Objective-The ability of apolipoprotein A-I (apoA-I) to transport cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. To gauge the potential of infused apoA-I to transport cholesterol, we quantified cholesterol transport markers in human subjects infused with a novel formulation of apoA-I (CSL112). Approach and Results-CSL112 was infused into human subjects in single (57 subjects) and multiple (36 subjects) ascending dose trials. Pharmacokinetic and biomarker assessments were conducted before and after infusions. CSL112 caused an immediate, up to 3-fold elevation of apoA-I and subsequent movement of tissue cholesterol into plasma. Cholesterol appeared first as unesterified cholesterol in the high-density lipoprotein (HDL) fraction and was promptly esterified by lecithin cholesterol acyltransferase. HDL cholesterol increased up to 81±16.5%. Underlying this movement of cholesterol was an immediate and strong rise in the ability of plasma to promote cholesterol efflux from cells ex vivo. CSL112 had its greatest impact on the fraction of efflux mediated by ATP-binding cassette transporter A1 (ABCA1), a cholesterol transporter induced in cholesterol-loaded tissues such as plaque. ABCA1-dependent efflux capacity increased ≤630±421% and total efflux capacity by ≤192±40%. In keeping with this finding, we observed a profound rise in very small HDL, also known as preβ1-HDL, the preferred substrate for ABCA1. Very small HDL increased ≤3596±941%.Elevations in apoA-I, cholesterol efflux, and very small HDL were dose-proportional over a wide range. No significant changes in atherogenic lipids were observed at any dose. Conclusions-Infusion Gille et al CSL112 Enhances Biomarkers of RCT 2107CSL112 is a novel formulation of apoA-I, the chief protein component of HDL, purified from human plasma and reconstituted with phosphatidylcholine to form HDL particles suitable for infusion. The production, physical characteristics of CSL112, and the pharmacokinetic and biomarker profile in rabbits have recently been described.14 CSL112 is a discoid particle containing 2 copies of apoA-I and ≈110 molecules of phosphatidylcholine. CSL112 was designed to provide improved particle uniformity and an improved safety profile compared with a previous formulation termed CSL111. The safety characteristics of CSL111 12 and improved safety characteristics of CSL112 15 have been previously described. CSL112 is also designed to optimize cholesterol efflux by ATP-binding cassette transporter A1 (ABCA1), a transporter induced by excess cellular cholesterol and present in atherosclerotic plaque.16 A detailed description of CSL112 pharmacokinetic in a multiple ascending dose (MAD) phase 1 study has been described. 15 Here, we report for the first time the effects of CSL112 on key biomarkers of RCT after single and multiple intravenous infusions in healthy adult subjects. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Demographics and Baseline Chara...

Purpose The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin’s lymphoma (NHL), and supported understanding of exposure-response relationships for efficacy and safety. Methods Bendamustine was administered as a 60-minute 120 mg/m2 intravenous infusion on Days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined. Results Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t1/2 (40 minutes) was considered the pharmacologically relevant (beta elimination) t1/2 since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m2 administration, except bendamustine Cmax was a significant (p-value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics. Conclusions The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t1/2 and low concentrations of bendamustine observed by 12 hours after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine Cmax increases.

CSL112 is apoA-I purified from human plasma and reconstituted with phosphatidylcholine (PC) to form high-density lipoprotein (HDL)-particles suitable for infusion. CSL112 is in development for the potential treatment of acute coronary syndromes (ACS) by optimizing cholesterol efflux. This study assesses the pharmacokinetics (PK), safety and tolerability of CSL112. Repeat doses of CSL112 or placebo were administered intravenously once- (3.4 g or 6.8 g) or twice-weekly (3.4 g) to healthy subjects in a placebo-controlled, randomized (3 CSL112: 1 placebo), ascending-dose study (NCT01281774). Twenty-seven subjects received CSL112 and nine received placebo. Study endpoints included plasma apoA-I and PC concentrations and specific PK parameters. CSL112 infusions immediately produced robust increases in apoA-I concentration in a dose-proportional manner, reaching levels higher than observed with currently available or investigational HDL products. After infusion of CSL112, apoA-I levels remained above baseline for approximately 3 days. Multiple infusions of CSL112 were safe and well tolerated with no evidence of major organ toxicity or immunogenicity. CSL112 may provide a novel option to rapidly transport cholesterol from atherosclerotic plaque to the liver and reduce early recurrent events following ACS. The data presented here support continued clinical development of CSL112 in patient populations.

BackgroundCSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease.Methods and ResultsPatients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug–related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (Tmax≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001).ConclusionsCSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation.Clinical Trial RegistrationURL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.

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