Model for characterizing copeptin kinetics and response in healthy volunteers
Gilbert Koch (1), Ingeborg Schnyder (2), Mirjam Christ-Crain (2), Konrad Strauss (3), Wiebke Fenske (3), Marc Pfister (1,4)
(1) Paediatric Pharmacology and Pharmacometrics Research Center, University of Basel, Children’s Hospital (UKBB) , Basel, Switzerland (2) Division of Endocrinology, University Hospitals, Basel, Switzerland (3) Endocrinology, University Hospital of Würzburg, Germany (4) Quantitative Solutions, Menlo Park, CA, USA
Objectives: Vasopressin, a neurohypophysal hormone, is used in clinic to diagnose diabetes insipidus. Copeptin is evaluated as a new biomarker because it is a more stable in-vitro and an easier to measure peptide than vasopressin. A semi-mechanistic model to characterize kinetics of copeptin and sodium related increase in central copeptin release in heathy subjects was developed.
Methods: Serum sodium and copeptin data were collected in a study in healthy subjects. The study consisted of two consecutive phases: (i) administration of hypertonic saline infusion to increase serum sodium for 180 min or until the target sodium concentration of 150 mmol/l was reached, (ii) administration of 5% glucose infusion to decrease serum sodium for 40-60 min. Data was fitted with a non-linear mixed-effect model.
Results: A total of 1019 sodium and 1017 copeptin measurements from 93 healthy subjects were available for model-based analysis. Infusion models with zero order input rates were applied to describe administered sodium and glucose infusions. Time varying sodium concentrations were modeled to quantify the stimulating effect of serum sodium on copeptin release. The developed semi-mechanistic model adequately characterized kinetics of copeptin and indicated that central copeptin release instantaneously increases with increasing serum sodium to a maximum rate of ~0.5 pmol/min. Estimated elimination rate of copeptin was 0.017/min resulting in a plasma half-life of 40 min, which is ~2 fold longer than reported for vasopressin.
Conclusions: A semi-mechanistic model can be useful to characterize both kinetics and response of the new biomarker copeptin in healthy subjects. This model will be applied to investigate the diagnostic value of copeptin in adult and pediatric subjects with diabetes insipidus.
