RESUMEN
AST-001 is an L-isomer of serine that has protective effects on neurological disorders. This study aimed to establish a population pharmacokinetic (PK) model of AST-001 in healthy Korean to further propose a fixed-dose regimen in pediatrics. The model was constructed using 648 plasma concentrations from 24 healthy subjects, including baseline endogenous levels during 24 h and concentrations after a single dose of 10, 20, and 30 g of AST-001. For the simulation, an empirical allometric power model was applied to the apparent clearance and volume of distribution with body weight. The PK characteristics of AST-001 after oral administration were well described by a two-compartment model with zero-order absorption and linear elimination. The endogenous production of AST-001 was well explained by continuous zero-order production at a rate of 0.287 g/h. The simulation results suggested that 2 g, 4 g, 7 g, 10 g, and 14 g twice-daily regimens for the respective groups of 10-14 kg, 15-24 kg, 25-37 kg, 38-51 kg, 52-60 kg were adequate to achieve sufficient exposure to AST-001. The current population PK model well described both observed endogenous production and exogenous administration of AST-001 in healthy subjects. Using the allometric scaling approach, we suggested an optimal fixed-dose regimen with five weight ranges in pediatrics for the upcoming phase 2 trial.
RESUMEN
PURPOSE: LCB01-0371 is a novel broad-spectrum oxazolidinone antibacterial agent under investigation for the treatment of infection by gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. This study evaluated the safety, tolerability, and pharmacokinetics of LCB01-0371 after a single intravenous (IV) infusion and determined its absolute oral bioavailability at a therapeutic dose of 800 mg. METHODS: This study was conducted in 2 parts. The first part was a single-blind, placebo-controlled, escalating single IV dose study (200, 400, 800, and 1200 mg) of LCB01-0371 via 2 different infusion regimens (250 mL over 60 min or 150 mL over 30 min) in 36 healthy male volunteers. The second part was an open-label, 2-way crossover design study in which 8 subjects were randomly assigned to 1 of 2 sequences of a single oral (800 mg) or IV (400 mg) administration of LCB01-0371. Safety assessments were conducted at regular intervals. Blood and urine were serially sampled, and drug concentrations were measured for up to 24 h to calculate pharmacokinetic parameters. FINDINGS: LCB01-0371 after IV administration was generally safe and well tolerated up to 800 mg regardless of the infusion regimen. Adverse events were mild, excluding nausea at the highest dose, and resolved spontaneously. After a single IV administration, LCB01-0371 exhibited linear pharmacokinetic properties over the range of 200-800 mg. The elimination t1/2, volume of distribution, and clearance ranged from 1.48 to 1.68 h, 57.74-76.72 L, and 33.17-43.31 L/h, respectively, and they remained unchanged over the corresponding dose range. Cmax, AUC0-last, and AUC0-∞ increased in a dose-dependent manner. The dose-normalized total exposure after single PO and IV dosing were equivalent, with 90% CIs of the geometric least squares mean ratio of 86.6%-110% for AUC0-last and 86.6%-111% for AUC0-∞. The dose-normalized Cmax was not equivalent between oral and IV dosing, with a 90% CI of the geometric least squares mean ratio of 50.0%-105%. The absolute oral bioavailability of LCB01-0371 after a single 800-mg dose was 99.75%. IMPLICATIONS: After a single IV administration, LCB01-0371 was well tolerated in healthy volunteers at doses up to 800 mg, and it exhibited linear pharmacokinetic properties. The comparable total systemic exposure between IV and oral administration supports the ability to switch administration routes without a need for dose adjustment. ClinicalTrials.gov identifier: NCT02882789.
