DDMODEL00000302: Time_to_event_Peripheral_Neuropathy_2019

  public model
Short description:
Peripheral neuropathy (PN) is a common long-term debilitating toxicity of antimicrotubule agents. PN was the most frequent adverse event resulting in dose modifications and/or discontinuation of treatment for valine-citrulline-monomethylauristatin E antibody-drug conjugates (ADCs) developed at Genentech. A pooled time-to-event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade ? 2) PN. In addition, the impact of demographic and pathophysiological risk factors on the risk for PN was explored. The time-to-event analysis suggested that the development of PN risk increased with ADC exposure, treatment duration, body weight, and previously reported PN. This model can be used to inform clinical strategies such as adaptations to dosing regimen and/or treatment duration as well as inform clinical eligibility to reduce the incidence of grade ? 2 PN.
Original code
  • Time-to-Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E Antibody-Drug Conjugates.
  • Kågedal M, Samineni D, Gillespie WR, Lu D, Fine BM, Girish S, Li C, Jin JY
  • CPT: pharmacometrics & systems pharmacology, 8/2019, Volume 8, Issue 8, pages: 606-615
  • Genentech Inc., South San Francisco, California, USA.
  • Peripheral neuropathy (PN) is a common long-term debilitating toxicity of antimicrotubule agents. PN was the most frequent adverse event resulting in dose modifications and/or discontinuation of treatment for valine-citrulline-monomethylauristatin E antibody-drug conjugates (ADCs) developed at Genentech. A pooled time-to-event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade ? 2) PN. In addition, the impact of demographic and pathophysiological risk factors on the risk for PN was explored. The time-to-event analysis suggested that the development of PN risk increased with ADC exposure, treatment duration, body weight, and previously reported PN. This model can be used to inform clinical strategies such as adaptations to dosing regimen and/or treatment duration as well as inform clinical eligibility to reduce the incidence of grade ? 2 PN.
Matts Kågedal
Context of model development: Variability sources in PK and PD (CYP, Renal, Biomarkers); Dose & Schedule Selection and Label Recommendation;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: A pooled time-to-event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade â?¥ 2) PN. In addition, the impact of demographic and pathophysiological risk factors on the risk for PN was explored.;
Modelling task in scope: estimation;
Nature of research: Early clinical development (Phases I and II);
Therapeutic/disease area: Oncology;
Annotations are correct.
This model is not certified.
  • Model owner: Matts Kågedal
  • Submitted: Sep 25, 2019 8:29:04 AM
  • Last Modified: Sep 25, 2019 8:29:04 AM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Sep 25, 2019 8:29:04 AM
    • Submitted by: Matts Kågedal
    • With comment: Updated model annotations.
 
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