Pharmacokinetics, safety and tolerability of human recombinant alkaline phosphatase in healthy volunteers
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ABSTRACT:
SUBMITTER: Peters E
PROVIDER: S-EPMC4471820 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
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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
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
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
Project description:ObjectivesTo compare the pharmacokinetics (PK), safety and tolerability of subcutaneous (SC) and intravenous anifrolumab, an anti-type I interferon receptor monoclonal antibody in development for SLE, in healthy volunteers.MethodsIn this Phase I randomised, placebo-controlled study, 30 adults were assigned to three treatment cohorts (anifrolumab 300 mg SC (n=6), anifrolumab 300 mg intravenous (n=6), anifrolumab 600 mg SC (n=6)) and placebo (n=4/cohort). Serial blood samples were collected up to Day 84 to measure anifrolumab concentrations and antidrug antibodies (ADAs). PK parameters were estimated by noncompartmental analysis.ResultsMaximum serum concentrations in SC cohorts occurred after 4-7 days. Anifrolumab serum concentrations were below the limit of detection in all individuals by Day 84. Exposure to SC anifrolumab increased dose proportionally from 300 mg to 600 mg based on area under the serum concentration-time curve. Anifrolumab 300 mg SC exposure reached 87% of the intravenous exposure. Anifrolumab 300 mg SC and placebo administration elicited minimal injection-site reactions. Transient injection-site induration occurred in five of six individuals after anifrolumab 600 mg SC and two of four individuals after placebo. Transient, mild to moderate injection-site induration and pruritus occurred simultaneously in two of six individuals after anifrolumab 600 mg SC. Adverse events were reported by 50% (n=9) of anifrolumab-treated individuals and 33% (n=4) of placebo-treated individuals. ADAs were detected in only one individual in the anifrolumab 300-mg intravenous group at the Day 84 assessment.ConclusionAnifrolumab 300-mg SC exposure was 87% of intravenous administration, with single SC anifrolumab administrations well tolerated in healthy volunteers.
| S-EPMC5890854 | biostudies-literature
Project description:Background and purposeActivated Protein C (APC) stimulates multiple cytoprotective pathways via the protease activated receptor-1 (PAR-1) and promotes anticoagulation. 3K3A-APC was designed for preserved activity at PAR-1 with reduced anticoagulation. This Phase 1 trial characterized pharmacokinetics and anticoagulation effects of 3K3A-APC.MethodsSubjects (n=64) were randomly assigned to receive 3K3A-APC (n=4) at 6, 30, 90, 180, 360, 540 or 720 µg/kg or placebo (n=6) and were observed for 24 hr. After safety review additional subjects received drug every 12 hr for 5 doses (n=6 per group) at 90, 180, 360, or 540 µg/kg or placebo (n=8) and were observed for 24 hr.ResultsAll subjects returned for safety assessments at 72 hours and 15 days. We found few adverse events in all groups. Systolic blood pressure increased in both active and placebo groups. Moderately severe headache, nausea and vomiting were reported in one of two subjects treated with 720 µg/kg so 540 µg/kg was considered the highest tolerated dose. Mean plasma concentrations increased in proportion to dose. Clearance ranged from 11,693 ± 807 to 18,701 ± 4,797 mL/hr, volume of distribution ranged from 4,873±828 to 6,971 ± 1,169 mL, and elimination half-life ranged from 0.211 ± 0.097 to 0.294 ± 0.054 hours. Elevations in aPTT were minimal.Conclusions3K3A-APC was well tolerated at multiple doses as high as 540 µg/kg. These results should be confirmed in stroke patients with relevant co-morbidities. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660230.
| S-EPMC4040367 | biostudies-literature
Project description:The objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics (PKs) of RO7049389 in healthy Chinese volunteers (HVs) and evaluate potential ethnic differences in the safety and PKs using data from this study and the first-in-human study (in which most of the HVs were non-Asian). HVs randomly received a single dose of 200-600 mg of RO7049389 or a placebo in a single ascending dose (n = 28) or multiple doses of 200-400 mg of RO7049389 or a placebo in multiple ascending doses (n = 24). Safety and tolerability were monitored throughout the study. Serial blood samples were collected for PK analysis. RO7049389 was safe and well-tolerated in the HVs. The time to maximum concentration ranged from 1.5 to 3.0 h, and terminal half-life ranged from 3.66 to 14.6 h. A single dose of 200-600 mg and multiple doses of 200-400 mg exhibited nonlinear PKs. In general, the safety profiles were comparable between non-Asian and Asian HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non-Asian HVs. The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus.