Asunto(s)
Antibacterianos/administración & dosificación , Oxazolidinonas/administración & dosificación , Administración Oral , Adulto , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Humanos , Infusiones Intravenosas , Masculino , Oxazolidinonas/efectos adversos , Oxazolidinonas/farmacocinética , Método Simple Ciego , Adulto JovenRESUMEN
PURPOSE: LCB01-0371 is a novel oxazolidinone broad-spectrum antibacterial that is more potent than linezolid against systemic infections in animals. The goal of this investigation was to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple-dose LCB01-0371 as well as the pharmacokinetic characteristics of a new 400-mg tablet formulation. METHODS: Thirty-two healthy male subjects received BID 400-1600 mg multiple oral dosing of LCB01-0371 (200-mg tablet or 400-mg tablet) for 7 days, and 6 subjects received an 800-mg single oral dose of LCB01-0371 (400-mg tablet). Safety assessments were undertaken at regular intervals. Blood and urine were sampled, and drug concentration and inhibitory and bactericidal titers were measured. FINDINGS: LCB01-0371 was generally safe and well tolerated up to 1200 mg BID for 7 days. Adverse events were mild, except for headache, nausea, and dizziness at the dose of 1600 mg, and resolved spontaneously. LCB01-0371 was absorbed rapidly within 2 h after administration, and its accumulation observed on day 7 ranged between 1.10- and 1.46-fold. The elimination t1/2 was 1.64-1.94 h, which remained unchanged across all doses. AUC0-12 and Cmax were not dose proportional across the dose range from 400 to 1200 mg after both single and multiple dosing, indicating a nonlinear pharmacokinetic profile. The percentage of the dose excreted via the urine ranged from 7.84% to 8.95%. The new (400-mg tablet) formulation exhibited less interindividual variability with pharmacokinetic characteristics similar to the original formulation (200-mg tablet). LCB01-0371 exhibited both early serum inhibitory and bactericidal activities against the 4 strains tested in the ex vivo pharmacodynamics study. IMPLICATIONS: BID doses of LCB01-0371 up to 1200 mg for 7 days were well tolerated and exhibited rapid serum inhibitory and bactericidal activities against common gram-positive pathogens. The results warrant further clinical investigation of the antibacterial effect of BID LCB01-0371 administration. ClinicalTrial.gov identifier: NCT01842516.
Asunto(s)
Antibacterianos , Oxazolidinonas , Administración Oral , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Área Bajo la Curva , Bacterias/efectos de los fármacos , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Oxazolidinonas/administración & dosificación , Oxazolidinonas/efectos adversos , Oxazolidinonas/farmacocinética , Comprimidos , Adulto JovenRESUMEN
BACKGROUND: LCB01-0371 is a novel oxazolidinone antibiotic that blocks protein production by binding to bacterial 23S ribosomes. This antibiotic is active against Gram-positive bacteria. This study aimed to evaluate the effect of food on the pharmacokinetics (PKs) of LCB01-0371 and evaluate its safety profile. SUBJECTS AND METHODS: A randomized, open-label, two-way crossover study was performed in 18 healthy Korean male subjects. All subjects received a single oral 800 mg dose of LCB01-0371 in each period under fed or fasting condition with a 7-day washout in between. The fed condition was defined as consumption of a meal of 800-1,000 kcal containing50% of fat content. Serial blood samples were collected over 24 h after dosing, and the PK parameters were calculated by noncompartment analysis. All available data of the subjects who received LCB01-0371 at least once were included in the safety data summaries. RESULTS: In the fed condition, both the maximum plasma concentration (Cmax) and the total systemic exposure (area under the plasma concentration-time curve from time zero to the last observed time point [AUClast]) decreased by ~33% and 10%, respectively. The time to reach Cmax was delayed by ~1.25 h in the fed condition, whereas the mean elimination half-life remained similar in both conditions. In the fed/fasting condition, the geometric mean ratios and 90% CI of the Cmax and AUClast were 0.666 (0.470-0.945) and 0.897 (0.761-1.057), respectively. There were no drug-related adverse events (AEs) or serious AEs. CONCLUSION: Although the Tmax after a single oral 800 mg dose of LCB01-0371 was slightly delayed under the fed condition compared to the fasting condition, the total systemic exposure was similar under both conditions. Therefore, LCB01-0371 could be administered regardless of food intake.
