Givosiran
Sources réglementaires consultées
Indications approuvées
- Traitement de la porphyrie hépatique aiguë chez l'adulte et l'adolescent âgé de 12 ans ou plus.
Contre-indications
Absolues
- Hypersensibilité sévère au givosiran, y compris l'anaphylaxie.
Mises en garde cliniques
- Mise en garde majeure · Une anaphylaxie peut survenir ; surveiller et arrêter immédiatement le traitement si elle apparaît, avec une prise en charge médicale appropriée. — https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.html
- Mise en garde majeure · Contrôler la fonction hépatique avant le traitement, chaque mois pendant les 6 premiers mois, puis selon les besoins cliniques ; interrompre ou arrêter en cas d'élévation significative. — https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.html
- Mise en garde majeure · Surveiller la fonction rénale, en particulier en cas de néphropathie préexistante, et mesurer l'homocystéine avant et pendant le traitement. — https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.html
Interactions médicamenteuses
- SévèreSubstrats sensibles du CYP1A2
Mécanisme: Le givosiran réduit l'activité hépatique de cette enzyme et a augmenté l'ASC du substrat de référence de 3,1 fois.
Recommandation: Éviter les substrats à marge thérapeutique étroite lorsqu'une faible augmentation peut entraîner une toxicité grave ; si l'association est inévitable, réduire leur dose conformément au résumé des caractéristiques.
https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=167e663c-11e1-497b-a3fc-951d65d58eaa
- SévèreSubstrats sensibles du CYP2D6
Mécanisme: Le givosiran réduit l'activité hépatique de cette enzyme et a augmenté l'ASC du substrat de référence de 2,4 fois.
Recommandation: Éviter les substrats à marge thérapeutique étroite lorsqu'une faible augmentation peut entraîner une toxicité grave ; si l'association est inévitable, réduire leur dose conformément au résumé des caractéristiques.
https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=167e663c-11e1-497b-a3fc-951d65d58eaa
- ModéréeSubstrats du CYP2C19
Mécanisme: Le givosiran a réduit l'activité hépatique de cette enzyme et augmenté de 1,6 fois l'ASC du substrat de référence ; le résumé des caractéristiques considère que ce changement n'est pas cliniquement significatif.
Recommandation: Aucun ajustement systématique n'est requis pour cette interaction ; individualiser la prise en charge si le substrat présente une sensibilité clinique particulière.
https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=167e663c-11e1-497b-a3fc-951d65d58eaa
- ModéréeSubstrats du CYP3A4
Mécanisme: Le givosiran a réduit l'activité hépatique de cette enzyme et augmenté de 1,5 fois l'ASC du substrat de référence ; le résumé des caractéristiques considère que ce changement n'est pas cliniquement significatif.
Recommandation: Aucun ajustement systématique n'est requis pour cette interaction ; individualiser la prise en charge si le substrat présente une sensibilité clinique particulière.
https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=167e663c-11e1-497b-a3fc-951d65d58eaa
Effets indésirables
Communs (≥1%)
Réactions au site d'injection · Nausées · Fatigue · Élévation des transaminases · Éruption cutanée · Diminution du débit de filtration glomérulaire
Rares mais graves
Anaphylaxie · Pancréatite · Altération de la fonction rénale · Hyperhomocystéinémie
Grossesse et allaitement
Catégorie FDA: Evaluación individual de beneficio-riesgo
Les données pendant la grossesse sont limitées ; mettre en balance le bénéfice maternel attendu et le risque potentiel pour le fœtus. Pendant l'allaitement, décider d'interrompre l'allaitement ou le traitement selon le bénéfice pour l'enfant et la mère.
