Effects of Mild to Severe Hepatic Impairment on the Pharmacokinetics of Sonidegib: A Multicenter, Open-Label, Parallel-Group Study

Horsmans, Yves; Zhou, Jocelyn; Liudmila, Mateva; Golor, George; Shibolet, Oren; Quinlan, Michelle; Emotte, Corinne; Boss, Hildegard; Castro, Henry; Sellami, Dalila; Preston, Richard A.

doi:10.1007/s40262-017-0560-2

Cited by 16 publications

(7 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The safety of sonidegib was also confirmed by a phase I multicenter single-dose study evaluating the pharmacokinetics of 800 mg oral dose sonidegib in subjects with hepatic impairment. Overall, sonidegib exposures were similar or decreased, and it was generally well tolerated, not requiring any dose adjustment even in patients with severe hepatic impairment [32]. Based on the pharmacokinetics of sonidegib, another phase I study investigated the effect of a proton pump inhibitor (esomeprazole) on the oral absorption of Hh inhibitor [33].…”

Section: Other Studies Evaluating Sonidegib Efficacymentioning

confidence: 99%

Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

Villani

Fabbrocini

Costa

et al. 2020

Dermatol Ther (Heidelb)

View full text Add to dashboard Cite

Hedgehog inhibitors are promising alternative treatments for patients with advanced basal cell carcinomas. Sonidegib (Odomzo Ò ), an oral smoothened (SMO) antagonist, is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) who present recurrence following surgery or radiation therapy, or those who are not candidates for surgery or radiotherapy. Several studies and randomized controlled trials have been conducted to evaluate the efficacy, safety, and tolerability of this new molecule that has demonstrated a good response rate (44%). Grade 1-2 adverse events have also been repor-ted. Further studies of real-world experiences are needed to better understand the correct management of the drug, alternative dosing regimens, and differences with other hedgehog inhibitors. This article provides a complete overview of the pharmacology and pharmacokinetics of sonidegib and a report of the trials and studies conducted. The most frequent adverse events and their correct management are also discussed.

show abstract

Section: Other Studies Evaluating Sonidegib Efficacymentioning

confidence: 99%

Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

Villani

Fabbrocini

Costa

et al. 2020

Dermatol Ther (Heidelb)

View full text Add to dashboard Cite

show abstract

“…This phase I, multicenter, open-label study showed that sonidegib exposures were similar or decreased in the hepatic impairment groups compared with the normal group, and sonidegib was generally well-tolerated in all subjects. Dose adjustment is not considered necessary for subjects with mild, moderate, or severe hepatic impairment 85 . Sonidegib has already shown survival benefits in patients with advanced HCC 73 .…”

Section: Hh Signaling In Liver Cancersmentioning

confidence: 99%

Role of canonical Hedgehog signaling pathway in liver

Gao¹,

Zhang²,

Zhang³

et al. 2018

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Hedgehog (Hh) signaling pathway plays an important role in embryonic development. It becomes reactivated in many types of acute and chronic liver injuries. Hh signaling is required for liver regeneration, regulates capillarisation, controls the fates of hepatic stellate cells, promotes liver fibrosis and liver cancers. In this review, we summarize the current knowledge of the role of canonical Hh signaling pathway in adult liver. This help to understand the pathogenesis of liver diseases and find out the new effective targeted therapeutic strategies for liver diseases treatments.

show abstract

“…Participants with hepatic impairment may have changes in gastrointestinal environment, such as bile salt content and phospholipids, which influence the solubility of the drug and thus reduce ivosidenib absorption. The lower C max in participants with hepatic impairment may be explained by reduced absorption of ivosidenib and has been observed with other drugs 9‐11 . Protein binding is another important factor.…”

Section: Discussionmentioning

confidence: 84%

Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of a Single Dose of Oral Ivosidenib in Otherwise Healthy Participants

Fan

Dai

Cohen

et al. 2020

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

Ivosidenib, a small‐molecule inhibitor of mutant isocitrate dehydrogenase 1, is primarily cleared by hepatic metabolism. This open‐label study investigated the impact of hepatic impairment on ivosidenib pharmacokinetics (ClinicalTrials.gov: NCT03282513). Otherwise healthy participants with mild (n = 9) or moderate (n = 8) hepatic impairment (Child‐Pugh score) and matched participants with normal hepatic function (n = 16) received 1 oral dose of 500‐mg ivosidenib. Mild hepatic impairment had a negligible effect on total ivosidenib plasma exposure, with geometric mean ratios (90% confidence interval [CI]) of 0.933 (0.715‐1.22) for maximum concentration (Cmax) and 0.847 (0.624‐1.15) for area under the plasma concentration–time curve (AUC) in participants with mild hepatic impairment versus matched controls. Moderate hepatic impairment reduced total ivosidenib exposure by 28% to 44%, with geometric mean ratios (90%CI) of 0.565 (0.419‐0.763) for Cmax and 0.716 (0.479‐1.07) for AUC, although the 90%CI for AUC included 1.00. The ivosidenib unbound fraction was concentration dependent and higher in participants with mild/moderate hepatic impairment compared with matched controls. There was no apparent trend to increasing unbound Cmax with increased hepatic impairment severity. A single 500‐mg ivosidenib dose was well tolerated, with no serious or severe adverse events and no adverse events leading to discontinuation. We conclude that mild/moderate hepatic impairment did not lead to clinically relevant changes in ivosidenib exposure following a single 500‐mg dose.

show abstract

Effects of Mild to Severe Hepatic Impairment on the Pharmacokinetics of Sonidegib: A Multicenter, Open-Label, Parallel-Group Study

Abstract: Overall, sonidegib exposures were similar or decreased in the hepatic impairment groups compared with the normal group, and sonidegib was generally well-tolerated in all subjects. Dose adjustment is not considered necessary for subjects with mild, moderate, or severe hepatic impairment.

Cited by 16 publications

References 10 publications

Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

Role of canonical Hedgehog signaling pathway in liver

Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of a Single Dose of Oral Ivosidenib in Otherwise Healthy Participants

Contact Info

Product

Resources

About