Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia
Sokolov V., Helmlinger G., Nilsson C., Zhudenkov K., Skrtic S., Hamrén B., Peskov K. V., Hurt-Camejo E., Jansson-Löfmark R.
Journal of Lipid Research
Vol.60, Issue9, P. 1610-1621
Опубликовано: 2019
Тип ресурса: Статья
Аннотация:
Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDLC), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an additional ∼20[%] LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences w
Ключевые слова:
Atherosclerosis; Cholesterol metabolism; Lipoproteins; Plasma proprotein convertase subtilisin/kexin type 9; Quantitative modeling; Translational pharmacology
alirocumab; apolipoprotein B; evolocumab; high density lipoprotein cholesterol; inclisiran; lipoprotein A; low density lipoprotein cholesterol; monoclonal antibody; proprotein convertase 9; rg 7652; small interfering RNA; triacylglycerol; unclassified drug; very low density lipoprotein cholesterol; alirocumab; apolipoprotein B; evolocumab; high density lipoprotein cholesterol; lipoprotein A; low density lipoprotein cholesterol; monoclonal antibody; proprotein convertase 9; small interfering RNA; triacylglycerol; very low density lipoprotein cholesterol; Article; benchmarking; enzyme inhibition; familial hypercholesterolemia; high density lipoprotein cholesterol level; human; hypercholesterolemia; lipoprotein blood level; lipoprotein metabolism; low density lipoprotein cholesterol level; mathematical model; phase 1 clinical trial; phase 2 clinical trial; phase 3 clinical trial; prediction; priority journal; protein synthesis; triacylglycerol blood level; blood; genetics; hypercholestero
Язык текста: Английский
ISSN: 1539-7262
Sokolov V.
Helmlinger G.
Nilsson C.
Zhudenkov K.
Skrtic S.
Hamrén B.
Peskov K. V. Kirill Vitalyevich 1982-
Hurt-Camejo E.
Jansson-Löfmark R.
Соколов В.
Хелмлингер Г.
Нилссон C.
Жуденков К.
Скртиc С.
Хамрéн Б.
Песков К. В. Кирилл Витальевич 1982-
Хурт-Cамейо Е.
Йанссон-Лöфмарк Р.
Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia
Текст визуальный непосредственный
Journal of Lipid Research
Lipid Research, Inc.
Vol.60, Issue9 P. 1610-1621
2019
Статья
Atherosclerosis Cholesterol metabolism Lipoproteins Plasma proprotein convertase subtilisin/kexin type 9 Quantitative modeling Translational pharmacology
alirocumab apolipoprotein B evolocumab high density lipoprotein cholesterol inclisiran lipoprotein A low density lipoprotein cholesterol monoclonal antibody proprotein convertase 9 rg 7652 small interfering RNA triacylglycerol unclassified drug very low density lipoprotein cholesterol alirocumab apolipoprotein B evolocumab high density lipoprotein cholesterol lipoprotein A low density lipoprotein cholesterol monoclonal antibody proprotein convertase 9 small interfering RNA triacylglycerol very low density lipoprotein cholesterol Article benchmarking enzyme inhibition familial hypercholesterolemia high density lipoprotein cholesterol level human hypercholesterolemia lipoprotein blood level lipoprotein metabolism low density lipoprotein cholesterol level mathematical model phase 1 clinical trial phase 2 clinical trial phase 3 clinical trial prediction priority journal protein synthesis triacylglycerol blood level blood genetics hypercholestero
Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDLC), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an additional ∼20[%] LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences w