Safety, Tolerability, and Pharmacokinetics of Sumatriptan Suppositories Following Single and Multiple doses in Healthy Volunteers

Cephalalgia ◽  
1997 ◽  
Vol 17 (4) ◽  
pp. 532-540 ◽  
Author(s):  
RL Kunka ◽  
EK Hussey ◽  
S Shaw ◽  
P Warner ◽  
B Aubert ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Plasma Concentrations ◽  
Repeat Dose ◽  
Oral Tablet ◽  
Single Dose Study ◽  
Multiple Doses ◽  
Dose Study ◽  
To Receive ◽  
Male Subjects

A suppository formulation of file 5HT1 agonist sumatriptan could prove an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administration is unsuitable because of severe migraine-related vomiting. Two independent double-blind, randomized clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of sumatriptan suppositories following ascending single dose. (four different dose levels) and multiple doses. In the four-period, crossover, single-dose study, 24 healthy male subjects were randomized to receive a suppository containing 12.5, 25, 50, or 100 mg on separate occasions 3–14 days apart. The suppositories were generally well tolerated; transient asthenia, drowsiness, and headache were the most frequently reported adverse events, and these were not close-related. Peak plasma concentrations (Cmax) of sumatriptan were proportional to close from 25 to 100 mg; area under the plasma concentration-time curve (AUCx) values were proportional to dose except at the highest doses, when they were greater than those predicted from lower doses. For all doses, the tmax of sumatriptan occurred within 2.5h, and the t1/2 was approximately 2h. In the two-period, placebo-controlled, crossover, repeat-dose study, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rectally twice a day, for 11 doses (5 1/2 days). Adverse events were no more frequent with sumatriptan than with placebo, and stool guaiac, rectal examinations, and physical examinations remained normal. No significant differences were noted between Day 1 and Day 6 values in the AUC, Cmax, time of peak serum concentration (tmax), elimination half-life (t1/2), fraction of the dose excreted in the urine (fe), or renal clearance (Clr) of sumatriptan or its pharmacologically inactive indole acetic acid metabolite. Serum metabolite concentrations were two to threefold higher than corresponding sumatriptan concentrations. No clinically significant accumulation of sumatriptan or its metabolite occurred. Overall, these studies show that sumatriptan administration via a suppository formulation is well tolerated, allows rapid absorption of sumatriptan, results in sumatriptan Cmax values that are proportion I to dose from 25 to 100 mg, and is not associated with accumulation of sumatriptan or its nnetabolite.

scholarly journals Pharmacokinetics and Safety of an Antirhinoviral Agent, Ruprintrivir, in Healthy Volunteers

2002 ◽  
Vol 46 (2) ◽  
pp. 392-397 ◽  
Author(s):  
Poe-Hirr Hsyu ◽  
Yazdi K. Pithavala ◽  
Merril Gersten ◽  
Carol A. Penning ◽  
Bradley M. Kerr
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Systemic Exposure ◽  
Upper Respiratory Tract ◽  
Irreversible Inhibitor ◽  
Double Blind ◽  
Measured Concentration ◽  
Single Dose Study ◽  
Multiple Doses ◽  
Dose Study

ABSTRACT A single-dose study and a multiple-dose study of the safety and pharmacokinetics of ruprintrivir, a new selective irreversible inhibitor of human rhinovirus 3C protease, were conducted with healthy adult volunteers. Both studies were double-blind, randomized, placebo-controlled, parallel-group investigations of ruprintrivir administered intranasally at two dose levels. The parent drug and its acid metabolite, AG7185, were measured in plasma samples and nasal washings, and the safety of the treatments was monitored. Intranasal ruprintrivir, administered as single doses of 4 and 8 mg or every 3 h, six times per day, for 7 days was safe and well tolerated. Adverse events were mild, short-lived, and confined to the upper respiratory tract (i.e., nose and throat, taste and smell perceptions). Adverse events were similar after placebo and after single or multiple doses of active drug. Systemic exposure to ruprintrivir was rarely detectable with the highest measured concentration of ≤0.52 ng/ml; the assay had a lower limit of quantification of 0.2 ng/ml. Systemic exposure to the metabolite was also low, with a highest measured concentration of 3.25 ng/ml. Concentrations of AG7185 observed during multiple dosing were higher than those observed after the first dose but were no more than predicted from the single-dose study. Substantial amounts of ruprintrivir were observed intranasally for at least 9 h after multiple doses of ruprintrivir.

scholarly journals Pharmacokinetics of Tigecycline after Single and Multiple Doses in Healthy Subjects

