Phase I study conducted in healthy male volunteers in two experiments. GET 73 was administered as single ascending doses (N=48; Experiment 1; 10, 30, 100, 300, 450, 600-mg) or multiple ascending doses (N=32; Experiment 2; 100, 300, 450, 450-mg twice a day). Primary endpoints were the incidence of adverse events (AEs) among drug conditions and drug tolerability. The secondary endpoints were the PK parameters of GET 73 and its metabolite MET 2. Single GET 73 doses of up to 600-mg and repeated ascending doses of up to 450-mg twice/day were safe and well-tolerated. There were no serious or severe AEs. All AEs were mild or moderate in severity. Total GET 73 exposure increased with each increased GET 73 dose. A dose-related increase in mean maximum plasma drug concentration was observed after repeated dosing. Maximum plasma drug concentrations occurred between 0.5 and 2.05h after administration in all groups for both single and repeated doses. This first-in-human study indicates that GET 73, as single or multiple ascending doses, is safe and well-tolerated when administered to healthy male volunteers.
Project description:OBJECTIVE:Fabry disease is a rare X-linked disease caused by mutations to the GLA gene, resulting in a deficiency of the lysosomal enzyme alpha-galactosidase A. This study evaluated the pharmacokinetics, safety, and tolerability of ascending single doses of oral migalastat hydrochloride (HCl), an investigational drug, in healthy Japanese volunteers. METHODS:In this phase I, randomized, placebo-controlled, single-blind, ascending single-dose, cross-over study, migalastat HCl (50?mg, 150?mg, or 450?mg) or placebo was administered orally to 14 fasting male Japanese volunteers (aged 20-55 years) on 4 non-consecutive days. Main plasma and urine pharmacokinetic end-points included maximum observed plasma concentration (C max), time to C max (t max), area under the plasma concentration-time curve (AUC), apparent terminal-phase half-life (t 1/2), urinary recovery of unchanged drug, renal clearance, and percentage of drug excreted in urine. Safety end-points included adverse events, clinical signs and symptoms (e.g., hematology, chemistry, and urinalysis), vital signs (blood pressure and heart rate), and 12-lead electrocardiogram. CLINICAL TRIAL REGISTRATION NUMBER:ClinicalTrials.gov registration identifier is NCT01853852. RESULTS:Median t max of migalastat was 3.0-3.5?h. Migalastat HCl concentrations declined relatively rapidly, with a mean t 1/2 of 3.2-4.0?h. The amount of migalastat HCl recovered in the urine and the percentage of migalastat HCl excreted unchanged over 24?h were consistent (?45-50%) across the dose range. The AUC and C max of migalastat HCl were dose proportional from 50-450?mg. Safety results were similar to those observed in non-Japanese populations. CONCLUSIONS:This study demonstrated that ascending single doses of migalastat HCl (50?mg, 150?mg, 450?mg) are absorbed at a moderate rate and eliminated relatively rapidly, with a safety profile consistent with that observed in non-Japanese populations. These results confirm the dose-proportional pharmacokinetics of migalastat HCl from 50-450?mg. This study was limited by a small subject population and a short-term follow-up.
Project description:The goal of this study is to define the molecular signatures of prednisolone and BMS-791826 in normal healthy volunteers. IM125001 (NCT03198013) is a phase I, placebo-controlled, double-blind, ascending single and multiple oral dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of bms-791826 and to assess its marker specific pharmacodynamics in relation to prednisolone in healthy males, sponsored by Bristol-Myers Squibb. Overall design: Total RNA from normal healthy volunteers taking prednisolone, BMS-791826 or placebo over time were collected.
Project description:M281 is a fully human, anti-neonatal Fc receptor (FcRn) antibody that inhibits FcRn-mediated immunoglobulin G (IgG) recycling to decrease pathogenic IgG while preserving IgG production. A randomized, double-blind, placebo-controlled, first-in-human study with 50 normal healthy volunteers was designed to probe safety and the physiological maximum for reduction of IgG. Intravenous infusion of single ascending doses up to 60 mg/kg induced dose-dependent serum IgG reductions, which were similar across all IgG subclasses. Multiple weekly doses of 15 or 30 mg/kg achieved mean IgG reductions of ≈85% from baseline and maintained IgG reductions ≥75% from baseline for up to 24 days. M281 was well tolerated, with no serious or severe adverse events (AEs), few moderate AEs, and a low incidence of infection-related AEs similar to placebo treatment. The tolerability and consistency of M281 pharmacokinetics and pharmacodynamics support further evaluation of M281 in diseases mediated by pathogenic IgG.
