Population PK/PD of Alprazolam in the Attenuation of ACTH Activation Induced by Cognitive Performance in Metyrapone-treated Healthy Volunteers
L. Iavarone(1), R. Gomeni(1), E. Merlo-Pich(2)
(1) CPK&MS, GSK, Verona, Italy; (2) CPDM, GSK, Verona, Italy;
Objectives: The control of ACTH release from the pituitary is under hormonal controls. Stimulating effects are produced by the peptide CRH released from the hypothalamus under stress. Inhibiting effects are produced by circulating cortisol, whose release from the adrenal glands is in ACTH-dependent. Metyrapone, an inhibitor of the cortisol synthesis, attenuate the cortisol negative feedback on ACTH release, resulting in an enhanced sensitivity to the stimulating effects of CRH. In this work we investigated the effects of Alprazolam on ACTH levels over time(4h) following dosing and in response to a cognitive performance test in volunteers receiving metyrapone 8 h before. The objective was to model the time-course of the inhibition produced by Alprazolam.
Methods: The relationship between ACTH and Alprazolam plasma levels was studied using an indirect PD response model. The rate of change of the ACTH response over time with no drug present can be described by dR/dt=kin-kout∙R, kin is the zero-order constant for production and kout is the first-order rate constant for loss. The PK/PD model was developed in a stepwise fashion and described the change in ACTH over time and the effect of cognitive test at 3h post-dose. The final model represents inhibitory processes that operate according to the classical inhibitory function, I(t)=1-(Cp/(Cp+IC50) where Cp is the Alprazolam plasma levels and IC50 is the Alprazolam plasma levels producing 50% of maximum inhibition. The rate of change of R can be described by dR/dt= kin∙I(t)-kout∙R. A Mixed effect modelling (NONMEM) was used to estimate the model parameters. The circadian fluctuation of ACTH in the absence of Metyrapone was described by a cosine function over a 24h period
Results: Increase of ACTH over time was produced by metyrapone, further enhanced by the cognitive test. Alprazolam was able to decrease ACTH level in the experimental settings. The PK/PD relationships between ACTH exposure and Alprazolam plasma levels able to overall inhibit over the 24h the release of ACTH of the 50% (IC50) was estimated to be 6.22ng/mL.
Conclusions:
Metyrapone increased ACTH level over time and cognitive test produced a peak of ACTH. Both effects were attenuated by alprazolam in exposure-dependent manner, with an IC50 estimated a 6.22 ng/mL. This work indicates the possibility to investigate GABAergic compound using endocrinologic endpoints and PKPD modelling.
References:
[1] M Hossain et al. Pharmaceutical Research, Vol. 14, No3, 309-315 (1997)
