Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations
| Autor: | Eric Bruckert, Yi Zhang, Paul N. Hopkins, Stephen Donahue, A. Thomas DiCioccio, Feng Yang, Michel Krempf |
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| Přispěvatelé: | University of Utah, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Regeneron Pharmaceuticals Inc. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
medicine.medical_specialty Adolescent Apolipoprotein B Endocrinology Diabetes and Metabolism Familial hypercholesterolemia 030204 cardiovascular system & hematology Antibodies Monoclonal Humanized Placebo Hyperlipoproteinemia Type II PCSK9 Young Adult 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Internal medicine Internal Medicine Humans Medicine 030212 general & internal medicine LDL-C Aged Apolipoproteins B Alirocumab Nutrition and Dietetics biology business.industry Cholesterol LDL Middle Aged [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism medicine.disease 3. Good health Clinical trial Endocrinology Gain of Function Mutation Pharmacodynamics biology.protein Kexin lipids (amino acids peptides and proteins) Proprotein Convertase 9 Cardiology and Cardiovascular Medicine business [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition |
| Zdroj: | Journal of clinical lipidology Journal of clinical lipidology, Elsevier, 2019, 13 (6), pp.970-978. ⟨10.1016/j.jacl.2019.10.007⟩ |
| ISSN: | 1933-2874 |
| DOI: | 10.1016/j.jacl.2019.10.007⟩ |
| Popis: | Background Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). Objective The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. Methods Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. Results At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. Conclusions Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. Clinical Trial Registration NCT01604824; clinicaltrials.gov. |
| Databáze: | OpenAIRE |
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