2011 - Athens - Greece

PAGE 2011: CNS
Zheng Guan

Population pharmacokinetic and pharmacodynamic analysis of cortisol in serum and saliva in healthy male volunteers after an acute 5-hydroxytryptophan (5-HTP) challenge test

Z. Guan, J. Freijer, G. E. Jacobs, J. Van Pelt, J. M. A. Van Gerven

Centre for human drug research, Leiden, Netherlands

Objectives: Serum cortisol is a frequently used neuroendocrine endpoint of the 5-HTP challenge test, which quantifies central serotonergic neurotransmission. Sampling cortisol from saliva is increasingly used as an alternative for serum cortisol measurement. This non-invasive method avoids blood sampling stress, and salivary cortisol represents the amount of free and thus biologically active cortisol [1, 2]. The current study aims at developing a population PK/PD model for the effect of the 5-HTP challenge test on acute serum cortisol increases, and explores the relationships between salivary and serum cortisol.

Methods: Three randomized, double-blind, placebo-controlled, cross-over studies were carried out at CHDR. 5-HTP with carbidopa co-treatment and granisetron were orally administrated [3, 4, 5]. The population approach was applied to analyze both PK and PD data. A compartmental model was used to fit the PK profile of 5-HTP. A baseline model of serum cortisol was built to assess the circadian rhythm [6] before a sigmoid model was selected to model the drug effect of the 5-HTP challenge on cortisol. Finally, linear and power function relationships were used to predict the salivary cortisol based on serum cortisol, which was presented by total or free serum cortisol.

Results: The PK of 5-HTP could be described with a one compartment model with first-order elimination. A transit absorption compartment was introduced to improve the description of the concentration upswing after oral drug administration. The typical value for clearance showed inter-study variability (23.9L.h-1 or 10.5 L.h-1). A cosine function with a trend was chosen to describe the circadian rhythm of serum cortisol. The challenge test involved only one level of 5-HTP, which prevented estimating both the Emax and EC50 in the sigmoid model. Instead, an approximation with the linear model was applied in absence of a plateau in the drug effect (slope=0.0406 ng/ml per ng/ml). A power function provided a better description than a linear function to relate the salivary and serum cortisol.

Conclusions: The PK/PD model could describe and predict total serum cortisol concentration for the proposed dose level in the challenge test, but limitations exist when extrapolating to higher dose levels that were not tested in these experiments. The results provide a rationale to sample cortisol from saliva instead of serum, even after acute stimulation of the hypothalamic-pituitary-adrenal axis.

[1] Vining RF, McGinley RA, Maksvytis JJ, et al. Salivary cortisol: A better measure of adrenal cortical function than serum cortisol. Ann Clin Biochem 1983; 20:329-35.
[2] Kirschbaum C, Hellhammer DH. Salivary cortisol. In: Fink G, editor. Encyclopedia of stress. San Diego: Academic Press; 2000. p. 379-83.

Reference: PAGE 20 (2011) Abstr 2068 [www.page-meeting.org/?abstract=2068]
Poster: CNS