Many physiological changes are associated with obesity and can potentially impact pharmacokinetics (PK). This can require adjustments to be made to the standard doses for normal weight patients in order to ensure safety and efficacy of drug therapy. Dosing of specific drugs in this population is dependent on their physico-chemistry as well as changes in body composition and drug elimination. Physiologically-based pharmacokinetic (PBPK) models combine the known, relevant demographic, anatomical and physiological variables associated with obesity, together with the drugs’ characteristics, to predict drug clearance with reasonable accuracy in obese and morbidly obese subjects.
Predicting drug clearance in obese subjects
Certara scientists applied a “systems biology” approach to identify the likelihood of observing variations in drug clearance in obese and morbidly obese patients for a set of compounds for which clinical data, as well as the necessary in vitro information, were available. First, obese and morbidly obese virtual populations were built through collation of data on a variety of parameters including: body surface area, fat free mass, cardiac output, liver and kidney volumes, organ blood flow for the liver, kidney and gastrointestinal tract, enzyme activity for specific CYPs and plasma protein binding.
The models were implemented in the Simcyp Simulator and used to predict the clearance of oral alprazolam, oral caffeine, oral chlorzoxazone, oral ciclosporin, intravenous and oral midazolam, intravenous phenytoin, oral theophylline and oral triazolam. The design of the simulated studies closely matched that of the clinical studies. The PBPK models successfully predicted clearance in obese subjects for six out of eight drugs.1
Improve decision-making regarding the need for clinical studies in obese subjects
The Simcyp Simulator allows the impact of obesity on drug clearance and other PK parameters to be assessed prior to generating clinical PK data. This assists with critical decision-making on whether dedicated clinical trials in obese subjects are warranted as well as guiding elements of trial design such as initial dosing and number of participants required for the study to have sufficient power.
The increasing prevalence of obesity worldwide drives the need for more information regarding optimal dosing in this patient subgroup. The Simcyp consortium of pharmaceutical companies recognized this a few years ago when they requested that we compile obese and morbid obese populations. The framework is now in place to use modeling and simulation to support precision dosing for obese patients. Modeling and simulation can be used prospectively to predict the impact on pharmacokinetics prior to clinical development or retrospectively to adjust the dosing of approved drugs where clinical data in obese subjects are not available.
 Ghobadi C, Johnson TN, Aarabi M, Almond LM, Allabi AC, Rowland-Yeo K, Jamei M, Rostami-Hodjegan A. Application of a systems approach to the bottom-up assessment of pharmacokinetics in obese patients: Expected variations in clearance. Clinical Pharmacokinetics. 2011; 50(12):809-22.
Optimize your drug label using PBPK methodology
Gastric bypass surgery is increasingly being used to treat obesity and its complications. This surgery impacts drug PK, yet it is not practical to routinely conduct clinical trials in this subpopulation. My colleague, Dr. Steve Toon, gave a webinar where he discussed how PBPK models can be used in special populations, including gastric bypass surgery patients, to predict potential changes in drug disposition and inform drug label claims. I hope that you’ll watch the webinar and let me know what you think in the comments section!