PK/PD modeling of 5‐hydroxytryptophan (5‐HTP) challenge test with cortisol measurement in serum and saliva

Abstract

This research was planned to build a Pharmacokinetic/Pharmacodynamic (PK/PD) model of 5‐hydroxytryptophan (5‐HTP) challenge study including a circadian rhythm component of cortisol and to predict serum cortisol based on saliva cortisol. Data from three 5‐HTP challenge studies in healthy volunteers were collected. Serum 5‐HTP, saliva, and serum cortisol were sampled as PK and PD marker. The population PK/PD modeling approach was applied. A baseline model of serum cortisol was built to assess the circadian rhythm before a pharmacodynamic model was used to evaluate the drug effect of the 5‐HTP on cortisol. Finally, linear and power function relationships were tested to predict serum cortisol based on saliva cortisol. The PK of 5‐HTP could be described using a one‐compartment model with a transit compartment. The typical value for clearance was 20.40 L h−1 and showed inter‐study variability. A cosine function was chosen and properly described the circadian rhythm of serum cortisol. A linear approximation model was applied to fit the 5‐HTP PD effect on cortisol data with a slope of 4.16 ng mL−1 h. A power function provided a better description than a linear function to relate the saliva and serum cortisol. In conclusion, a circadian rhythm component was built in the PK/PD model of the 5‐HTP challenge test which could better improve the understanding of the stimulating effect on HPA with cortisol change. After the 5‐HTP challenge, saliva cortisol correlated well with serum cortisol and was predictable by a population PK‐PD model.