scholarly journals 731. Pharmacokinetics of Gepotidacin (GSK2140944) in Subjects with Hepatic Impairment

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S327-S327
Author(s):  
Jonathan T Hands ◽  
Yu Tao ◽  
Courtney Tiffany ◽  
Caroline R Perry ◽  
Etienne Dumont ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Hepatic Impairment ◽  
Geometric Mean ◽  
Hepatic Clearance ◽  
Hepatic Function ◽  
Major Route ◽  
Bacterial Replication

Abstract Background Gepotidacin (GEP), a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro and in vivo efficacy activity against key pathogens, including drug-resistant strains, associated with a range of infections. In a previous absorption, distribution, metabolism, and excretion study for GEP, the mean recovery of radioactivity in urine and feces accounted for approximately 31.2% and 52.5%, respectively, of [14C]-GEP administered as a single oral dose. GEP was eliminated mainly as parent in urine, accounting for approximately 20% of the administered dose. Elimination via metabolism accounted for a total of 13% to 19% of the dose. Average total intravenous clearance of approximately 43 L/hour and renal clearance (CLr) of approximately 16 L/hour provides a hepatic clearance of 27 L/hour, suggesting that hepatic clearance is a major route of elimination of GEP. Methods Participants with normal and varying degrees of hepatic impairment (HI) received a single oral dose of GEP 1,500 mg. PK collections of blood, urine and saliva were performed. Results Relative to normal hepatic function, GEP Cmax and AUC(0-∞) in plasma were increased by 1.2-fold in subjects with moderate, and between 1.7-fold to 1.9-fold in severe HI. The fraction of dose excreted in urine increased with an increase in hepatic impairment. GEP urine concentrations remained high over a 12-hour period. Saliva concentrations displayed a linear relationship with plasma (both total and unbound) concentrations (R2 = 0.76). The geometric mean ratio of saliva AUC to unbound plasma AUC values ranged from 0.746 to 0.839 across all groups. Administration of 1,500 mg oral GEP was generally tolerated. Conclusion An increase in the dosing interval or dose reduction may be required in patients with severe hepatic impairment. Disclosures All authors: No reported disclosures.

Effects of Child-Pugh B Cirrhosis on Pharmacokinetics of Tofogliflozin, a New Sodium-Glucose Co-Transporter (SGLT2) Inhibitor

Drug Research ◽  
2020 ◽  
Vol 70 (09) ◽  
pp. 401-409
Author(s):  
Haruki Yamada ◽  
Hiromasa Ohira ◽  
Fumiaki Ikegami ◽  
Koichi Nakamura ◽  
Atsushi Takahashi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Oral Dose ◽  
Laboratory Test ◽  
Single Oral Dose ◽  
Hepatic Impairment ◽  
Geometric Mean ◽  
Sglt2 Inhibitor ◽  
Mean Value ◽  
Moderate Hepatic Impairment ◽  
Urinary Glucose

Abstract Background Tofogliflozin is a highly selective sodium-glucose co-transporter 2 (SGLT2) inhibitor. A mass balance study with combinations of microdoses revealed that tofogliflozin has high oral bioavailability (97.5%) and that tofogliflozin in circulation is eliminated primarily by metabolic pathways, with the liver playing a prominent role in elimination. Objectives This study aimed to evaluate the effect of moderate hepatic impairment on the pharmacokinetics of tofogliflozin and on the pharmacodynamics (urinary glucose excretion [UGE]). Methods In an open-label, parallel-group study, 17 subjects (9 with moderate hepatic impairment [Child-Pugh Class B, score 7–9] and 8 healthy) received a single oral dose of 40 mg tofogliflozin. Plasma and urine concentrations of tofogliflozin were determined. Accumulated UGE, adverse events, and physiological and laboratory test data were monitored. Results Geometric mean ratio (GMR; geometric mean value for subjects with moderate hepatic impairment / geometric mean value for healthy subjects) of Cmax was 1.47 and GMR of AUCinf was 1.70. Moderate hepatic impairment had only a little effect on tmax and CLR but it prolonged MRT. The levels of cumulative UGE were similar between the 2 groups. No clinically significant adverse events, laboratory test values, or physiological test values were observed in any subject. Conclusions Moderate hepatic impairment increased Cmax and AUCinf of tofogliflozin by 47% and 70%, respectively. This increase in tofogliflozin exposure did not increase UGE in hepatically impaired subjects. A single oral dose of 40 mg tofogliflozin was well tolerated, supporting dose adjustment is unnecessary even in moderately hepatically impaired subjects.