2005 ◽  
Vol 49 (1) ◽  
pp. 220-229 ◽  
Author(s):  
Gopal Muralidharan ◽  
Marlynne Micalizzi ◽  
John Speth ◽  
Donald Raible ◽  
Steven Troy
Keyword(s):  
Liquid Chromatography ◽  
Single Dose ◽  
Healthy Subjects ◽  
Antimicrobial Agents ◽  
Phase 1 ◽  
Bacterial Species ◽  
Strong Activity ◽  
Single Dose Study ◽  
Multiple Doses ◽  
Dose Study

ABSTRACT Tigecycline, a novel glycylcycline antibiotic, exhibits strong activity against gram-positive, gram-negative, aerobic, anaerobic, and atypical bacterial species, including many resistant pathogens, i.e., vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The safety and tolerability of tigecycline administered as single or multiple doses or at various infusion rates were explored in three phase 1, randomized, double-blind, placebo-controlled studies in healthy subjects. Full pharmacokinetic profiles of tigecycline were determined in two of these studies. Subjects in the single-dose study received 12.5 to 300 mg of tigecycline, which differed with respect to the duration of infusion, subjects' feeding status, and ondansetron pretreatment. Subjects in the ascending multiple-dose study received 25 to 100-mg doses of tigecycline as a 1-h infusion every 12 h. The variable volume and infusion rate study consisted of administration of 100-mg loading dose of tigecycline, followed by 50 mg every 12 h for 5 days. Serum samples were analyzed for tigecycline by validated high-pressure liquid chromatography or liquid chromatography/tandem mass spectrometry methods. Systemic clearance ranged from 0.2 to 0.3 liters/h/kg, and the tigecycline half-life ranged from 37 to 67 h. Tigecycline had a large volume of distribution (7 to 10 liters/kg), indicating extensive distribution into the tissues. Food increased the maximum tolerated single-dose from 100 to 200 mg, but the duration of infusion did not affect tolerability. Side effects, mainly nausea and vomiting, which are common to the tetracycline class of antimicrobial agents, were seen in these studies. Tigecycline exhibits linear pharmacokinetics and is safe and well tolerated in the dose ranges examined.

scholarly journals A Randomized, Double-Blind, Single-Dose Study Comparing the Biosimilarity of HOT-1010 With Bevacizumab (Avastin®) in Chinese Healthy Male Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Kai Huang ◽  
Linling Que ◽  
Ying Ding ◽  
Nannan Chu ◽  
Zhenzhong Qian ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Geometric Mean ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pharmacokinetic Parameters ◽  
Healthy Male ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Single Dose Study ◽  
Male Subjects

Objective: This study was conducted to compare the pharmacokinetics, safety and immunogenicity of HOT-1010 with bevacizumab (Avastin®) in Chinese healthy male subjects.Methods: A single-center, randomized, double-blind, single-dose, parallel trial was performed in 84 Chinese healthy male subjects who randomly (1:1) received a single intravenous infusion of 1 mg/kg HOT-1010 or Avastin® for 90 min and followed up for 85 days. Serum concentrations of bevacizumab were analyzed by enzyme-linked immunosorbent assay. Primary pharmacokinetic parameters, Cmax, AUC0-t and AUC0-∞, were calculated and evaluated the bioequivalence between HOT-1010 and Avastin®, the safety and immunogenicity of investigational drugs were also assessed.Results: A total of 82 subjects completed the study. The 90% Confidence Intervals for geometric mean ratios of Cmax, AUC0-t and AUC0-∞ were 91.81–103.64%, 85.19–95.39% and 85.04–95.36%, which were all within the bioequivalence margin. Treatment-emergent adverse events were reported in 27 (65.9%) subjects in HOT-1010 group and 23 (56.1%) subjects in Avastin® group. Most TEAEs were mild or moderate. No TEAEs, Serious Adverse Events or deaths leading to discontinuation was reported. Subjects were all tested negative for Anti-drug Antibody.Conclusion: HOT-1010 exhibited the similar pharmacokinetics, safety and immunogenicity profiles of bevacizumab (Avastin®) in Chinese healthy male subjects.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/index.html, CTR20181610.

scholarly journals Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 889
Author(s):  
Bassam M. Ayoub ◽  
Haidy E. Michel ◽  
Shereen Mowaka ◽  
Moataz S. Hendy ◽  
Mariam M. Tadros
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Brain Tissue ◽  
Concentration Ratio ◽  
Liquid Extraction ◽  
Single Dose Study ◽  
Liquid Liquid Extraction ◽  
Multiple Doses ◽  
Dose Study ◽  
Plasma Concentration Ratio

The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.

Sign in / Sign up

Export Citation Format

Share Document