Pharmacokinetics and Safety of CSL112 (Apolipoprotein A-I [Human]) in Adults With Moderate Renal Impairment and Normal Renal Function

Abstract

CSL112 (Apolipoprotein A-I [human]) is an intravenous preparation of apolipoprotein A-I (apoA-I), formulated with phosphatidylcholine (PC) and stabilized with sucrose, in development to prevent early recurrent cardiovascular events following acute myocardial infarction (AMI). This phase 1 study was designed to determine if moderate renal impairment (RI) influenced the pharmacokinetics (PK) and safety of CSL112. Thirty-two subjects, 16 with moderate RI (estimated glomerular filtration rate [eGFR] ≥ 30 and < 60 mL/min/1.73 m2 ) and 16 age-, sex-, and weight-matched subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2 ) were randomized 3:1 to receive a single infusion of CSL112 2 g (n = 6) or placebo (n = 2), or CSL112 6 g (n = 6) or placebo (n = 2). PK sampling was at prespecified times from 48 hours prior to 144 hours following infusions, with final safety assessments at 90 days. Renal and hepatic safety, and adverse events (AEs) were monitored throughout the study. Plasma apoA-I and PC PK profiles were similar between renal function cohorts at both doses. For CSL112 6 g mean ± SD apoA-I AUC0-last was 7670 ± 1900 and 9170 ± 2910 mg·h/dL in normal renal function and moderate RI subjects, respectively. Renal apoA-I clearance was <1% of CSL112 dose. In moderate RI, sucrose clearance was slower; however, approximately 70% was excreted within 48 hours in both renal function cohorts. No CSL112-related serious AEs or clinically significant renal or hepatic safety changes were observed. Dose adjustment of CSL112 is not required in subjects with moderate RI, supporting its further investigation in AMI patients with moderate RI.

Trial registration: ClinicalTrials.gov NCT02427035.

Keywords: atherosclerosis; chronic kidney disease; lipids; pharmacokinetics; randomized controlled trial.

© 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1

Study design (A) and schedule of visits and assessments (B). Dose escalation to 6 g CSL112 was recommended following Data Safety and Monitoring Board review of data for the 2 g CSL112 dose. DSMB, Data and Safety Monitoring Board; Mod RI, moderate renal impairment; NRF, normal renal function; PD, pharmacodynamics; PK, pharmacokinetics.

Figure 2

Plasma pharmacokinetic profiles of apolipoprotein A‐I and phosphatidylcholine following CSL112 infusion. Shown are mean + standard deviation unadjusted (A) apolipoprotein A‐I (apoA‐I) and (B) phosphatidylcholine (PC) plasma concentration‐time profiles by renal function group, moderate renal impairment (RI), and normal renal function following infusion of CSL112 2 or 6 g. Please note that the small differences in the 2 g curves are attributable to differences in values at baseline rather than differences in response to CSL112.

Figure 3

Relationship between plasma clearance and baseline eGFR for apolipoprotein A‐I. Slope (90% confidence band), −0.000417 (−0.0015 to 0.000314). CL, systematic plasma clearance; eGFR, estimated glomerular filtration rate.

Figure 4

Pharmacokinetic profile of sucrose in plasma following CSL112 infusion. Shown are mean + standard deviation unadjusted sucrose plasma concentration‐time profiles for each renal function group, moderate renal impairment (RI), and normal renal function following infusion of CSL112 2 or 6 g.