Innovative adaptive dose simulations in NONMEM to allow simulation-based model evaluation of titration-based dosing, applied to a population dose-hemoglobin model for daprodustat
Objectives: Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that is currently approved for the treatment of anemia in patients with chronic kidney disease (CKD) in Japan; global phase 3 studies have recently completed. In the five global phase 3 studies, the daprodustat dose is individualized according to frequent monitoring of hemoglobin (Hgb) using an adaptive dose algorithm to reach target levels of Hgb. To allow simulation-based evaluation of a population dose-Hgb model for daprodustat [1, 2], the study specific adaptive dose algorithm was incorporated in simulations within NONMEM.
Methods: The development of the dose-Hgb model using NONMEM 7.5.0 is described in a companion poster [2]. As a comparison, standard Visual Predictive Check (VPC) and prediction-corrected VPC were attempted without the use of adaptive dosing. The adaptive dosing algorithm was implemented in the simulation code for NONMEM 7.5.0. This algorithm determined the dose change on the two most recent Hgb observations and the current dose level at each point in time during the study. The code $ABBREVIATED COMRES=5 was used to keep track of the following variables that are required to determine the dose change:
- Simulated Hgb observation for the two most recent visits
- Dose level at the most recent visit
- Visit number of the most recent visit
- Dose level prior to temporary treatment discontinuation (only for patients that had their treatment discontinued before the most recent visit)
The individual starting dose was retained as this depended on prior ESA and Hgb level at inclusion. Dropout was modelled in part, in the sense that simulated patients were discontinued when they qualified for rescue treatment due to low Hgb levels. Other potential dropout reasons were not included.
Results: The use of standard VPC and prediction-corrected VPC resulted in an inadequate representation of the variability of Hgb levels due to a mismatch between the individual model parameters of simulated patients and their corresponding daprodustat dose levels over time. When incorporating the adaptive dose algorithm in the simulations, the VPC showed good agreement between the simulated and observed data.
Conclusions: A complex study-specific adaptive-dose algorithm was implemented into a simulation workflow in NONMEM, which allowed adequate model evaluation of a daprodustat dose-Hgb model using a VPC. This could possibly be used for clinical trial simulations after inclusion of a more complete dropout model.
Citations:
[1] Upton et al. Basic Concepts in Population Modeling, Simulation, and Model-Based Drug Development: Part 3—Introduction to Pharmacodynamic Modeling Methods. CPT Pharmacometrics Syst Pharmacol 2014;3:e88.
[2] Companion Poster: van Noort et al. Population Dose-Hgb modelling of daprodustat across five Phase 3 studies in chronic kidney disease (CKD) patients with anemia. ACoP; October 30–November 2, 2022.
Author(s)
- Paul van den Berg, Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), The Netherlands (Presenting Author)
- Sebastiaan C. Goulooze, Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), The Netherlands (CoAuthor)
- Martijn van Noort, Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), The Netherlands (CoAuthor)
- Shuying Yang, Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, London, UK (CoAuthor)
- Misba Beerahee, Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, London, UK (CoAuthor)
- Kelly M. Mahar, Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, Collegeville, Pennsylvania, USA (CoAuthor)
- Teun M. Post, Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), The Netherlands (CoAuthor)