Project description:Nacubactam is a novel ?-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine ?-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000?mg, multiple ascending doses of nacubactam of 1,000 to 4,000?mg every 8?h (q8h) for up to 7?days, or nacubactam of 2,000?mg plus meropenem of 2,000?mg q8h for 6?days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential ?-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].).
Project description:RATIONALE:Schizophrenia is a complex neuropsychiatric disorder characterized, in part, by impaired dopamine signaling. TAK-063 is a selective inhibitor of phosphodiesterase 10A, a key regulator of intracellular signaling pathways that is highly expressed in the striatum. OBJECTIVE:Safety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study. METHODS:Healthy Japanese and non-Japanese volunteers were randomized into dose cohorts of 3, 10, 30, 100, 300, and 1000 mg. Each fasting volunteer randomly received a single dose of TAK-063 or placebo. Individuals from the 100-mg cohort also received a post-washout, 100-mg dose under fed conditions. A total of 84 volunteers enrolled (14 per cohort). RESULTS:The most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). The three severe AEs recorded occurred at the highest doses: orthostatic hypotension (n = 1; 300 mg) and somnolence (n = 2; 1000 mg). There were no deaths, serious AEs, or discontinuations due to AEs. TAK-063 exposure increased in a dose-dependent manner. Median T max was reached 3 to 4 h postdose. Fed conditions slowed absorption (T max = 6 h) and increased oral bioavailability. Renal elimination was negligible. Safety and pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Impairments in cognitive function consistent with the effects of other sedative or hypnotic agents were detected using a validated, computerized cognition battery, CNS Vital Signs. CONCLUSIONS:TAK-063 was safe and well tolerated at doses up to 1000 mg and demonstrated a pharmacokinetic profile supporting once-daily dosing. Further evaluation of the clinical safety and efficacy of TAK-063 is warranted.
Project description:<h4>Aims</h4>To evaluate the safety and pharmacokinetics of naringenin in healthy adults consuming whole-orange (Citrus sinensis) extract.<h4>Methods and methods</h4>In a single-ascending-dose randomized crossover trial, 18 adults ingested doses of 150?mg (NAR150), 300?mg (NAR300), 600?mg (NAR600) and 900?mg (NAR900) naringenin or placebo. Each dose or placebo was followed by a wash-out period of at least 1?week. Blood safety markers were evaluated pre-dose and 24?hours post-dose. Adverse events (AEs) were recorded. Serum naringenin concentrations were measured before and over 24?hours following ingestion of placebo, NAR150 and NAR600. Four- and 24-hour serum measurements were obtained after placebo, NAR300 and NAR900 ingestion. Data were analysed using a mixed-effects linear model.<h4>Results</h4>There were no relevant AEs or changes in blood safety markers following ingestion of any of the naringenin doses. The pharmacokinetic variables were: maximal concentration: 15.76?±?7.88??M (NAR150) and 48.45?±?7.88??M (NAR600); time to peak: 3.17?±?0.74?hours (NAR150) and 2.41?±?0.74?hours (NAR600); area under the 24-hour concentration-time curve: 67.61?±?24.36??M?×?h (NAR150) and 199.05?±?24.36??M?×?h (NAR600); and apparent oral clearance: 10.21?±?2.34?L/h (NAR150) and 13.70?±?2.34?L/h (NAR600). Naringenin half-life was 3.0 hours (NAR150) and 2.65?hours (NAR600). After NAR300 ingestion, serum concentrations were 10.67?±?5.74??M (4 hours) and 0.35?±?0.30??M (24?hours). After NAR900 ingestion, serum concentrations were 43.11?±?5.26??M (4 hours) and 0.24?±?0.30??M (24?hours).<h4>Conclusions</h4>Ingestion of 150 to 900?mg doses of naringenin is safe in healthy adults, and serum concentrations are proportional to the dose administered. Since naringenin (8 ?M) is effective in primary human adipocytes, ingestion of 300?mg naringenin twice/d will likely elicit a physiological effect.
