Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Evaluations Following Single Oral Doses of GSK2330672 in Healthy Japanese Volunteers

Ino, Hiroko; Endo, Akira; Wakamatsu, Akira; Ogura, Hirofumi; Numachi, Yotaro; Kendrick, Stuart

doi:10.1002/cpdd.576

Cited by 9 publications

(5 citation statements)

References 25 publications

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“…All three IBAT inhibitors showed similar adverse events: dose-dependent diarrhea (up to 50, 100, and 83% with A4250, SHP626, and GSK2330672, respectively) and abdominal pain (up to 33, 78, and 17% with A4250, SHP626, and GSK2330672, respectively) ( Graffner et al, 2016 ; Ino et al, 2018 ; Tiessen et al, 2018 ).…”

Section: Phase I Clinical Trials With Ibat Inhibitorsmentioning

confidence: 87%

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Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH

Al-Dury

Marschall

2018

Front. Pharmacol.

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Bile acids are synthesized from cholesterol in the liver, excreted with bile into the duodenum, almost completely taken up again in the distal ileum and finally returned to the liver with portal blood in a process termed enterohepatic circulation. Bile acid synthesis, excretion, and reuptake are tightly regulated. The apical sodium-dependent bile acid transporter [ASBT; also known as ileal bile acid transporter (IBAT) and SLC10A2] is pivotal for the almost complete reabsorption of conjugated bile acids in the ileum. Dysfunctional IBAT may be the cause of bile acid diarrhea. Pharmacological IBAT inhibition results in an increased bile acid load in the colon and subsequently a lower bile acid pool, which is associated with improved liver histology in animal models of cholestatic liver disease and non-alcoholic steatohepatitis (NASH). In humans, IBAT inhibitors have been tested in clinical trials with widely different indications: in patients with idiopathic chronic constipation, an increased number of bowel movements was observed. In adult and pediatric cholestatic liver diseases with pruritus, various IBAT inhibitors showed potential to improve itching. Adverse events of IBAT inhibitors, based on their mode of action, are abdominal pain and diarrhea which might patients to withdraw from study medications. So far, no data are available of a study of IBAT inhibitors in patients with NASH. In this review we summarize the preclinical and most recent clinical studies with various IBAT inhibitors and discuss the difficulties that should be addressed in future studies.

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Section: Phase I Clinical Trials With Ibat Inhibitorsmentioning

confidence: 87%

“…The third trial evaluated the IBAT inhibitor GSK2330672 in a 4-period crossover study in 16 Japanese subjects with single oral doses of GSK2330672 (10–180 mg) or placebo in each period. A dose-dependent tendency for total serum BAs to reduce and for serum C4 to increase was observed ( Ino et al, 2018 ).…”

Section: Phase I Clinical Trials With Ibat Inhibitorsmentioning

confidence: 99%

Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH

Al-Dury

Marschall

2018

Front. Pharmacol.

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“…In this matter, a later study in healthy Japanese volunteers investigated the safety and tolerability of GSK2330672 versus placebo. No serious adverse events were present and the main side effects was diarrhea [74]. Another, but larger placebo-controlled trial found that GSK2330672 was not significantly different versus placebo [75].…”

Section: Asbt Inhibitorsmentioning

confidence: 94%

Current Therapies for Cholestatic Diseases

Méndez-Sánchez¹,

Coronel-Castillo²,

Ordoñez-Vázquez³

2023

Preprint

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Cholestasis is a condition defined as an abnormal decrease of bile flow due to progressive pathological states or cholestatic liver diseases that affect the biliary tree at intrahepatic and extrahepatic level. It induces complications such as cirrhosis, liver failure, malignancies, pruritus, fatigue, bone disease and nutritional deficiencies that merit close follow-up and specific interventions to improve quality of life. Furthermore, cholestasis can progress to end-stage liver disease and represents an entity with high morbidity and mortality; and economic burden, Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. This review addresses the pathophysiology of cholangiopathies, a general view of current treatments and their molecular targets, and a specific review of those groups of drugs. The objective is to provide clinicians with an overview of the current treatment of cholangiopathies based on evidence on its efficacy and safety.

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“…In this matter, a later study in healthy Japanese volunteers investigated the safety and tolerability of GSK2330672 versus a placebo. No serious adverse events were present and the main side effect was diarrhea [ 77 ]. Another, but larger, placebo-controlled trial found that GSK2330672 was not significantly different versus placebo [ 78 ].…”

Section: Therapeutic Optionsmentioning

confidence: 99%

Current Therapies for Cholestatic Diseases

2023

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Cholestasis is a condition characterized by decrease in bile flow due to progressive pathological states that lead to chronic cholestatic liver diseases which affect the biliary tree at the intrahepatic level and extrahepatic level. They induce complications such as cirrhosis, liver failure, malignancies, bone disease and nutritional deficiencies that merit close follow-up and specific interventions. Furthermore, as those conditions progress to liver cirrhosis, there will be an increase in mortality but also an important impact in quality of life and economic burden due to comorbidities related with liver failure. Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. With a general view of therapeutic options and their molecular targets, this review addresses the pathophysiology of cholangiopathies. The objective is to provide clinicians with an overview of the safety and efficacy of the treatment of cholangiopathies based on the current evidence.

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Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Evaluations Following Single Oral Doses of GSK2330672 in Healthy Japanese Volunteers

Cited by 9 publications

References 25 publications

Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH

Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH

Current Therapies for Cholestatic Diseases

Current Therapies for Cholestatic Diseases

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