Givosiran
Regulatory sources consulted
Approved indications
- Treatment of acute hepatic porphyria in adults and adolescents aged 12 years or older.
Contraindications
Absolute
- Severe hypersensitivity to givosiran, including anaphylaxis.
Clinical warnings
- Major warning · Anaphylaxis may occur; monitor and discontinue immediately if it develops, with appropriate medical treatment. — https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.html
- Major warning · Check liver function before treatment, monthly for the first 6 months and thereafter as clinically indicated; interrupt or discontinue for significant elevations. — https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.html
- Major warning · Monitor renal function, particularly in patients with pre-existing kidney disease, and measure homocysteine before and during treatment. — https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.html
Drug interactions
- HighSensitive CYP1A2 substrates
Mechanism: Givosiran reduces hepatic activity of this enzyme and increased the reference substrate AUC 3.1-fold.
Recommendation: Avoid narrow-therapeutic-index substrates when small increases may cause serious toxicity; if unavoidable, reduce their dose according to the approved label.
https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=167e663c-11e1-497b-a3fc-951d65d58eaa
- HighSensitive CYP2D6 substrates
Mechanism: Givosiran reduces hepatic activity of this enzyme and increased the reference substrate AUC 2.4-fold.
Recommendation: Avoid narrow-therapeutic-index substrates when small increases may cause serious toxicity; if unavoidable, reduce their dose according to the approved label.
https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=167e663c-11e1-497b-a3fc-951d65d58eaa
- ModerateCYP2C19 substrates
Mechanism: Givosiran reduced hepatic activity of this enzyme and increased the reference substrate AUC 1.6-fold; the label considers this change not clinically relevant.
Recommendation: No routine adjustment is required for this interaction; individualise management if the substrate is particularly clinically sensitive.
https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=167e663c-11e1-497b-a3fc-951d65d58eaa
- ModerateCYP3A4 substrates
Mechanism: Givosiran reduced hepatic activity of this enzyme and increased the reference substrate AUC 1.5-fold; the label considers this change not clinically relevant.
Recommendation: No routine adjustment is required for this interaction; individualise management if the substrate is particularly clinically sensitive.
https://cima.aemps.es/cima/dochtml/ft/1201428001/FT_1201428001.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=167e663c-11e1-497b-a3fc-951d65d58eaa
Adverse events
Common (≥1%)
Injection-site reactions · Nausea · Fatigue · Increased transaminases · Rash · Decreased glomerular filtration rate
Rare but serious
Anaphylaxis · Pancreatitis · Renal impairment · Hyperhomocysteinaemia
Pregnancy and lactation
FDA category: Evaluación individual de beneficio-riesgo
Pregnancy data are limited; weigh the expected maternal benefit against the potential fetal risk. During breastfeeding, decide whether to discontinue breastfeeding or treatment according to the benefit for the child and mother.
Recent literature (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