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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.

SUBMITTER: Tortorici MA

PROVIDER: S-EPMC6618313 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Tortorici Michael A MA Duffy Danielle D Evans Rebecca R Feaster John J Gille Andreas A Mant Timothy G K TGK Wright Samuel D SD D'Andrea Denise D

Clinical pharmacology in drug development 20180921 5

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] ...[more]

PMID: 30240132

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Project description:Background and objectiveZibotentan, a selective endothelin A receptor antagonist, is in development for chronic liver and kidney disease. The pharmacokinetics (PK) of zibotentan were previously investigated in patients with either renal impairment or hepatic impairment, but the impact of both pathologies on PK was not evaluated. This study evaluated the PK and tolerability of a single oral dose of zibotentan in participants with concurrent moderate renal impairment and moderate hepatic impairment versus control participants.MethodsTwelve participants with moderate renal and hepatic impairment and 11 healthy matched control participants with no clinically significant liver or kidney disease were enrolled in an open-label, parallel-group study design. After administration of a single oral dose of zibotentan 5 mg, blood and urine sampling was performed. Pharmacokinetic parameters were determined for each of the two cohorts and compared. Comparisons between the cohorts were based on the geometric least squares mean ratio for the primary endpoints, which were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) and from time zero to the time of the last measurable concentration (AUClast), and maximum plasma drug concentration (Cmax) on Day 1 through 120 h post-dose. Secondary endpoints included apparent total body clearance (CL/F) on Day 1 through 120 h post-dose. Safety endpoints were assessed up to discharge.ResultsIn total, 11 participants with concurrent moderate renal and hepatic impairment, and 11 controls, completed the study. Zibotentan was generally well tolerated, and no new clinically significant safety findings were observed. Total exposure (AUC∞ and AUClast) was approximately 2.10-fold higher in participants with concurrent moderate renal and hepatic impairment versus controls, while Cmax and total nonrenal body clearance were similar among all groups. A regression-based post hoc analysis, comparing exposure and CL/F in patients with concurrent impairment to patients with either renal or hepatic impairment alone, showed that CL/F with concurrent impairment was approximately half of that in controls and was positively correlated with reduction of renal function. Inclusion of the data on concurrent moderate renal and hepatic impairment in the regression analysis led to a narrower confidence interval for the predicted mean CL/F in participants with moderate hepatic impairment.ConclusionThe presented findings advance the understanding of the PK of zibotentan in both renal impairment and hepatic impairment, with and without overlapping pathologies, and will thus increase the confidence of dose selection in future studies, particularly in vulnerable patient populations with concurrent renal and hepatic impairment.Trial registrationClinicalTrials.gov identifier: NCT05112419.

Dataset Information

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

Publications

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

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