scholarly journals Probenecid inhibits SARS-CoV-2 replication in vivo and in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jackelyn Murray ◽  
Robert J. Hogan ◽  
David E. Martin ◽  
Kathy Blahunka ◽  
Fred D. Sancilio ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Virus Replication ◽  
Mammalian Cells ◽  
Clinical Utility ◽  
Plasma Concentrations ◽  
Hamster Model ◽  
Potential Clinical Utility

AbstractEffective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC90 value are achievable for 24 h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans.

scholarly journals Glycyrrhetinic acid might increase the nephrotoxicity of bakuchiol by inhibiting cytochrome P450 isoenzymes

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2723 ◽  
Author(s):  
Aifang Li ◽  
Nana Ma ◽  
Zijing Zhao ◽  
Mei Yuan ◽  
Hua Li ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Liver Microsomes ◽  
Glycyrrhetinic Acid ◽  
Internal Exposure ◽  
Functional Markers ◽  
Dependent Manner ◽  
Cyp Isoforms

BackgroundLicorice, a popular traditional Chinese medicine (TCM), is widely used to moderate the effects (detoxification) of other herbs in TCM and often combined withFructus Psoraleae. However, the classical TCM book states thatFructus Psoraleaeis incompatible with licorice; the mechanism underlying this incompatibility has not been identified. Glycyrrhetinic acid (GA), the active metabolite of licorice, may increase the toxicity of bakuchiol (BAK), the main chemical ingredient inPsoralea corylifolia, by inhibiting its detoxification enzymes CYP450s.MethodsThe effect of concomitant GA administration on BAK-induced nephrotoxicity was investigated, and the metabolic interaction between BAK and GA was further studied in vitro and in vivo. The cytotoxicity was assessed using an MTT assay in a co-culture model of HK-2 cell and human liver microsomes (HLMs). The effect of GA on the metabolism of BAK, and on the activities of CYP isoforms were investigated in HLMs. The toxicokinetics and tissue exposure of BAK as well as the renal and hepatic functional markers were measured after the administration of a single oral dose in rats.ResultsIn vitrostudies showed that the metabolic detoxification of BAK was significantly reduced by GA, and BAK was toxic to HK-2 cells, as indicated by 25∼40% decreases in viability when combined with GA. Further investigation revealed that GA significantly inhibited the metabolism of BAK in HLMs in a dose-dependent manner. GA strongly inhibits CYP3A4 and weakly inhibits CYP2C9 and CYP1A2; these CYP isoforms are involved in the metabolism of BAK.In vivoexperiment found that a single oral dose of BAK combined with GA or in the presence of 1-aminobenzotriazole (ABT), altered the toxicokinetics of BAK in rats, increased the internal exposure, suppressed the elimination of BAK prototype, and therefore may have enhanced the renal toxicity.ConclusionThe present study demonstrated that GA inhibits CYP isoforms and subsequently may increase the nephrotoxicity of BAK, which underlie one of the possible mechanisms responsible for the incompatibility of Licorice withFructus Psoraleae.

Influence of mild and moderate hepatic impairment on the pharmacokinetics (PK) of the pan-HER inhibitor dacomitinib.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2568-2568 ◽  
Author(s):  
Nagdeep Giri ◽  
Anna Plotka ◽  
Yali Liang ◽  
Tanya Boutros ◽  
Grace Ni ◽  
...  
Keyword(s):  
Liver Function ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Hepatic Impairment ◽  
Hepatic Function ◽  
Moderate Hepatic Impairment ◽  
Open Label ◽  
Post Dose ◽  
Normal Hepatic Function ◽  
Mild Impairment

2568 Background: Dacomitinib (D) is a highly selective irreversible small molecule inhibitor of the HER family of tyrosine kinases in clinical development for NSCLC.Prior clinical studies of D, which has minimal renal excretion (~3%), enrolled pts with protocol-defined adequate liver function. Liver metastases, leading to abnormal liver function tests, are common in pts with advanced cancer. This study evaluated the effect of hepatic impairment on PK and safety of D following a single oral dose in subjects with mild or moderate hepatic impairment. Methods: In this phase I, open-label, parallel group study, 25 subjects with either normal hepatic function (n=8) or mild (Child-Pugh A; n=8) or moderate (Child-Pugh B; n=9) hepatic impairment were administered a single, oral dose of D (30 mg). PK samples were collected at intervals up to 264 h post-dose and safety was assessed by laboratory abnormalities, physical examination, vital signs, ECGs, and AE monitoring. Analysis of variance was performed on natural log-transformed AUC and Cmaxto estimate adjusted mean differences between groups and 90% CIs, which were exponentiated to produce the adjusted GMR and 90% CI of the ratios. Results: GMR and 90% CI for AUCinf and Cmax (preliminary analyses) are listed.Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Moderate hepatic impairment decreased D exposure by 15% and 20% for AUCinf and Cmax, respectively, vs normal hepatic function, but the 90% CI was relatively wide, and included 1. Plasma protein binding of D was similar in the 3 groups. No clinically significant treatment-related AEs were reported. Conclusions: Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Mean D exposure appeared slightly lower in subjects with moderate impairment. Dose reduction of D in subjects with mild or moderate hepatic impairment may not be necessary. A single 30 mg dose of D was well tolerated in subjects with mild or moderate hepatic impairment. Clinical trial information: NCT01571388. [Table: see text]