Bibliographie récente (PubMed)
Small interfering RNAs (siRNAs) represent a new class of drugs with tremendous potential for battling previously "undruggable" diseases. After nearly 2 decades of efforts in addressing the problems of the poor drug profile of naked unmodified siRNAs, this new modality has finally come to fruition, with 5 agents (patisiran, givosiran, lumasiran, inclisiran, and vutrisiran) being approved since 2018, and with many others in the different phases of clinical development. Unlike small-molecule drugs and protein therapeutics, siRNAs have different sizes, distinct mechanisms of action, differing physicochemical and pharmacological properties, and, accordingly, a unique pharmacokinetic/pharmacodynamic (PK/PD) relationship. To support the continuous development of siRNAs, it is important to have a thorough and deep understanding of the PK/PD and clinical pharmacology related features of siRNAs. As most of the current siRNA products are conjugated by N-acetylgalactosamine (GalNAc), this review focuses on the PK/PD relationships and clinical pharmacology of GalNAc-conjugated siRNAs, including their absorption, distribution, metabolism, excretion (ADME) properties, PK/PD models, drug-drug interactions, clinical pharmacology in special populations, and safety evaluation. In addition, necessary background information related to the development of siRNAs as a therapeutic modality, including the mechanisms of action, the advantages of siRNAs, the problems of naked siRNAs, as well as the strategies used to enhance the clinical utility of siRNAs, have also been covered. The goal of this review is to serve as a "primer" on siRNA PK/PD, and I hope the readers, especially those who have a limited background on siRNA therapeutics, will have a fundamental understanding of siRNA PK/PD and clinical pharmacology after reading this review.
RNA interference (RNAi) provides researchers with a versatile means to modulate target gene expression. The major forms of RNAi molecules, genome-derived microRNAs (miRNAs) and exogenous small interfering RNAs (siRNAs), converge into RNA-induced silencing complexes to achieve posttranscriptional gene regulation. RNAi has proven to be an adaptable and powerful therapeutic strategy where advancements in chemistry and pharmaceutics continue to bring RNAi-based drugs into the clinic. With four siRNA medications already approved by the US Food and Drug Administration (FDA), several RNAi-based therapeutics continue to advance to clinical trials with functions that closely resemble their endogenous counterparts. Although intended to enhance stability and improve efficacy, chemical modifications may increase risk of off-target effects by altering RNA structure, folding, and biologic activity away from their natural equivalents. Novel technologies in development today seek to use intact cells to yield true biologic RNAi agents that better represent the structures, stabilities, activities, and safety profiles of natural RNA molecules. In this review, we provide an examination of the mechanisms of action of endogenous miRNAs and exogenous siRNAs, the physiologic and pharmacokinetic barriers to therapeutic RNA delivery, and a summary of the chemical modifications and delivery platforms in use. We overview the pharmacology of the four FDA-approved siRNA medications (patisiran, givosiran, lumasiran, and inclisiran) as well as five siRNAs and several miRNA-based therapeutics currently in clinical trials. Furthermore, we discuss the direct expression and stable carrier-based, in vivo production of novel biologic RNAi agents for research and development. SIGNIFICANCE STATEMENT: In our review, we summarize the major concepts of RNA interference (RNAi), molecular mechanisms, and current state and challenges of RNAi drug development. We focus our discussion on the pharmacology of US Fo
Five small interfering RNA (siRNA)-based therapeutics have been approved by the Food and Drug Administration (FDA), namely patisiran, givosiran, lumasiran, inclisiran, and vutrisiran. Besides, siRNA delivery to the target site without toxicity is a big challenge for researchers, and naked-siRNA delivery possesses several challenges, including membrane impermeability, enzymatic degradation, mononuclear phagocyte system (MPS) entrapment, fast renal excretion, endosomal escape, and off-target effects. The siRNA therapeutics can silence any disease-specific gene, but their intracellular and extracellular barriers limit their clinical applications. For this purpose, several modifications have been employed to siRNA for better transfection efficiency. Still, there is a quest for better delivery systems for siRNA delivery to the target site. In recent years, nanoparticles have shown promising results in siRNA delivery with minimum toxicity and off-target effects. Patisiran is a lipid nanoparticle (LNP)-based siRNA formulation for treating hereditary transthyretin-mediated amyloidosis that ultimately warrants the use of nanoparticles from different classes, especially lipid-based nanoparticles. These nanoparticles may belong to different categories, including lipid-based, polymer-based, and inorganic nanoparticles. This review briefly discusses the lipid, polymer, and inorganic nanoparticles and their sub-types for siRNA delivery. Finally, several clinical trials related to siRNA therapeutics are addressed, followed by the future prospects and conclusions. No information is available on the clinical use of lumasiran during breastfeeding. Because lumasiran is 85% bound to plasma proteins and has a molecular weight of about 17,000 Da, the amount in milk is likely to be low. In addition, because lumasiran is poorly absorbed orally, it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants. The drug is approved for use in children
Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well-defined short double-stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA-induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off-target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability to allow successful clinical translation. Patisiran (hereditary transthyretin-mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use N-acetylgalactosamine (GalNAc) linkage for effective liver-directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non-communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially