Quantitative Systems Pharmacology Model of hUGT1A1-modRNA Encoding for the UGT1A1 Enzyme to Treat Crigler-Najjar Syndrome Type 1

被引：41

作者：

Apgar, Joshua F. ^{[1
]}

Tang, Jian-Ping ^{[2
]}

Singh, Pratap ^{[2
]}

Balasubramanian, Nanda ^{[2
]}

Burke, John ^{[1
]}

Hodges, Michael R. ^{[2
]}

Lasaro, Melissa A. ^{[2
]}

Lin, Lin ^{[1
]}

Miliard, Bjorn L. ^{[1
]}

Moore, Kristi ^{[2
]}

Jun, Lucy S. ^{[2
]}

Sobolov, Susan ^{[2
]}

Wilkins, Anna Katharina ^{[1
]}

Gao, Xiang ^{[2
]}

机构：

[1] Appl BioMath, Lincoln, MA USA

[2] Alexion Pharmaceut Inc, New Haven, CT 06510 USA

来源：

CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY | 2018年 / 7卷 / 06期

关键词：

HUMAN PHARMACOKINETICS; GUNN RAT; HEPATOCYTE TRANSPLANTATION; BILIRUBIN DYNAMICS; PREDICTION; KINETICS; PHOTOTHERAPY; DISPOSITION; METABOLISM;

D O I：

10.1002/psp4.12301

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Crigler-Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine-diphosphate-glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1-modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first-in-human studies, a quantitative systems pharmacology (QSP) model was developed. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First-in-human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels.

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收藏

页码：404 / 412

页数：9

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