Non-Linear Mixed Effects PK/PD Modelling of Acute Autoinhibitory Feedback Effects of Escitalopram (ESC) on Extracellular Serotonin (5-HT) Levels in Rat Brain
F. Larsen (1), C. Bundgaard (2)
(1) Clinical Pharmacology & Pharmacokinetics, (2) Discovery ADME, H. Lundbeck A/S, Copenhagen, Denmark.
Objectives: To characterise the PK/PD relationships including inter-individual variability (IIV) of ESC-induced 5‑HT response after acute administration to rats. A mechanistic turnover feedback model was assessed using a non-linear mixed effects (NLME) modelling approach.
Methods: Rats (n=17) were infused with 2.5, 5, or 10 mg/kg ESC or vehicle over 60 min. Extracellular 5-HT in hippocampus was monitored using microdialysis. Simultaneously, serial blood was sampled for ESC unbound plasma levels. The structural PK/PD model was a turnover model with drug-induced inhibition of loss of response (kout) and an inhibitory feedback moderator function resembling the acute mechanism of action of ESC[1]. Response acted linearly on the production (ktol) of the moderator, which acted inversely on the production (kin) of response (% of basal level 5-HT normalised to 100%). Additional model parameters were RBAS (baseline 5-HT), n (Hill-factor), Imax (maximal inhibition of loss of response) and IC50 (plasma levels of ESC resulting in 50% inhibition of loss of response). The PK model was fitted and the final parameter estimates were fixed in the combined PK/PD analysis. The PD model was described by differential equations (ADVAN9). IIV was modelled using exponential errors. The residual variability was proportional for the PK and additive for the PD. The final modelwas evaluated using 95% predictive performance plots and bootstrap analysis. NONMEM VI (Globomax) was used for the modelling.
Results: A two-compartment PK model (ADVAN3, TRANS4) adequately described the ESC plasma levels. IIV was identified for CL (17%), V1 (45%), Q (15%). Dose level on clearance was the only significant covariate. 5-HT levels were significantly increased following drug administration. However, at high doses, the mean response-time curves were almost identical. Therefore, a simple intrinsic turnover model was considered inappropriate. The final model included no further covariates and fitted all the response-data well and resulted in parameter estimates with acceptable precision. IIV was identified for RBAS (16%), Imax (14%) and IC50 (82%). The residual variability was 18% for the PK and 30 response units (%) for the PD.
Conclusion: The NLME turnover feedback model was successfully implemented. Variability estimates were low to moderate except for IIV of the in vivo potency (IC50). The model may serve as a tool to compare the PK/PD behaviour of different SSRIs.
Reference:
[1] C. Bundgaard, F. Larsen, M. Jørgensen, J. Gabrielsson, 2006. Mechanistic model of acute autoinhibitory feedback action after administration of SSRIs in rats: application to escitalopram-induced effects on brain serotonin levels. Eur. J. Pharm. Sci. 29, 394-404.
