A latent variable approach for modeling categorical endpoints among patients with rheumatoid arthritis treated with golimumab plus methotrexate.

Journal of Pharmacokinetics and Pharmacodynamics
Chuanpu HuHonghui Zhou

Abstract

The need for accurate exposure-response modeling is critical in the drug development process. Few methods are available for linking discrete endpoints, especially ordered categorical variables, to mechanistic (e.g., indirect response) models. Here we describe a latent-variable approach that is proposed in conjunction with an inhibitory indirect response model to link the placebo/comedication effect and drug exposure to the endpoints. The model is parsimonious, with desirable characteristics at initial timepoints, and allows simultaneous modeling of multiple endpoints that are categorically ordered. Application of the model is demonstrated with data from a phase 3 clinical trial of golimumab, a human IgG1kappa monoclonal antibody that binds with high affinity and specificity to tumor necrosis factor (TNF)-alpha, in patients with rheumatoid arthritis. The efficacy endpoints were 20, 50, and 70% improvement in the American College of Rheumatology criteria (ACR20, ACR50, and ACR70, respectively) as measures of improvement in disease severity. The modeling results were shown to be consistent by using either a sequential or simultaneous pharmacokinetic/pharmacodynamic modeling approach. The suitability of likelihood profiling and pro...Continue Reading

References

Feb 7, 1998·Journal of Pharmaceutical Sciences·W Krzyzanski, W J Jusko
Mar 6, 2004·Journal of Pharmacokinetics and Pharmacodynamics·Liping ZhangLewis B Sheiner
Nov 12, 2005·Journal of Pharmacokinetics and Pharmacodynamics·Stuart L Beal
Dec 7, 2007·Journal of Pharmacokinetics and Pharmacodynamics·Matthew M HutmacherKenneth G Kowalski
May 21, 2008·Journal of Clinical Pharmacology·Chuanpu Hu, Honghui Zhou
Apr 16, 2009·Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions·Bernhard Meier
Jul 14, 2010·Journal of Clinical Pharmacology·Chuanpu HuHonghui Zhou

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Citations

Nov 1, 2011·Journal of Pharmacokinetics and Pharmacodynamics·Matthew M Hutmacher, Jonathan L French
Jan 1, 2013·Journal of Pharmacokinetics and Pharmacodynamics·Chuanpu HuHonghui Zhou
Nov 13, 2012·Critical Reviews in Biomedical Engineering·Hoi-Kei LonWilliam J Jusko
Jul 21, 2014·Journal of Pharmacokinetics and Pharmacodynamics·Chuanpu HuHonghui Zhou
Oct 25, 2012·Pharmacology & Therapeutics·Zhenhua XuHonghui Zhou
Nov 26, 2013·Journal of Clinical Pharmacology·Andrew T ChowUNKNOWN Population PK TPDI Working Group
Nov 21, 2021·Journal of Pharmacokinetics and Pharmacodynamics·Chuanpu Hu, Honghui Zhou

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