Population Pharmacokinetic–Pharmacodynamic Modeling of Inotersen, an Antisense Oligonucleotide for Treatment of Patients with Hereditary Transthyretin Amyloidosis
| Autor: | Jon W Collins, Scott P. Henry, Richard S. Geary, Brett P. Monia, Elizabeth J. Ackermann, Shannon Hall, Yanfeng Wang, Rosie Z. Yu |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Oligonucleotides Gene Expression inotersen Biochemistry Gastroenterology Body Mass Index chemistry.chemical_compound 0302 clinical medicine Drug Discovery Prealbumin Drug Dosage Calculations hereditary TTR amyloidosis Aged 80 and over education.field_of_study biology Alanine Transaminase Middle Aged Original Papers Neuroprotective Agents 030220 oncology & carcinogenesis Molecular Medicine Female RNA Interference pharmacokinetics Glomerular Filtration Rate Adult oligonucleotide medicine.medical_specialty Bilirubin antisense Population Renal function 03 medical and health sciences Pharmacokinetics Internal medicine pharmacodynamics Genetics medicine Humans education Molecular Biology Serum Albumin Aged Amyloid Neuropathies Familial Models Statistical business.industry Confidence interval Transthyretin 030104 developmental biology chemistry Case-Control Studies Pharmacodynamics Mutation Lean body mass biology.protein business |
| Zdroj: | Nucleic Acid Therapeutics |
| ISSN: | 2159-3345 2159-3337 |
| DOI: | 10.1089/nat.2019.0822 |
| Popis: | A population pharmacokinetic (PK) and pharmacodynamic (PD) model was developed for inotersen to evaluate exposure–response relationships and to optimize therapeutic dosing regimen in patients with hereditary transthyretin (TTR) amyloidosis polyneuropathy (hATTR-PN). Inotersen PK and TTR level (PD) data were composed of one Phase 1 study in healthy subjects, one Phase 2/3 study in hATTR patients, and its one open-label extension study. Effects of intrinsic and extrinsic factors (covariates) on PK and PK/PD of inotersen were evaluated using a full model approach. Inotersen PK was characterized by a two-compartment model with elimination from the central compartment. The population PK analysis identified disease status and lean body mass (LBM) as significant covariates for inotersen PK. Nonetheless, the contribution of disease status and LBM on PK was small, as the difference in clearance (CL/F) was 11.1% between healthy subjects and patients with hATTR-PN and 38% between the lowest and highest LBM quartiles of the patient population. Age, race, sex, baseline renal function estimated glomerular filtration rate, and hepatic function markers (baseline albumin, bilirubin, and alanine aminotransferase values) were not statistically significant covariates affecting inotersen PK. An inhibitory effect indirect-response model (inhibition of TTR production) was used to describe the drug effect on TTR-time profiles, with baseline TTR included as a covariate. The overall population Imax and IC50, together with 95% confidence interval, was estimated to be 0.913 (0.899–0.925) and 9.07 (8.08–10.1) ng/mL, respectively. V30M mutation showed no effect on the estimated IC50 value for hATTR patients. The final population PK and PK/PD model was used to simulate four different treatment regimens. The population PK/PD model developed well described the PK and PD of inotersen in patients with hATTR-PN and has been used for label recommendation and trial simulations. |
| Databáze: | OpenAIRE |
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