scholarly journals Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants

2021 ◽  
Author(s):  
Aline Barth ◽  
Mohammad Hossain ◽  
Darin B. Brimhall ◽  
Caroline R. Perry ◽  
Courtney A. Tiffany ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Adult ◽  
Relative Bioavailability ◽  
Wet Granulation ◽  
Free Base ◽  
Formulation Development ◽  
Confidence Bounds ◽  
Time Curve ◽  
Bioavailability Study ◽  
New Treatment

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that may provide a new treatment option for antibiotic-resistant pathogens. Two pharmacokinetic evaluations of oral gepotidacin are presented; a relative bioavailability study that guided formulation development, followed by an adult and adolescent study of the final formulation. In the relative bioavailability study, after gepotidacin administration to 26 healthy adults as free base roller compacted (RC) tablets, free base high shear wet granulation (HSWG) tablets, and mesylate salt reference capsules, the RC tablet exposure ratios and 90% confidence intervals (CIs) were within the 0.80 to 1.25 confidence bounds; however, the HSWG tablet maximum observed concentration (C max ) was higher compared to the reference (ratio: 1.15; 90% CIs: 1.0113, 1.3047). In the healthy adult (n=16) and adolescent (n=17) study, a gepotidacin mesylate salt tablet was evaluated as a 1,500-mg single dose, 2 doses administered 6 or 12 h apart (6,000 mg total), or placebo. Single-dose mean C max was ∼27% higher in adolescents versus adults and area under the concentration-time curve (AUC) was comparable in both populations. After 2 doses were administered, mean C max was similar for both ages and mean AUC was ∼35% higher in adolescents versus adults. Concentrations increased proportionally with dose. Safety-risk profiles were similar in both ages. Across studies, the most common adverse events were gastrointestinal. Overall, the pharmacokinetics of the final gepotidacin mesylate salt tablet have been well-characterized, enrollment of adolescents into the pivotal trials is supported, and dosing intervals were determined that should provide adequate exposures for microbiological efficacy.

scholarly journals Comparative single-dose bioavailability study of two 10 mg Zolpidem tablet formulations in healthy volunteers

2019 ◽  
Vol 65 (01) ◽  
pp. 11-17
Author(s):  
Dimce Zafirov ◽  
Jasmina Trojacanec ◽  
Dragica Zendelovska ◽  
Nikola Kolovcevski ◽  
Bojan Labachevski
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
Bioequivalence Study ◽  
Relative Bioavailability ◽  
Serious Adverse Events ◽  
Test Formulation ◽  
Single Oral Administration ◽  
Hypnotic Agent ◽  
Bioavailability Study

Zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs with known hypnotic properties. Zolpidem as conventional tablets is used as a hypnotic agent in the short-term management of insomnia, generally for periods not exceeding 7–10 days in duration. The objective of this study was to evaluate and compare the relative bioavailability, and therefore the bioequivalence of Zolpidem 10 mg test formulation versus a reference Zolpidem 10 mg formulation, following a single dose administration under fasting conditions The study was a single center, open, single dose, randomized, two - way crossover study in healthy male volunteers with a wash - out period of one week between study periods. Twenty-eight male healthy volunteers, aged 20-49 years were included into study. Blood samples for determination of zolpidem plasma concentrations were withdraw at 0 (pre-drug administration), 0.33, 0.66, 1, 1.33, 1.66, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-drug. The zolpidem concentrations in plasma were determined with HPLC, using fluorescence detection. The test formulation of zolpidem, dosed at 10 mg is bioequivalent for primary zolpidem parameters (Cmax, AUC0-t and AUC0-∞) to the reference formulation after a single oral administration of 10 mg zolpidem. Both medications are well tolerated with no serious adverse events. Thus, in view of the clinical use, both formulations are exchangeable without restrictions. Keywords: Zolpidem, bioavailability, bioequivalence study, single-dose

scholarly journals 0745 The Pharmacokinetics of FT218, Once Nightly Sodium Oxybate: Food Effect and Bioavailability Compared to Twice Nightly Sodium Oxybate

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A283-A283
Author(s):  
M Thorpy ◽  
D Seiden ◽  
J Grassot ◽  
D Monteith ◽  
J Dubow ◽  
...  
Keyword(s):  
Single Dose ◽  
Controlled Release ◽  
Food Effect ◽  
Relative Bioavailability ◽  
Sodium Oxybate ◽  
Pharmacokinetic Studies ◽  
Release Formulation ◽  
Fed State ◽  
Fasted State ◽  
Bioavailability Study

