Hereditárny angioedém (HAE) je vrodené zriedkavé ochorenie prejavujúce sa rekurentnými atakmi angioedému. Postihnutá môže byť koža a podkožie, sliznice (tráviaci, respiračný, uropoetický trakt) a podslizničné tkanivo. U žien vo fertilnom veku má manažment ochorenia špecifiká, ktoré sa týkajú ako priebehu ochorenia, tak možností liečby. Tieto špecifiká sa týkajú jednak liečby samotných žien, ako aj špecifických situácií (tehotenstvo, dojčenie). Prinášame informáciu o prvom použití podkožného C1 inhibítora v rámci dlhodobej profylaxie atakov HAE u dvoch tehotných pacientok.
Hereditary angioedema (HAE) is a rare, inborn disease manifested with recurrent attacks of angioedema. They can affect the skin and subcutaneous tissue, mucous membranes (gastrointestinal, respiratory, and uropoietic tracts), and submucous tissue. Women in reproductive age require specific management of the disease regarding both the course of the disease and treatment options. It is not only the treatment in female patients that is specific, but also the situations (pregnancy, breastfeeding). We present a case report of the initial use of a subcutaneous C1 inhibitor in the long-term prophylaxis of HAE attacks in two pregnant patients.
- MeSH
- hereditární angioedémy * diagnóza farmakoterapie genetika prevence a kontrola MeSH
- inhibiční protein komplementu C1 * aplikace a dávkování ekonomika MeSH
- lidé MeSH
- mladý dospělý MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- mladý dospělý MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Slovenská republika MeSH
BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.
- MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- hereditární angioedémy * farmakoterapie prevence a kontrola MeSH
- klinické křížové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- plazmatický kalikrein * antagonisté a inhibitory MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- randomizované kontrolované studie MeSH
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- MeSH
- antagonisté bradykininových receptorů aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- dospělí MeSH
- hereditární angioedémy * farmakoterapie prevence a kontrola MeSH
- inhibiční protein komplementu C1 * aplikace a dávkování terapeutické užití MeSH
- injekce subkutánní MeSH
- lidé MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- hereditární angioedémy * dějiny epidemiologie prevence a kontrola MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- MeSH
- esterasy MeSH
- hereditární angioedémy * farmakoterapie prevence a kontrola MeSH
- inhibiční protein komplementu C1 * terapeutické užití MeSH
- komplement C1 - inaktivátory MeSH
- lidé MeSH
- rekombinantní proteiny MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antagonisté bradykininových receptorů terapeutické užití MeSH
- antiflogistika nesteroidní škodlivé účinky MeSH
- diferenciální diagnóza MeSH
- hereditární angioedémy * farmakoterapie genetika prevence a kontrola MeSH
- inhibiční protein komplementu C1 terapeutické užití MeSH
- kyselina tranexamová terapeutické užití MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
Hereditární angioedém je vzácné dědičné onemocnění, které se projevuje otoky v různých lokalitách. Nejčastější formou je hereditární angioedém způsobený deficitem C1 inhibitoru. Pro léčbu otoků u pacientů s touto diagnózou máme v současnosti k dispozici koncentráty lidského plazmatického a rekombinantního C1 inhibitoru a icatibant, který funguje jako antagonista receptorů pro bradykinin. U pacientů s častými a závažnými atakami používáme terapii profylaktickou. Až donedávna byly k dispozici pouze kyselina tranexamová a danazol, ale nově se na našem trhu objevil lanadelumab, monoklonální protilátka proti kalikreinu.
Hereditary angioedema is rare inherited disease presenting itself as edemas of different parts of the body. Most common type is caused by C1 inhibitor deficiency. For the treatment of acute attacks we currently have available concentrates of human plasma-derived and recombinant C1 inhibitor and icatibant, which works as bradykinin receptor antagonist. For patients with frequent and severe attacks we use prophylactic treatment like danazol and tranexamic acid. Recently lanadelumab, monoclonal antibody against kallikrein, became available too.
- Klíčová slova
- icatibant acetát,
- MeSH
- antiflogistika nesteroidní aplikace a dávkování MeSH
- danazol aplikace a dávkování MeSH
- hereditární angioedém, typy I a II farmakoterapie prevence a kontrola MeSH
- hereditární angioedémy * farmakoterapie klasifikace prevence a kontrola MeSH
- inhibiční protein komplementu C1 aplikace a dávkování MeSH
- injekce subkutánní MeSH
- intravenózní podání MeSH
- krevní plazma MeSH
- kyselina tranexamová aplikace a dávkování MeSH
- lidé MeSH
- těhotenství účinky léků MeSH
- Check Tag
- lidé MeSH
- těhotenství účinky léků MeSH