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Project description:The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics (PKs) of rhEGF eyedrops after the administration of single and multiple doses in healthy subjects. A phase 1, randomized, double-blind, placebo-controlled, and single-ascending dose (SAD) and multiple-ascending dose (MAD) study were conducted in three dose groups (10, 50, and 100 μg/mL). The subjects randomly received rhEGF eyedrops or the placebo in a 3:1 ratio. Serial blood and tear samples for PK analysis were collected up to 36 h and 180 h post-dose in SAD and MAD studies, respectively. In addition, the serum and tear EGF concentrations were measured. Immunogenicity evaluations were conducted using serum anti-EGF antibody levels. A total of 50 subjects were enrolled and 48 subjects completed the study. Adverse drug reactions were mild and transient. There were no serious adverse events in this study. The tear EGF concentrations rapidly increased and returned to baseline after 4 h without any serum EGF level change after the administration of rhEGF eyedrops. rhEGF eyedrops were safe and well-tolerated in healthy subjects in a dose range of 10-100 μg/mL, indicating suitability for further studies in patients with corneal injury.
| S-EPMC9697941 | biostudies-literature
Project description:RO6870868 is an oral prodrug of the toll-like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first-in-human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200-2000 mg). Single oral doses were generally well-tolerated with a predictable safety profile associated with dose-dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half-life ranging 2-6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC0-∞ ) increasing proportionally with dose. A pattern of dose and time-dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose-dependent manner with adequate safety and tolerability. Single-dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.
| S-EPMC8301559 | biostudies-literature
Project description:Neuropathic pain affects ~ 6.9-10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage-dependent and use-dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo-controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7-day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax ), area under the concentration-time curve from predose to 24 hours postdose (AUC0-24 ), time to Cmax (Tmax ), and terminal half-life (t1/2), among others, were assessed. Drug-related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug-related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1-2 hours, and t1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady-state was achieved from day 5 onward. These data indicate that oral vixotrigine is well-tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.
| S-EPMC8301589 | biostudies-literature
Project description:L-asparaginase has been an important component of acute lymphoblastic leukemia (ALL) therapy for over 40 years, and is standard therapy during ALL induction and consolidation treatment. L-asparaginases are immunogenic and can induce hypersensitivity reactions; inability to receive asparaginase has been associated with poor patient outcomes. There are L-asparaginases of varied bacterial origins, with the most commonly used being Escherichia coli (E. coli); therefore, to ensure that patients who develop hypersensitivity to E. coli-derived asparaginases receive an adequate therapeutic course, alternative preparations are warranted. JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme with no immunologic cross-reactivity to E. coli-derived asparaginases. To evaluate the safety, tolerability, and pharmacokinetics (PK) of a single dose of JZP-458, a randomized, single-center, open-label, phase I study was conducted with JZP-458 given via i.m. injection or i.v. infusion to healthy adult volunteers. At the highest doses tested for each route of administration (i.e., 25 mg/m2 i.m. and 37.5 mg/m2 i.v.), JZP-458 achieved serum asparaginase activity (SAA) levels ≥ 0.1 IU/mL at 72 hours postdose for 100% of volunteers. Bioavailability for i.m. JZP-458 was estimated at 36.8% based on SAA data. All dose levels were well-tolerated, with no unanticipated adverse events (AEs), no serious AEs, and no grade 3 or higher AEs. Based on PK and safety data, the recommended JZP-458 starting dose for the pivotal phase II/III study in adult and pediatric patients is 25 mg/m2 i.m. and 37.5 mg/m2 i.v. on a Monday/Wednesday/Friday dosing schedule.
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