Accurate modeling of ACTH and cortisol dynamics for Cushing’s disease treatment
Alvaro Ruiz-Martinez, PhD, Senior Modeler, Rosa & Co. LLC
Dr. Alvaro Ruiz-Martinez has twelve years of computational and modeling experience related to mechanical, chemical, and biological systems. He has developed models focused on immuno-oncology, biopolymer assembly, and pharmacokinetics and pharmacodynamics. Dr. Ruiz-Martinez received his Ph.D. in Mechanical Engineering from the University of California, San Diego, and his postdoctoral degree from Johns Hopkins University.
Collaborators on this Project:
Alvaro Ruiz-Martinez - Rosa & Co. LLC, USA
Rebecca Baillie - Rosa & Co. LLC, USA
Renee Myers - Rosa & Co. LLC, USA
Robert Sheehan - Rosa & Co. LLC, USA
Mike Reed - Rosa & Co. LLC, USA
Jakob Kisbye Dreyer - Lundbeck, Denmark
Frederik Rode - Lundbeck, Denmark
Lene Hansen - Lundbeck, Denmark
Cushing’s disease is a rare condition that results from having too much cortisol in the blood. The most common cause is a pituitary noncancerous tumor (adenoma) secreting adrenocorticotropic hormone (ACTH), which increases secretion of cortisol. The biological pathway regulating cortisol production in the hypothalamic-pituitary-adrenal (HPA) axis has been modeled previously, but hourly ACTH and cortisol oscillations are not captured easily. Also, tissue growth occurs over the course of weeks to months and stops if hormone concentrations decrease to normal levels. For these reasons, a proper Cushing’s disease model should be stable and accurate from hours to months. This work recalibrates the model presented in Bangsgaard and Ottesen, 2017 to represent the HPA axis dynamics accurately and expands it with the aim of studying Cushing’s disease. Previous publications show most of the hormone concentration peaks and ultradian oscillations rapidly decreasing after the first 24 hours of simulation upon calibration, which is not consistent with clinical data. Our calibration approach, however, solves that issue and remains stable and accurate in long-term scenarios. The model also replicates a healthy and a Cushing’s disease patient and both VP responses to CRH and dexamethasone tests are in agreement with results reported in literature.