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Pharmacokinetics and Pharmacodynamic of Alpelisib

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Abstract

Advanced breast cancers are frequently hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative. Some of them harbor a mutation in PIK3CA, a gene encoding the PI3K catalytic subunit α of phosphatidyl-inositol 3-kinase (PI3K), which confers resistance to hormone therapy. Alpelisib is the first oral selective p110 \(\alpha\) PI3K inhibitor approved by FDA and EMA, in association with fulvestrant, based on PFS improvement as compared to fulvestrant alone. The aim of this review is to summarize and critically review the key aspects of alpelisib pharmacokinetics (PK) and pharmacodynamics (PD). Preclinical data have shown that alpelisib IC50 was 50 times lower for the α enzyme than for the β, δ and γ PI3K enzymes, leading to a decrease in intra-tumoral AKT phosphorylation. The PK properties of alpelisib are somehow favorable, with a rapid and important absorption, a limited CYP P450-mediated metabolism and a predominant biliary excretion, with a half-life of 17.5 ± 5.9 h. Only limited drug–drug interactions are expected and there is no need for dose adaptation in mild and moderate renal impaired and mild to severe hepatic impaired patients. Pharmacokinetic/pharmacodynamic relationships were evidenced during drug development for exposure/efficacy, but also exposure/safety. Main adverse events are hyperglycemia, rash, and diarrhea. The first, if not fully contra-indicated in (pre-)diabetic patients, warrants a close follow up when treatment is started and a potential dose reduction when needed. Because of its safety profile, alpelisib require stringent patient selection and close follow-up.

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Authors and Affiliations

  1. Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France

    Bernard Royer

  2. Laboratoire de Pharmacologie Clinique et Toxicologie, CHU Besançon, Besançon, France

    Bernard Royer

  3. Oncology Department, Centre Georges-François Leclerc, Dijon, France

    Courèche Guillaume Kaderbhaï

  4. Pharmacy Department, Centre Georges-François Leclerc, 1 rue Pr Marion, 21079, Dijon Cedex, France

    Antonin Schmitt

  5. INSERM U1231, University of Burgundy Franche-Comté, Dijon, France

    Antonin Schmitt

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  1. Bernard Royer
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Writing—original draft preparation, BR, CGK, and AS; writing—review and editing, AS; supervision, AS. All authors have read and agreed to the published version of the manuscript.

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Royer, B., Kaderbhaï, C.G. & Schmitt, A. Pharmacokinetics and Pharmacodynamic of Alpelisib. Clin Pharmacokinet 62, 45–53 (2023). https://doi.org/10.1007/s40262-022-01195-2

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