Changes in the binding of oestradiol to uterine oestrogen receptors induced by some progesterone and 19-nor-testosterone derivatives

1983 ◽  
Vol 98 (3) ◽  
pp. 385-389 ◽  
Author(s):  
Francesco Di Carlo ◽  
Elena Gallo ◽  
Giuseppe Conti ◽  
Silvia Racca
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Medroxyprogesterone Acetate ◽  
The Other ◽  
Receptor Interaction ◽  
Oestrogen Receptors ◽  
Rat Uterus ◽  
The Hours

The effects of two progesterone derivatives, namely medroxyprogesterone acetate (MPA) and chlormadinone, and two 19-nor-testosterone derivatives, namely norgestrel and norethisterone, on the binding of oestradiol to its cytoplasmic receptors in the rat uterus were compared. In experiments performed in vivo, the rats were given a single oral dose (15 mg/kg) of one of the four progestins and killed 1, 6, 24 and 48 h later. Norgestrel, norethisterone and MPA induced a prompt and remarkable decrease in oestradiol–receptor interaction 1 h after treatment. This reduction lasted almost unchanged for 24 h in rats treated with MPA or norgestrel, but was much lower in animals given norethisterone. In the hours that followed, the effect of MPA and norgestrel began to decrease, but was still detectable after 48 h, whereas the effect of norethisterone had disappeared by this time. The effect of chlormadinone was much less than that induced by both MPA and norgestrel 1, 6 and 24 h after treatment. On the other hand, this effect was less than that caused by norethisterone 1 h after administration, equal after 6 h and much greater after 24 and 48 h. In experiments performed in vitro, the different ability of the four progestins to interfere with the capacity of oestradiol to bind to its receptors was confirmed. In conclusion, all the synthetic progestins used were able to reduce the binding of oestradiol to its cytoplasmic receptors, although there was a clear difference between the progestins in the intensity and duration of this effect. This could be one of the mechanisms by which progestins modulate the activity of oestrogens in target tissues.

scholarly journals Probenecid Inhibits SARS-CoV-2 Replication In Vivo and In Vitro

2021 ◽  
Author(s):  
Jackelyn Murray ◽  
Robert J. Hogan ◽  
David E. Martin ◽  
Kathy Blahunka ◽  
Fred Sancillo ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Virus Replication ◽  
Mammalian Cells ◽  
Clinical Utility ◽  
Plasma Concentrations ◽  
Hamster Model ◽  
Potential Clinical Utility

Effective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC90 value are achievable for 24h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans.

A single dose of lithium carbonate acutely elevates intact parathyroid hormone levels in humans

1989 ◽  
Vol 121 (2) ◽  
pp. 174-176 ◽  
Author(s):  
Ellen W. Seely ◽  
Thomas J. Moore ◽  
Meryl S. LeBoff ◽  
Edward M. Brown
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Human Subjects ◽  
Lithium Carbonate ◽  
Serum Levels ◽  
Ionized Calcium ◽  
Intact Parathyroid Hormone ◽  
Intact Pth

Abstract. Hyperparathyroidism has been reported in patients receiving lithium therapy, and lithium alters calcium-regulated PTH release in vitro. Previous studies in vivo have used assays which measure fragments of PTH as well as the intact hormone. To determine if lithium acutely elevates intact PTH levels, we studied 9 subjects who received a single oral dose of lithium carbonate (600 mg). Serum levels of intact PTH, ionized calcium, and lithium were measured before, 2 and 14 h after the dose of lithium. PTH levels rose significantly 2 h following the dose of lithium (before 22 ± 5.0, post 32 ± 7.3 ng/l, p < 0.02). PTH levels had returned to baseline at 14 h (22 ± 3.8 ng/l). There were no significant changes in ionized calcium levels. Therefore, a single oral dose of lithium carbonate acutely elevates intact PTH values in human subjects.

