Effect of Liver Cirrhosis on the Pharmacokinetics, Metabolism, and Tolerability of Daridorexant, A Novel Dual Orexin Receptor Antagonist

Berger, Benjamin; Dingemanse, Jasper; Sabattini, Giancarlo; Delahaye, Stéphane; Duthaler, Urs; Muehlan, Clemens; Krähenbühl, Stephan

doi:10.1007/s40262-021-01028-8

Cited by 16 publications

(28 citation statements)

References 44 publications

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“…In comparison to the moderate to high extraction drugs, the effect of liver cirrhosis on the pharmacokinetics of the low to moderate extraction drugs caffeine, efavirenz, and flurbiprofen was much less accentuated. In contrast to caffeine, efavirenz and flurbiprofen have a high protein binding (Table 1 of the ESM), which is usually associated with an increase in the free fraction (and possibly free concentration) of such drugs in patients with liver cirrhosis [ 8 , 20 , 22 ], potentially overriding a negative effect of liver cirrhosis on drug clearance. As shown in Table 2 , this appears to be the case for efavirenz and flurbiprofen.…”

Section: Discussionmentioning

confidence: 99%

“…As shown in Table 2 , this appears to be the case for efavirenz and flurbiprofen. As the MR 0–24h may be influenced by protein binding (protein binding between the parent drug and the metabolite may be different), the elimination rate constant, which is independent of protein binding [ 8 , 20 ], may represent the best marker for CYP activity for such compounds. The results of the current study show a significant decrease in the MR 0–24h for caffeine and efavirenz but no significant effect on elimination rate constant or MR 0–24h of flurbiprofen.…”

Section: Discussionmentioning

confidence: 99%

“…The markers used for CYP activity should be independent of protein binding and bioavailability, which can change substantially in patients with liver cirrhosis [ 4 ]. An ideal candidate is the elimination rate constant, which is independent of both protein binding and bioavailability if protein binding of the drug considered is not saturable [ 8 ]. The MR can be considered to be independent of bioavailability but may not be independent of protein binding, which may differ between parent compound and metabolite.…”

Section: Discussionmentioning

confidence: 99%

“…For drugs with a moderate hepatic extraction (30–70%) both hepatic blood flow and activity of metabolizing enzymes determine the hepatic clearance. For drugs with a high protein binding (e.g., > 95%), the fraction of free drug can vary considerably in patients with liver cirrhosis owing to a reduced serum concentration of drug-binding proteins such as albumin and acid α-glycoprotein and displacement from the protein binding [ 8 ]. For low and moderate extraction drugs, an increase in the free drug concentration should result in an increase in hepatic drug clearance, which, however, is often overruled by a decrease in the activity of drug-metabolizing enzymes in the cirrhotic liver.…”

Section: Introductionmentioning

confidence: 99%

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Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently

et al. 2022

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Background Activities of hepatic cytochrome P450 enzymes (CYPs) are relevant for hepatic clearance of drugs and known to be decreased in patients with liver cirrhosis. Several studies have reported the effect of liver cirrhosis on CYP activity, but the results are partially conflicting and for some CYPs lacking. Objective In this study, we aimed to investigate the CYP activity in patients with liver cirrhosis with different Child stages (A-C) using the Basel phenotyping cocktail approach. Methods We assessed the pharmacokinetics of the six compounds and their CYP-specific metabolites of the Basel phenotyping cocktail (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A: midazolam) in patients with liver cirrhosis ( n = 16 Child A cirrhosis, n = 15 Child B cirrhosis, n = 5 Child C cirrhosis) and matched control subjects ( n = 12). Results While liver cirrhosis only marginally affected the pharmacokinetics of the low to moderate extraction drugs efavirenz and flurbiprofen, the elimination rate of caffeine was reduced by 51% in patients with Child C cirrhosis. For the moderate to high extraction drugs omeprazole, metoprolol, and midazolam, liver cirrhosis decreased the elimination rate by 75%, 37%, and 60%, respectively, increased exposure, and decreased the apparent systemic clearance (clearance/bioavailability). In patients with Child C cirrhosis, the metabolic ratio (ratio of the area under the plasma concentration–time curve from 0 to 24 h of the metabolite to the parent compound), a marker for CYP activity, decreased by 66%, 47%, 92%, 73%, and 43% for paraxanthine/caffeine (CYP1A2), 8-hydroxyefavirenz/efavirenz (CYP2B6), 5-hydroxyomeprazole/omeprazole (CYP2C19), α-hydroxymetoprolol/metoprolol (CYP2D6), and 1′-hydroxymidazolam/midazolam (CYP3A), respectively. In comparison, the metabolic ratio 4-hydroxyflurbiprofen/flurbiprofen (CYP2C9) remained unchanged. Conclusions Liver cirrhosis affects the activity of CYP isoforms differently. This variability must be considered for dose adjustment of drugs in patients with liver cirrhosis. Clinical Trial Registration NCT03337945. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01119-0.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently

