Paediatric research sets new standards for therapy in paediatric and adult cholestasis

Jeyaraj, Rebecca; Maher, Eamonn R; Kelly, Deirdre

doi:10.1016/s2352-4642(23)00259-6

Cited by 4 publications

References 61 publications

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Getting the Dose Right in Drug Development for Rare Diseases: Barriers and Enablers

Ahmed,

Krishna,

Rayad

et al. 2024

Clin Pharma and Therapeutics

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In the relentless pursuit of optimizing drug development, the intricate process of determining the ideal dosage unfolds. This involves “dose‐finding” studies, crucial for providing insights into subsequent registration trials. However, the challenges intensify when tackling rare diseases. The complexity arises from poorly understood pathophysiologies, scarcity of appropriate animal models, and limited natural history understanding. The inherent heterogeneity, coupled with challenges in defining clinical end points, poses substantial challenges, hindering the utility of available data. The small affected population, low disease awareness, and restricted healthcare access compound the difficulty in conducting dose‐finding studies. This white paper delves into critical dose selection aspects, focusing on key therapeutic areas, such as oncology, neurology, hepatology, metabolic rare diseases. It also explores dose selection challenges posed by pediatric rare diseases as well as novel modalities, including enzyme replacement therapies, cell and gene therapies, and oligonucleotides. Several examples emphasize the pivotal role of clinical pharmacology in navigating the complexities associated with these diseases and emerging treatment modalities.

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Getting the Dose Right in Drug Development for Rare Diseases: Barriers and Enablers

Ahmed,

Krishna,

Rayad

et al. 2024

Clin Pharma and Therapeutics

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Biliary atresia

Tam,

Wells,

Tang

et al. 2024

Nat Rev Dis Primers

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IBAT inhibitors in pediatric cholestatic liver diseases: Transformation on the horizon?

Sutton,

Sokol,

Kamath

2024

Hepatology

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Historically, the therapeutic options available to hepatologists managing cholestasis have been limited. Apart from bile acid–-binding resins and the choleretic ursodeoxycholic acid, the medical management of cholestasis in children has been predominately focused on managing the complications of cholestasis, namely pruritus, malnutrition, fat-soluble vitamin deficiencies, and portal hypertension. As such, invasive surgical procedures such as biliary diversion and liver transplantation may become the only options for progressive and unremitting cases of cholestasis. Particularly in the pediatric population, where debilitating pruritus is a common indication for a liver transplant, effective anti-cholestatic medications have the potential to prolong native liver survival without the need for biliary diversion. Ileal bile acid transporter (IBAT) inhibitors are a relatively new class of drugs which that target the ileal re-uptake of bile acids, thus interrupting the enterohepatic circulation and reducing the total bile acid pool size and exposure of the liver. Oral, minimally absorbed IBAT inhibitors have been demonstrated to reduce serum bile acid levels and pruritus with a minimal side effect profile in clinical trials in Alagille Ssyndrome and progressive familial intrahepatic cholestasis, leading to FDA and EMA approval. The indications for IBAT inhibitors will likely expand in the coming years as clinical trials in other adult and pediatric cholestatic conditions are ongoing. This review will summarize the published clinical and pre-clinical data on IBAT inhibitors and offer providers guidance on their practical use.

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Paediatric research sets new standards for therapy in paediatric and adult cholestasis

Cited by 4 publications

References 61 publications

Getting the Dose Right in Drug Development for Rare Diseases: Barriers and Enablers

Getting the Dose Right in Drug Development for Rare Diseases: Barriers and Enablers

Biliary atresia

IBAT inhibitors in pediatric cholestatic liver diseases: Transformation on the horizon?

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