Potassium homeostasis and therapeutic intervention with sodium zirconium cyclosilicate: A model-informed drug development case study.

Potassium (K + ) is the main intracellular cation in the body. Elevated K + levels (hyperkalemia) increase the risk of life-threatening arrhythmias and sudden cardiac death. However, the details of K + homeostasis and the effects of orally administered K + binders, such as sodium zirconium cyclosilicate (SZC), on K + redistribution and excretion in patients remain incompletely understood. We built a fit-for-purpose systems pharmacology model to describe K + homeostasis in hyperkalemic subjects and capture serum K + (sK + ) dynamics in response to acute and chronic administration of SZC. The resulting model describes K + distribution in the gastrointestinal (GI) tract, blood, and extracellular and intracellular spaces of tissue, renal clearance of K + , and K + -SZC binding and excretion in the GI tract. The model, which was fit to time-course sK + data for individual patients from two clinical trials, accounts for bolus delivery of K + in meals and oral doses of SZC. The virtual population of patients derived from fitting the model to these trials was then modified to predict the SZC dose-response and inform clinical trial design in two new applications: emergency lowering of sK + in severe hyperkalemia and prevention of hyperkalemia between dialysis sessions in patients with end-stage chronic kidney disease. In both cases, the model provided novel and useful insight that was borne out by the now completed clinical trials, providing a concrete case study of fit-for-purpose, model-informed drug development after initial approval of a drug.