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Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Interacciones Alimento-Droga , Oxazolidinonas/administración & dosificación , Oxazolidinonas/farmacocinética , Administración Oral , Adulto , Antibacterianos/sangre , Área Bajo la Curva , Estudios Cruzados , Ayuno/sangre , Semivida , Voluntarios Sanos , Humanos , Masculino , Tasa de Depuración Metabólica , Modelos Biológicos , Oxazolidinonas/sangre , Periodo Posprandial , República de Corea , Adulto JovenRESUMEN
LCB01-0371 is a novel oxazolidinone with broad-spectrum activity against Gram-positive pathogens in both in vitro studies and animal infection models. The objectives of this study were to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics following single ascending doses. Single oral doses of 600 mg linezolid, a placebo, or LCB01-0371 of between 50 mg and 3,200 mg were tested in 69 healthy male subjects. Blood and urine were sampled, LCB01-0371 concentrations were measured, and the serum inhibitory and bactericidal titers of LCB01-0371 and linezolid were determined. LCB01-0371 was well tolerated up to 2,400 mg. The most common drug-related clinical and laboratory adverse events were nausea with or without vomiting, decreased neutrophil counts, and increased total bilirubin levels. The frequency of adverse events and drug-related adverse events was similar among the treatment groups. The systemic exposure was approximately dose proportional over the range of 50 mg to 800 mg, which includes the anticipated clinical dose. The mean clearance, renal clearance, and volume of distribution were significantly decreased at higher doses (above 800 mg). LCB01-0371 exhibited early bacteriostatic activity against all tested strains except for Streptococcus pneumoniae strains, and the potency of LCB01-0371 at 800 mg was similar to that of linezolid at the therapeutic dose (600 mg). However, LCB01-0371 had less bactericidal activity than linezolid. Taken together, LCB01-0371 was well tolerated, exhibited approximate dose proportionality within the anticipated clinically relevant dose range, and showed bacteriostatic and bactericidal activity comparable to that of linezolid. These results support the further clinical development of LCB01-0371. (This study has been registered at ClinicalTrials.gov under registration no. NCT01554995.).
Asunto(s)
Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Oxazolidinonas/efectos adversos , Oxazolidinonas/farmacocinética , Adulto , Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Voluntarios Sanos , Humanos , Linezolid/farmacología , Masculino , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/farmacología , Adulto JovenRESUMEN
BACKGROUND: LCB01-0371 is a new oxazolidinone antibiotic, which targets most Gram-positive organisms. High rates of adverse reactions including myelosuppression have been reported for existing oxazolidinones, limiting their long-term use. OBJECTIVES: The safety, tolerability and pharmacokinetics (PK) of 21 day multiple oral administrations of LCB01-0371 in healthy male subjects (clinicaltrials.gov: NCT02540460) were investigated. METHODS: In this randomized, double-blind, placebo-controlled study, subjects received 800 mg of LCB01-0371 once or twice daily or 1200 mg of LCB01-0371 twice-daily for 21 days in a fasting state. Safety and tolerability profiles including laboratory tests were evaluated during the study and on a post-study visit and the results were analysed using repeated-measures analysis of variance (RM-ANOVA). Serial blood samples for PK analysis were collected up to 12 h after dosing on day 21. RESULTS: A total of 40 subjects were enrolled and 34 subjects completed the study. Two subjects dropped out according to stopping rules. In the 1200 mg twice-daily dose group, the absolute value of red blood cell count, haematocrit and haemoglobin decreased by 500â×â106/L (6.5%), 4.5% (6.8%) and 1.6 g/dL (6.9%), respectively, after 21 day administrations of LCB01-0371. However, mean relative changes from baseline of all haematology values were not significantly different among doses, including placebo (all, P < 0.05). PK profiles of LCB01-0371 in the dose range of 800 mg once daily to 1200 mg twice daily were consistent with previous studies. CONCLUSIONS: LCB01-0371 is well tolerated in healthy male subjects with comparable haematology profiles to placebo, after multiple doses of up to 1200 mg twice daily for 21 days.