title: Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach.
abstract: The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate.
authors.affiliation: Genentech Research and Early Development, South San Francisco, CA gadkar.kapil@gene.com.
authors.forename: Kapil
authors.initials: K
authors.lastname: Gadkar
authors.affiliation: Roche Pharma Research and Early Development, Clinical Pharmacology, Disease Modeling Group, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: James
authors.initials: J
authors.lastname: Lu
authors.affiliation: Genentech Research and Early Development, South San Francisco, CA.
authors.forename: Srikumar
authors.initials: S
authors.lastname: Sahasranaman
authors.affiliation: Genentech Research and Early Development, South San Francisco, CA.
authors.forename: John
authors.initials: J
authors.lastname: Davis
authors.affiliation: Roche Pharma Research and Early Development, Clinical Pharmacology, Disease Modeling Group, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Norman A
authors.initials: NA
authors.lastname: Mazer
authors.affiliation: Genentech Research and Early Development, South San Francisco, CA.
authors.forename: Saroja
authors.initials: S
authors.lastname: Ramanujan
mesh_terms: D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D002784:Cholesterol / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008954:Models, Biological; D011799:Quinazolines / Q000494:pharmacology; D052999:Quinazolinones; D012307:Risk Factors; D015854:Up-Regulation
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D015415:Biomarkers; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D011799:Quinazolines; D052999:Quinazolinones; C000628794:apabetalone; D002784:Cholesterol
keywords: apolipoprotein A-I; cholesterol metabolism; cholesteryl ester transport protein; high density lipoprotein; in-silico model; low density lipoprotein; reverse cholesterol transport