scholarly journals P291 Pharmacokinetics, safety, and tolerability of etrasimod (APD334) in subjects with mild, moderate, or severe hepatic impairment: a single-dose, open-label, parallel-group study

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S321-S322
Author(s):  
C Lee ◽  
Y Tang ◽  
C Schroeder ◽  
J Zhang ◽  
T Nguyen-Cleary ◽  
...  
Keyword(s):  
Single Dose ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Normal Control ◽  
Hepatic Impairment ◽  
Hepatic Function ◽  
Control Groups ◽  
Severe Hepatic Impairment ◽  
Open Label ◽  
Mean Values

Abstract Background Etrasimod is an oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders, including ulcerative colitis, Crohn’s disease, and eosinophilic esophagitis. The objective of this study was to evaluate the effect of hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of etrasimod. Methods This single-dose, open-label, parallel-group study included 36 adult subjects (aged 18-80 years; body mass index ≥18 kg/m2) with hepatic impairment, based on Child-Pugh score at screening (mild=5 to 6 [n=8], moderate=7 to 9 [n=8], severe=10 to 14 [n=6]), and their demographically matched control subjects with normal hepatic function (n=14 total). The first subject with severe hepatic impairment was enrolled after ≥2 subjects with mild and ≥2 subjects with moderate hepatic impairment had been enrolled and followed for ≥48 hours after dosing to ensure no observed significant safety signals. On Day 1, subjects received a single oral dose of etrasimod 2 mg after a ≥10 hour fast. PK and safety data were collected over a 21-day follow-up period. Results Thirty-six subjects were enrolled and dosed; 35 subjects completed the study. When compared with their respective demographically matched normal control groups, single dose etrasimod peak exposure (Cmax) was comparable for all hepatic impairment groups, whereas etrasimod total exposure (AUC) measures were progressively higher (up to 57.3% higher) in the mild, moderate, and severe hepatic impairment groups (Table 1). Unbound etrasimod Cmax values were progressively lower (up to 42.0% lower) in the mild, moderate, and severe hepatic impairment groups, whereas unbound etrasimod AUC values were typically comparable for all hepatic impairment groups, when compared with their respective demographically matched normal control groups (Table 2). Etrasimod t1/2 only moderately increased as hepatic function decreased, with mean values ranging from 43.9 to 59.5 hours in the demographically matched normal control groups and mean values of 55.7, 69.7, and 76.5 hours in the mild, moderate, and severe hepatic impairment groups, respectively. A single oral dose of etrasimod 2 mg was well tolerated; there were no clinically significant safety findings when administered to subjects with normal hepatic function or subjects with mild, moderate, or severe hepatic impairment. Conclusion A single oral dose of etrasimod 2 mg was well tolerated, with relatively modest changes in etrasimod exposure observed in subjects with mild, moderate, or severe hepatic impairment. These results suggest that etrasimod dose adjustment may not be warranted in subjects with hepatic impairment.

Effects of alcoholic extract from Ma-Klua (Diospyros mollis) on adults and larvae of the dwarf tapeworm, Hymenolepis nana in mice and on the infectivity of the eggs

Parasitology ◽  
1983 ◽  
Vol 87 (1) ◽  
pp. 103-111 ◽  
Author(s):  
Jun Maki ◽  
Asami Kondo ◽  
Toshio Yanagisawa
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Drug Administration ◽  
Post Infection ◽  
Alcoholic Extract ◽  
Severe Damage ◽  
Hymenolepis Nana ◽  
Anthelmintic Effect

SUMMARYThe anthelmintic effect of an alcoholic extract from a shrub, Diospyros mollis, popularly known as Ma-Klua in Thailand, on the adults and larvae of the dwarf tapeworm, Hymenolepis nana, in mice was studied in comparison with that of flubendazole. The experimentally infected mice were given a single oral dose of 10–1000 mg of Ma-Klua extract or flu-bendazole/kg body wt 1, 2, 3, 4, or 12 days post-infection and autopsied 14 days post-infection. Ma-Klua extract was effective in the elimination of adults (ED50 = 79 mg/kg) but not larvae. Drastic effects of Ma-Klua extract on the motility and structure of adults were observed and the number of the adults in mice decreased with time after administration of the drug 12 days post-infection. The small numbers of adults remaining in the host intestine 2 days after the drug administration showed severe damage in the gravid segments. These facts were thought to be responsible for the significant reduction in egg output observed 1 and 2 days after medication. Fresh eggs exposed to Ma-Klua extract in vitro and in vivo, or in vivo alone showed reduced infectivity. The effect of flubendazole on adults and larvae was minimal.

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