et al. 2022

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“…Daridorexant is extensively metabolized, primarily by CYP3A4 (89%) and mostly excreted via faeces (≈ 57%) and urine (≈ 28%), primarily as metabolites [5,16] The pharmacokinetic properties of daridorexant are not clinically significantly affected by age, sex, race, body size [5], or mild to severe renal impairment (Cockcroft-Gault < 30 ml/ min, not on dialysis) [17]. The presence of moderate (Child-Pugh B), but not mild (Child-Pugh A), liver impairment has been shown to prolong the t ½ of daridorexant and thus the maximum dosage recommended in patients with Child-Pugh B impairment is 25 mg no more than once per night [5,18]. The effects of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of the drug have not been studied and use of daridorexant in this patient population is not recommended [5].…”

Section: Pharmacokineticsmentioning

confidence: 99%

Daridorexant: First Approval

Markham

2022

Drugs

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Daridorexant (Quviviq™; Idorsia Pharmaceuticals Ltd.) is an orally administered dual orexin type 1 and type 2 (OX 1 and OX 2 ) receptor antagonist (DORA) being developed for the treatment of insomnia. It was selected from a pool of drug candidates on the basis of an expected effect duration of ≈ 8 h at a dose of 25 mg, with a half-life intended to minimize residual effects that might impair daytime functioning. Based on the results of two pivotal phase III trials, daridorexant was recently approved in the USA for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. This article summarizes the milestones in the development of daridorexant leading to this first approval.

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Sleep disturbances in patients with cirrhosis: Pursuing just right

Hui,

Chen,

Sun

2023

Portal Hypertension & Cirrhosis

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Liver cirrhosis represents the end‐stage of chronic liver disease and is related to high morbidity and mortality. To date, there is no standard curative method for liver cirrhosis, but there is treatment for common complications. Therefore, improving the health‐related quality of life (HRQoL) of patients with cirrhosis has become a potential therapeutic intervention by limiting its symptoms and complications. Sleep is a complex and rhythmic physiological process and is crucial to human health. Sleep disturbances are commonly encountered in patients with cirrhosis and adversely affect their HRQoL. Recently, sleep disturbances in patients with cirrhosis have received growing attention owing to their reciprocal effects. To better understand the effect of sleep disturbances on patients with cirrhosis, this review provides a comprehensive summary of the epidemiology and underlying mechanisms of sleep disturbances in cirrhosis. We also elaborate on the mutual relationships between sleep disturbances and other complications, such as muscle cramps, malnutrition, frailty, sarcopenia, HRQoL, and hepatic encephalopathy, in the context of cirrhosis. Finally, we discuss the potential management to improve poor sleep quality in patients with cirrhosis.

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Effect of Liver Cirrhosis on the Pharmacokinetics, Metabolism, and Tolerability of Daridorexant, A Novel Dual Orexin Receptor Antagonist

Cited by 16 publications

References 44 publications

Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently

Liver Cirrhosis Affects the Pharmacokinetics of the Six Substrates of the Basel Phenotyping Cocktail Differently

Daridorexant: First Approval

Sleep disturbances in patients with cirrhosis: Pursuing just right

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