Base and Covariate Population Pharmacokinetic Analyses of Dupilumab Using Phase 3 Data

Clinical Pharmacology in Drug Development - Tập 9 Số 6 - Trang 756-767 - 2020
Pavel Kovalenko1, John D. Davis1, Meng Li2, Ronda Rippley1, Marius Ardeleanu1, Brad Shumel1, Neil M.H. Graham1, Gianluca Pirozzi2, Mohamed Kamal1, A. Thomas DiCioccio1
1Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
2Sanofi, Bridgewater, New Jersey, USA

Tóm tắt

AbstractPopulation pharmacokinetic base and covariate models were developed to study functional dupilumab for regulatory submissions, using data from healthy volunteers and patients with moderate‐to‐severe atopic dermatitis (AD) receiving intravenous or subcutaneous doses. Sixteen studies were pooled (N = 2115; 202 healthy volunteers, 1913 AD patients). The best model was a 2‐compartment model with linear and Michaelis‐Menten elimination and 3 transit compartments describing absorption. A stepwise approach to model building, with some parameters estimated using mostly rich data and subsequently fixed, was used to avoid adverse effects of sparse data and a steep target‐mediated phase on pharmacokinetic parameters, which require rich sampling for proper estimation. Parameterization of models in terms of rates was a useful alternative to the parameterization in terms of clearances, allowing for a reduced number of covariates while providing accurate predictions. While antidrug antibodies, albumin, race, body mass index, and Eczema Area and Severity Index score were statistically significant covariates, only body weight had a notable effect on central volume, explaining interindividual variability. The model adequately described dupilumab pharmacokinetics in phase 3 trials.

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Tài liệu tham khảo

10.1016/S0140-6736(15)00149-X

10.5021/ad.2010.22.2.125

10.1016/j.det.2017.02.002

10.1073/pnas.1323896111

10.1073/pnas.1324022111

10.1080/1744666X.2017.1298443

10.1056/NEJMoa1314768

10.1056/NEJMoa1304048

Radin A, 2013, First‐in‐human study of REGN668/SAR231893 (IL‐4Ra mAb): safety, tolerability and biomarker results of a randomized, double‐blind, placebo‐controlled, single ascending dose study in healthy volunteers [Abstract], J Allergy Clin Immunol, 131

10.1016/S0140-6736(15)00388-8

10.1056/NEJMc1700366

10.1016/S0140-6736(17)31191-1

10.1002/psp4.12136

10.1016/0008-8749(90)90209-A

D'Ippolito D, 2018, Dupilumab (dupixent): an interleukin‐4 receptor antagonist for atopic dermatitis, P T Community, 43, 532

10.1002/cpt.1058

10.1007/s11095-011-0481-y

10.1111/bjd.16156

10.1111/bjd.18476

Simpson EL, Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: a phase 3 randomized clinical trial [published online ahead of print November 6, 2019], JAMA Dermatol

10.1056/NEJMoa1804092

10.1056/NEJMoa1804093

10.1001/jama.2015.19330

10.1016/S0140-6736(19)31881-1

10.1053/j.gastro.2019.09.042

10.1016/j.jaci.2018.08.022

10.1016/j.jaad.2018.07.048

10.1111/bcp.12589

10.1034/j.1600-0625.2001.100102.x

10.1007/s10928-008-9094-4

Poskitt DS, 1987, Precision, complexity and Bayesian model determination, J Royal Statist Soc B, 49, 199, 10.1111/j.2517-6161.1987.tb01691.x

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Clinical Pharmacology in Drug Development

Tập 9 Số 6

756-767

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