Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings
| Autor: | Ronald Barbaras, Constance Keyserling, Jean-Louis Dasseux, Renee Benghozi |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Adult Male Apolipoprotein B Drug Evaluation Preclinical 030204 cardiovascular system & hematology Pharmacology Placebo 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Double-Blind Method Medicine Animals Humans Pharmacology (medical) Original Research Article Adverse effect Phospholipids Mice Knockout Cross-Over Studies biology Apolipoprotein A-I Dose-Response Relationship Drug business.industry Cholesterol Cholesterol HDL General Medicine Cholesterol LDL Middle Aged Crossover study Recombinant Proteins Dose–response relationship 030104 developmental biology chemistry biology.protein Female lipids (amino acids peptides and proteins) Rabbits business Blood sampling Lipoprotein |
| Zdroj: | Clinical Drug Investigation |
| ISSN: | 1173-2563 |
| DOI: | 10.1007/s40261-017-0506-3 |
| Popis: | Background CER-001 comprises recombinant human apolipoprotein A-I complexed with phospholipids that mimics natural, nascent, pre-β high-density lipoprotein (HDL). We present animal model data showing dose-dependent increases in cholesterol efflux with CER-001 and its subsequent elimination by reverse lipid transport, together with inhibition of atherosclerotic plaque progression. We report the first phase I study results with CER-001 in humans, starting at 0.25 mg/kg, which is 1/80th of the safe dose (20 mg/kg) established in 4-week multiple-dose animal studies dosed every second day. Methods Healthy volunteers, 18–55 years old with a low-density lipoprotein-cholesterol:HDL-cholesterol ratio greater than 3.0, received single intravenous escalating doses of CER-001 (0.25–45.0 mg/kg) and placebo in a double-blind randomised cross-over fashion. Subjects were followed up for 3 weeks post-dose. Assessments included adverse event monitoring, blood sampling, and clinical laboratory measurements. Results Thirty-two subjects were enrolled. All CER-001 doses (0.25–45 mg/kg) were safe and well tolerated, with an adverse event profile similar to placebo. Effects on clinical chemistry, haematology and coagulation parameters were comparable to placebo. No adverse effects of CER-001 on electrocardiograms were observed. No antibodies to apolipoprotein A-I were detected following single-dose administration of CER-001. Plasma apolipoprotein A-I levels increased in a dose-related manner and returned to baseline by 24 h post-dose for doses up to 10 mg/kg but remained in circulation for >72 h post-dose for doses >10 mg/kg. CER-001 caused elevations in plasma cholesterol and total and unesterified cholesterol in the HDL fraction. Mobilisation of unesterified cholesterol in the HDL fraction was seen with CER-001 at doses as low as 2 mg/kg. Conclusion CER-001 is well tolerated when administered to humans as single doses up to 45 mg/kg and mobilises and eliminates cholesterol via reverse lipid transport. Electronic supplementary material The online version of this article (doi:10.1007/s40261-017-0506-3) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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