Abstract Introduction Sodium oxybate is an effective treatment for excessive daytime sleepiness and cataplexy in patients with narcolepsy. The FDA approved formulation requires twice-nightly dosing; at bedtime and 2.5 - 4 hours later. FT218 is a controlled-release formulation of sodium oxybate intended for once-nightly dosing, using Avadel’s proprietary Micropump™ technology. The objective of this study was to evaluate the relative bioavailability of investigational once-nightly sodium oxybate, FT218, 6 g, compared to commercially available twice-nightly sodium oxybate and the food effect of FT218. Methods Two crossover, single-dose pharmacokinetic studies were conducted in healthy volunteers. The first, a relative bioavailability study (n=28) was completed comparing FT218 6 g to twice-nightly sodium oxybate 6 g (in two divided doses of 3 g). The second, evaluated the food effect (n=16) of FT218 6g in the Fed vs. Fasted state. Results FT218 had a lower overall Cmax than twice-nightly sodium oxybate, while AUC was equivalent. C8h level and variability was comparable between FT218 and twice-nightly sodium oxybate. In the Fed, compared to the Fasted state, FT218 had a longer Tmax, lower Cmax and decreased AUC (Cmax 67%, AUC 86%, Tmax 1-hour slower than Fasted values). Adverse Events with FT218 were mostly mild or moderate in severity, non-serious and known AEs associated with sodium oxybate. The safety profiles of FT218 and twice-nightly sodium oxybate at 6 g appeared similar. Conclusion Once-nightly FT218 at 6 g demonstrated a lower overall Cmax and similar exposure to twice-nightly sodium oxybate, with similar C8h plasma levels and C8h variability. In the Fed state, AUC and Cmax of FT218 was lower than in the Fasted State. FT218 was generally safe and well tolerated and the safety profile appeared comparable to twice-nightly sodium oxybate. Support This work was supported by Avadel Pharmaceuticals.

Influence of Enteral Feedings on Phenytoin Sodium Absorption from Capsules

1988 ◽  
Vol 22 (2) ◽  
pp. 130-133 ◽  
Author(s):  
Lyn Y. Nishimura ◽  
Edward P. Armstrong ◽  
Patricia M. Plezia ◽  
Robert P. Iacono
Keyword(s):  
Single Dose ◽  
Healthy Adult ◽  
Relative Bioavailability ◽  
Sodium Absorption ◽  
Crossover Fashion ◽  
Phenytoin Sodium ◽  
Enteral Feedings ◽  
Blood Specimens ◽  
Two Phases ◽  
Adult Volunteers

The influence of enteral feedings (with Ensure) on the absorption of phenytoin sodium from capsules was studied. Six healthy adult volunteers were given a single dose of phenytoin capsules 400 mg po on two occasions. Blood specimens were collected for 48 hours after each dose. In a randomized, crossover fashion, each subject completed the following two phases: (1) phenytoin without enteral feedings, and (2) concomitant enteral feedings before phenytoin and continued at 100 ml/h for ten hours. The areas under the concentration versus time curves from 0-48 hours (AUCo-48) were not significantly different between the two phases (p > 0.5). The percent relative bioavailability of phenytoin with enteral feedings was 101.7 percent. This study suggests that enteral feedings do not affect the serum concentrations of phenytoin after a single dose given in capsule form.

scholarly journals Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects

2014 ◽  
Vol 59 (2) ◽  
pp. 1219-1224 ◽  
Author(s):  
Helen Winter ◽  
Erica Egizi ◽  
Stephen Murray ◽  
Ngozi Erondu ◽  
Ann Ginsberg ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Pharmacokinetic Interaction ◽  
Time Curve ◽  
Concentration Time ◽  
Period 2 ◽  
Repeated Doses ◽  
Single Sequence ◽  
Time Point

ABSTRACTThis study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0–t), and AUC extrapolated to infinity (AUC0–inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for theCmax, AUC0–t, and AUC0–infof bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. TheCmax, AUC0–t, and AUC0–infof M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.)

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

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
E. Wenzler ◽  
E. J. Ellis-Grosse ◽  
K. A. Rodvold
Keyword(s):  
Single Dose ◽  
Oral Administration ◽  
Relative Bioavailability ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Time Curve ◽  
Blood And Urine Samples ◽  
Study Support ◽  
Tract Infections

ABSTRACT 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 (C max), 44.3 ± 7.6 and 370 ± 61.9 μg/ml; time to maximum concentration of drug in serum (T max), 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 μg·h/ml; and half-life (t 1/2), 2.4 ± 0.4 and 2.8 ± 0.6 h. After oral administration, the parameters were the following: C max, 26.8 ± 6.4 μg/ml; T max, 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 μg · h/ml; and t 1/2, 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.

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