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Comparative quantit...
Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia S
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Sokolov, V. (författare)
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Helmlinger, G. (författare)
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Nilsson, C. (författare)
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Zhudenkov, K. (författare)
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- Skrtic, Stanko, 1970 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin,Institute of Medicine
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Hamren, B. (författare)
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Peskov, K. (författare)
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Hurt-Camejo, E. (författare)
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Jansson-Lofmark, R. (författare)
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visa färre...
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(creator_code:org_t)
- 2019
- 2019
- Engelska.
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Ingår i: Journal of Lipid Research. - 0022-2275. ; 60:9, s. 1610-1621
- Relaterad länk:
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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 (HDL-C), 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 similar to 20% LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences were observed in HDL-C, Lp(a), TG, or apoB responses, suggesting that the disruption of PCSK9 synthesis would provide no additional effects on lipoprotein-related biomarkers in the patient segment investigated. Predictive model simulations further indicate that siRNA therapies may reach reductions in LDL-C levels comparable to those achieved with mAbs if the current threshold of 80% PCSK9 inhibition via siRNA could be overcome.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
Nyckelord
- atherosclerosis
- lipoproteins
- cholesterol metabolism
- plasma proprotein convertase subtilisin
- kexin
- subtilisin/kexin type 9
- density-lipoprotein cholesterol
- heterozygous
- familial hypercholesterolemia
- human monoclonal-antibody
- high
- cardiovascular risk
- ldl cholesterol
- healthy-volunteers
- pcsk9
- inhibition
- serine-protease
- clinical-trial
- Biochemistry & Molecular Biology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
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Sokolov, V.
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Helmlinger, G.
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Nilsson, C.
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Zhudenkov, K.
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Skrtic, Stanko, ...
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Hamren, B.
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visa fler...
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Peskov, K.
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Hurt-Camejo, E.
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Jansson-Lofmark, ...
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
- Artiklar i publikationen
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Journal of Lipid ...
- Av lärosätet
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Göteborgs universitet