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A comprehensive evaluation of exposure–response relationships in clinical trials: application to support guselkumab dose selection for patients with psoriasis

  • Chuanpu Hu
  • Zhenling Yao
  • Yang Chen
  • Bruce Randazzo
  • Liping Zhang
  • Zhenhua Xu
  • Amarnath Sharma
  • Honghui Zhou
Original Paper

Abstract

Guselkumab, a human IgG1 monoclonal antibody that blocks interleukin-23, has been evaluated in one Phase 2 and two Phase 3 trials in patients with moderate-to-severe psoriasis, in which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Investigator’s Global Assessment (IGA) scores. Through the application of landmark and longitudinal exposure–response (E–R) modeling analyses, we sought to predict the guselkumab dose–response (D–R) relationship using data from 1459 patients who participated in these trials. A recently developed novel latent-variable Type I Indirect Response joint model was applied to PASI75/90/100 and IGA response thresholds, with placebo effect empirically modeled. An effect of body weight on E–R, independent of pharmacokinetics, was identified. Thorough landmark analyses also were implemented using the same dataset. The E–R models were combined with a population pharmacokinetic model to generate D–R predictions. The relative merits of longitudinal and landmark analysis also are discussed. The results provide a comprehensive and robust evaluation of the D–R relationship.

Keywords

Exposure–response modeling NONMEM Ordered categorical endpoints Joint modeling Latent variable IDR modeling Clinical drug development 

Notes

Acknowledgements

The authors thank Michelle L. Perate MS, a professional medical writer funded by Janssen Scientific Affairs., LLC, for editorial support.

Supplementary material

10928_2018_9581_MOESM1_ESM.eps (731 kb)
Supplementary material 1 (EPS 730 kb). Fig. S1. Longitudinal model of predicted median and 90% PIs by BWT categories, at planned observation times, in overlay with observed PASI responses
10928_2018_9581_MOESM2_ESM.eps (749 kb)
Supplementary material 2 (EPS 748 kb). Fig. S2. Longitudinal model of predicted median and 90% PIs by BWT categories, at planned observation times, in overlay with observed IGA responses
10928_2018_9581_MOESM3_ESM.eps (586 kb)
Supplementary material 3 (EPS 585 kb). Fig. S3. Visual predictive check of landmark analysis of IGA ≤ 1/IGA0 at Week 16. The observed IGA ≤ 1/IGA0 response rates (red circle) were determined according to bins of the model-predicted guselkumab exposure metrics and were plotted at the median exposure within each bin. The n’s are the numbers of patients in each bin. The blue solid lines are the simulated median responses. The blue dotted lines and the shaded areas both represent the simulated 90% PIs from 1000 replicates
10928_2018_9581_MOESM4_ESM.eps (802 kb)
Supplementary material 4 (EPS 802 kb). Fig. S4. Visual predictive check of landmark analysis of PASI responses at Week 28. The observed PASI 75/90/100 response rates (red circle) were determined according to bins of the model-predicted guselkumab exposure metrics and were plotted at the median exposure within each bin. The n’s are the numbers of patients in each bin. The blue solid lines are the simulated median responses. The blue dotted lines and the shaded areas both represent the simulated 90% PIs from 1000 replicates
10928_2018_9581_MOESM5_ESM.eps (701 kb)
Supplementary material 5 (EPS 701 kb). Fig. S5. Visual predictive check of landmark analysis of IGA ≤ 1/IGA0 at Week 28. The observed IGA ≤ 1/IGA0 responses (red circle) were determined according to bins of the model-predicted guselkumab exposure metrics and were plotted at the median exposure within each bin. The n’s are the numbers of patients in each bin. The blue solid lines are the simulated median responses. The blue dotted lines and the shaded areas both represent the simulated 90% PIs from 1000 replicates
10928_2018_9581_MOESM6_ESM.eps (350 kb)
Supplementary material 6 (EPS 349 kb). Fig. S6. Longitudinal model of predicted dose–response for IGA ≤ 1/IGA0 at Week 16 and Week 28, for the guselkumab 50-, 100-, 150-, and 200-mg q8w dose regimens in the Phase 3 psoriasis trials
10928_2018_9581_MOESM7_ESM.eps (693 kb)
Supplementary material 7 (EPS 693 kb). Fig. S7. Landmark analysis of predicted exposure–response curve for IGA ≤ 1/IGA0 at Week 16 and Week 28. Solid red lines and shaded area represent the model-predicted median response and 90% CIs, respectively, from 200 replicates. The open circles and blue horizontal segments show the median and 5th/95th percentiles, respectively, of the predicted guselkumab AUC0-W16 and AUCss for the guselkumab 50-, 100-, and 200-mg q8w dose regimens. The black dotted lines indicate the 5th/95th percentile range of AUC0-W16 and AUCss for the guselkumab 100–mg q8w dose regimen
10928_2018_9581_MOESM8_ESM.docx (27 kb)
Supplementary material 8 (DOCX 26 kb)
10928_2018_9581_MOESM9_ESM.docx (29 kb)
Supplementary material 9 (DOCX 28 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Global Clinical PharmacologyJanssen Research & Development, LLCSpring HouseUSA
  2. 2.Clinical ImmunologyJanssen Research & Development, LLCSpring HouseUSA

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