Persistent changes in lipoprotein lipids after a single infusion of ascending doses of MDCO-216 (apoA-IMilano/POPC) in healthy volunteers and stable coronary artery disease patients.
Effects of single ascending doses of MDCO-216 on plasma lipid and lipoprotein levels were assessed in human healthy volunteers and in patients with stable coronary artery disease (CAD).



MDCO-216 was infused at a single dose of 5, 10, 20, 30 or 40 mg/kg over 2 h and blood was collected at 2, 4, 8, 24, 48, 168 and 720 h after start of infusion (ASOI). Lipoprotein lipids were assessed by FLPC and by 1H NMR.



Plasma concentrations of free cholesterol (FC) displayed a rapid and dose-dependent rise, peaking at 8 h, but remaining above baseline until 48 h ASOI, whereas levels of esterified cholesterol (CE) increased at lower doses but not at higher doses, and even decreased below baseline at the highest dose. Plasma cholesterol esterification rate (CER) decreased with a first nadir between 4 and 8 h and a second nadir at 48 h ASOI. Taken over all subjects receiving MDCO-216, the increase in FC at 8 h correlated inversely with the drop in CER at 4 h but positively with the increase in basal and scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux capacities at 2 h ASOI. Upon FPLC analysis, FC was found to increase first in high density lipoproteins (HDL) and very low density lipoproteins (VLDL) and later (at 48 or 168 h ASOI) in low density lipoproteins (LDL). CE initially decreased in LDL and HDL but after 24 h started to increase in VLDL and LDL whereas HDL-CE was still below baseline at 48 h. Phospholipids (PL) showed the same pattern as FC. Triglycerides (TG) also rose rapidly, most prominently in VLDL, but also in LDL and HDL. Apolipoprotein E (Apo-E) in VLDL increased at 4-8 h but returned to baseline at 24 h ASOI. 1H NMR analysis showed a rapid and dose-dependent increase in HDL particle size, peaking at 2 h and returning to baseline at 24 h, and a small increase in HDL particle concentration. After infusion of the 40 mg/kg dose, LDL and VLDL-particles also increased in number and size.



A single administration of MDCO-216 caused rapid changes in lipid levels and lipoprotein composition, some of which persisted for at least 7 days.
The Medicines Company (Schweiz) GmbH, Zürich, Switzerland. Electronic address: herman.kempen@gmail.com.
Herman J
HJ
Kempen
Center E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy. Electronic address: monica.gomaraschi@unimi.it.
Monica
M
Gomaraschi
Center E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
Sara
S
Simonelli
Center E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.
Laura
L
Calabresi
Centre for Human Drug Research, Leiden, The Netherlands.
Matthijs
M
Moerland
LipoScience, Laboratory Corporation of America(®) Holdings, Raleigh, NC, USA.
James
J
Otvos
LipoScience, Laboratory Corporation of America(®) Holdings, Raleigh, NC, USA.
Elias
E
Jeyarajah
The Medicines Company (Schweiz) GmbH, Zürich, Switzerland.
David
D
Kallend
The Medicines Company (Schweiz) GmbH, Zürich, Switzerland.
Peter L J
PLJ
Wijngaard
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D002788:Cholesterol Esters / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D064368:Healthy Volunteers; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D008074:Lipoproteins / Q000097:blood*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010713:Phosphatidylcholines / Q000008:administration & dosage* / Q000009:adverse effects; D066244:Proton Magnetic Resonance Spectroscopy; D013997:Time Factors; D016896:Treatment Outcome
D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D015415:Biomarkers; D018955:CD36 Antigens; D002788:Cholesterol Esters; D004338:Drug Combinations; D000960:Hypolipidemic Agents; D008074:Lipoproteins; C000609591:MDCO-216; D010713:Phosphatidylcholines
Atherosclerosis; Clinical trials; Drug therapy; HDL; Lipids; Lipoproteins