DDMODEL00000215: Executable_Pimasertib_AeDropout

  public model
Short description:
Simultaneous ocular adverse event and dropout model of pimasertib
Original code
  • Simultaneous ocular adverse event and treatment discontinuation model of pimasertib
  • P. Girard, B. Brockhaus, G. Massimini, E. Asatiani, N. Rejeb, R.A. Rajeswaran, C. Lüpfert, O von Richter, A. Munafo
  • PAGE meeting, 6/2012
  • Merck Serono S.A Geneva; Merck KGaA, Darmstadt, Germany
  • Objectives: Pimasertib is an oral inhibitor of MAPK/ERK Kinase, currently developed for treatment of pancreatic cancer and melanoma, that was given to patients with solid tumors and hematological malignancies in 2 phase I dose escalation studies. All patients were monitored for tolerability (diarrhea, skin rash, ophthalmology, etc). Since ocular adverse events (OAE) were the main dose-limiting events, the objective of present analysis was to develop a joint model for exposure, OAE and treatment discontinuation (TD). Methods: Population PK yielded estimates of individual exposure. A proportional odds model, with Markov components, was build for OAE weekly highest grade. The logits of the different cumulative probabilities (P) were a non linear function of AUC accumulating in a KPD compartment [1]. In addition, Cmax was tested as acting either continuously or on 1st month. Other covariates were schedule (QD/BID), hypertension history, comedications and demographic covariates. Time to TD and OAE were jointly modeled using Weibull hazard and completely at random, random and informative TD assumptions were tested [2]. All models were built using NONMEM (FOCEI for PK, Laplacian for OAE and TD). Results: 199 patients, receiving total daily dose ranging from 1 to 255 mg contributed to 4766 PK, OAEs or TD observations. A 3 compartment PK model with 1st order absorption and lag time provided individual Cmax and weekly AUC estimates. OAEs were fitted to the odds model. Markov parameters and AUC mediated through a KPD Emax model were highly significant. BID regimen was associated with a reduction in P(OAE), while higher Cmax was significantly but transiently increasing them on 1st month. For TD, Kaplan Meier curves showed that patients with either OAEs or highest doses were more likely to stay on treatment. Neither the random nor the informative TD models were successful and a simpler TD model with daily dose was found significant. Conclusion: This analysis showed that OAE are related to higher exposure (AUC, Cmax) and to QD administration. Presumably, BID regimen reduces P(OAE) by reducing peak concentrations, as indicated by higher P(OAE) linked to higher Cmax during 1st month of treatment. High TD rate was found to be dose related, with higher doses leading to less TD. This suggests a potential treatment benefit but needs to be tested further using efficacy data. Model results and simulations are being used to support the choice of dosing regimen for future studies.
Maria Luisa Sardu
Context of model development: Disease Progression model;
Discrepancy between implemented model and original publication: The original publication does not describe the dropout model ;
Long technical model description: The joint model describes the dynamics of ocular adverse events and dropout. Adverse events are graded from 0, no toxicity to 3. The risk of developing an ocular adverse event was described using a proportional odds model including a sigmoidal maximum effect on the exposure of pimasertib. A Markov model defining transition probabilities was used to take into account of the dependencies between two consecutive time points. For describing the pimasertib exposure the kinetics-pharmacodynamics (K-PD) approach was used. The occurrence of dropout events was described using the proportional hazard model assuming a Weibull baseline hazard function and DOSE as covariate. Maximum plasma concentration at month 1 (CMAXM1), individual clearance (CL_IND), dose (DOSE) were included in the model as continuous covariates. Medical history of hypertension (MHHY), BID dosing (BID), regimen (REGI) were included in the model as categorical covariates.;
Model compliance with original publication: No;
Model implementation requiring submitter’s additional knowledge: Yes;
Modelling context description: The model describes the ocular adverse events dynamics in in two phase I dose escalation studies involving patients with solid tumors and hematological malignancies receiving pimasertib. This model was developed to support the choice of dosing regimen.;
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: Maria Luisa Sardu
  • Submitted: Oct 4, 2016 9:49:52 AM
  • Last Modified: Oct 4, 2016 9:49:52 AM
  • Version: 6 public model Download this version
    • Submitted on: Oct 4, 2016 9:49:52 AM
    • Submitted by: Maria Luisa Sardu
    • With comment: change the name of command file