Project description:GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open-label relative bioavailability study comparing 20-mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24-hour period for the 60-mg and 120-mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.
Project description:BACKGROUND AND OBJECTIVE:Atacicept is an inhibitor of the B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), and is being studied in relation to immunological disease. Currently, limited data on atacicept are available in non-Caucasian subjects. Pharmacokinetic data from earlier studies of atacicept were derived using an enzyme-linked immunosorbent assay (ELISA), which was subsequently found to have inadequacies. Hence, a new bioanalytical ELISA for total atacicept was developed and validated. We conducted this randomized, double-blind, placebo-controlled phase I study to compare the safety, tolerability, pharmacokinetics, and pharmacodynamics of atacicept in healthy Japanese and Caucasian subjects while generating pharmacokinetic data using the new ELISA. METHODS:Japanese subjects aged???18 to???55 years (n? =?24) were randomized (1:1:1:1) to a single subcutaneous dose of atacicept 25, 75, or 150 mg or placebo. Caucasian subjects were then enrolled to match the Japanese subjects' gender, body weight (±?20%), and height (±?15%). RESULTS:Atacicept was well tolerated and there were no clinically significant differences in treatment-emergent adverse events (TEAEs), vital signs, or laboratory parameters between the Japanese and Caucasian subjects. Most (90%) TEAEs were mild; no severe or serious TEAEs or deaths occurred. Weight-adjusted atacicept exposure was comparable between ethnicities and across doses: the Japanese/Caucasian ratio of the area under the serum concentration-time curve from time zero to the last sampling point (AUC0-t) was 107.21% (90% CI 93.42-123.02%) and the Japanese/Caucasian ratio of maximum serum concentration (Cmax) was 95.74% (90% CI 74.26-123.43%; ANCOVA). Median time to reach Cmax (tmax) was 20-60 h across all subjects. Dose-exposure relationships were comparable for the two ethnicities, with dose-normalized AUC0-t decreasing with increasing dose, indicating nonlinear pharmacokinetics for the doses examined. There were no statistically significant differences between ethnicities in the pharmacokinetics-dose relationship. Some transient dose-related decreases in mean serum immunoglobulin (Ig)A and IgM, but not IgG, were observed after atacicept administration. There were small transient increases in peripheral B cell numbers in the first 4 days after dosing that were larger with atacicept than with placebo, with no apparent dose relationship. No anti-atacicept antibodies were detected. CONCLUSION:The safety, pharmacokinetic, and pharmacodynamic profiles of atacicept in healthy Japanese subjects were comparable to those in healthy Caucasian subjects. EudraCT-ID: 2013-002703-34.
Project description:Introduction:Extracellular tau is hypothesized to mediate the onset and progression of tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and a subset of frontotemporal lobar degenerations. A putative strategy for treating these disorders is to reduce extracellular tau levels using tau-directed immunotherapy. The results of the first-in-human study of BIIB092 (formerly BMS-986168/IPN007), a humanized monoclonal antibody that binds to N-terminal tau, are reported here. This randomized, double-blind, single ascending dose study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity profile of BIIB092 after a single intravenous infusion in healthy participants. Methods:Sixty-five participants were randomized to receive a single intravenous infusion of placebo or BIIB092 at doses of 21, 70, 210, 700, 2100, or 4200 mg (or 700 or 2100 mg for Japanese participants). Serial blood and cerebrospinal fluid samples were obtained for assessment of pharmacokinetic parameters and unbound N-terminal tau suppression. Results:There were no deaths, serious adverse events (AEs), severe AEs, or discontinuations due to an AE. The majority of AEs were mild. Serum BIIB092 concentrations increased in a dose-proportional manner and suppressed unbound cerebrospinal fluid N-terminal tau by 67%-97% at 28 days after dose, with doses of ?210 mg producing persistent unbound N-terminal tau suppression over 12 weeks. Levels of cerebrospinal fluid N-terminal tau suppression were similar for Japanese and non-Japanese participants. Discussion:BIIB092 was generally safe and well tolerated after a single dose of up to 4200 mg, and up to 2100 mg in Japanese participants. BIIB092 exhibited a dose-dependent increase in the extent and duration of unbound N-terminal tau suppression.