Pharmacokinetics of selonsertib, GS-9674, and/or GS-0976 in combination in healthy subjects

Nelson, Casey; Kirby, Beth J.; Lu, Nina; Mccolgan, B.; Djedjos, C. Stephen; Myers, Ronald; Cuvin, J.; Qin, Ann; Mathias, Anita

doi:10.1016/s0168-8278(17)30575-5

Cited by 5 publications

(6 citation statements)

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“…Furthermore, participants with renal impairment may also have underlying impaired hepatic function. Based on results from completed hepatic‐impairment studies, dose adjustments are not considered necessary for either firsocostat or cilofexor in people with mild hepatic impairment, while those with moderate/severe impairment are to be excluded from clinical studies at this time 13,14 …”

Section: Discussionmentioning

confidence: 99%

“…The pharmacokinetics of firsocostat and cilofexor have been previously characterized in healthy participants following multiple‐dose administration ranging from 20 to 200 mg and from 10 to 300 mg, respectively. Plasma exposures of firsocostat and cilofexor were approximately dose proportional in the dose ranges of 30‐200 mg and 30‐100 mg, respectively 11,12 ; both are highly bound (>99%) to plasma proteins 13,14 . Human mass balance study data from healthy participants have shown that the primary pathway of elimination is hepatic metabolism (>90% of dose recovered in feces) for both firsocostat and cilofexor (including their major metabolites: GS‐834773 for firsocostat and GS‐716070 and GS‐1056756 for cilofexor), while renal elimination is considered a minor pathway (<3% of dose recovered in urine) (unpublished cilofexor data, Gilead Sciences, Inc.) 15 .…”

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confidence: 99%

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Effect of Renal Impairment on the Pharmacokinetics of Firsocostat, an Acetyl‐Coenzyme A Carboxylase Inhibitor, and Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist

Weber

Younis

Nelson

et al. 2023

The Journal of Clinical Pharma

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Firsocostat, a liver-targeted acetyl-coenzyme A carboxylase inhibitor, and cilofexor, a nonsteroidal farnesoid X receptor agonist, are being developed in combination for treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated firsocostat and cilofexor pharmacokinetics and tolerability in participants with severe renal impairment (SRI) and healthy matched controls (HMCs). Ten participants with SRI (estimated glomerular filtration rate by Modification of Diet in Renal Disease <30 mL/min/1.73 m 2 ), and 10 HMCs received single oral doses of firsocostat (20 mg) on day 1 and cilofexor (100 mg) on day 7 in a fasted state. Plasma concentrations of firsocostat (and nonactive metabolite GS-834773) and cilofexor (and nonactive metabolites GS-716070 and GS-1056756) were collected over 96 hours and quantified; plasma exposures (area under the concentration-time curve [AUC] and peak concentration [C max ]) and plasma protein binding were characterized. Firsocostat AUC was ≈40% higher in SRI versus HMC, while C max was 8% lower. Observed exposures of the firsocostat metabolite were ≈4.6-fold higher in SRI participants versus HMC. Exposures (AUC and C max ) of cilofexor and metabolites and percentages of protein binding of all analytes were similar between SRI and HMC groups. Treatment-emergent adverse events were generally mild and not considered related to study drug. A <50% increase in firsocostat exposure was observed among SRI participants but was deemed not clinically relevant. There was no apparent effect of SRI on cilofexor exposure. Based on this trial, firsocostat and cilofexor dosing are not expected to require modification in patients who are renally impaired.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Effect of Renal Impairment on the Pharmacokinetics of Firsocostat, an Acetyl‐Coenzyme A Carboxylase Inhibitor, and Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist

Weber

Younis

Nelson

et al. 2023

The Journal of Clinical Pharma

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“…For NASH patients who received the 100 mg dose of Cilofexor, 39% showed ≥30% decline in magnetic resonance imaging-proton density fat fraction (MRI-PDFF), while only 14% of patients who received the 30 mg dose showed the same level of MRI-PDFF reduction [ 44 ]. Additionally, Cilofexor (GS-9674) is under evaluation in phase 2 clinical trials for treatment of NASH (NCT02781584) in combination with Firsocostat (GS-0976) and Selonsertib (GS-4997) [ 45 , 46 , 47 , 48 ].…”

Section: Nuclear Receptor Targets For Nafldmentioning

confidence: 99%

Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH

et al. 2022

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Non-alcoholic fatty liver (NAFLD) over the past years has become a metabolic pandemic linked to a collection of metabolic diseases. The nuclear receptors ERRs, REV-ERBs, RORs, FXR, PPARs, and LXR are master regulators of metabolism and liver physiology. The characterization of these nuclear receptors and their biology has promoted the development of synthetic ligands. The possibility of targeting these receptors to treat NAFLD is promising, as several compounds including Cilofexor, thiazolidinediones, and Saroglitazar are currently undergoing clinical trials. This review focuses on the latest development of the pharmacology of these metabolic nuclear receptors and how they may be utilized to treat NAFLD and subsequent comorbidities.

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“…Px-104 (GS-9674, also called cilofexor) was considered as the best example of FXR agonist in the clinical development derivative. A single 100 -mg dose of cilofexor showed good tolerance in healthy volunteers and no grade 3 adverse effects were observed ( Nelson et al, 2017 ). A Phase II trial with Px-104 (NCT01999101) was also conducted to evaluate the safety and tolerability of Px-104 in NAFLD patients.…”

Section: Fxr Modulatorsmentioning

confidence: 99%

Farnesoid X Receptor Agonists as Therapeutic Target for Cardiometabolic Diseases

Yang

Wang

et al. 2020

Front. Pharmacol.

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Cardiometabolic diseases are characterized as a combination of multiple risk factors for cardiovascular disease (CVD) and metabolic diseases including diabetes mellitus and dyslipidemia. Cardiometabolic diseases are closely associated with cell glucose and lipid metabolism, inflammatory response and mitochondrial function. Farnesoid X Receptor (FXR), a metabolic nuclear receptor, are found to be activated by primary BAs such as chenodeoxycholic acid (CDCA), cholic acid (CA) and synthetic agonists such as obeticholic acid (OCA). FXR plays crucial roles in regulating cholesterol homeostasis, lipid metabolism, glucose metabolism, and intestinal microorganism. Recently, emerging evidence suggests that FXR agonists are functional for metabolic syndrome and cardiovascular diseases and are considered as a potential therapeutic agent. This review will discuss the pathological mechanism of cardiometabolic disease and reviews the potential mechanisms of FXR agonists in the treatment of cardiometabolic disease.

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Pharmacokinetics of selonsertib, GS-9674, and/or GS-0976 in combination in healthy subjects

Cited by 5 publications

References 0 publications

Effect of Renal Impairment on the Pharmacokinetics of Firsocostat, an Acetyl‐Coenzyme A Carboxylase Inhibitor, and Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist

Effect of Renal Impairment on the Pharmacokinetics of Firsocostat, an Acetyl‐Coenzyme A Carboxylase Inhibitor, and Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist

Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH

Farnesoid X Receptor Agonists as Therapeutic Target for Cardiometabolic Diseases

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