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Objectives & Background: Drug X is a new CNS active compound which is currently under clinical development. X inhibits the re-uptake transporter of the neurotransmitter W and is mainly metabolised to Y, which is the only metabolite found in human plasma. Y shows significant in vitro activity, but has never been administered to any species, so its pharmacokinetic (PK) properties and also the in vivo activity are unknown. In order to investigate the in vivo contribution of the metabolite to the observed pharmacodynamic (PD) effect an animal study was performed to determine the potency and effect-time course of drug X and metabolite Y.
The objective of the data analysis was to develop a population PK/PD model in order to assess the potency of metabolite Y relative to parent drug X.

Methods: Single doses of drug X or its metabolite Y were administered intravenously (0.3-10 mg/kg) or orally (1-20 mg/kg) to 132 female NMRI mice, 64 female NMRI mice were treated with placebo and served as control group. Samples for PK (X and Y) and PD were taken at 0.75, 1.5, 3, 16 and 17.5 h after administration. The PD effect was determined by the competitive inhibition of the re-uptake transporter of the neurotransmitter W by substance Z in mouse brain after administration of X or Y. Like X and Y, substance Z inhibits the re-uptake transporter W and was administered intravenously in a dose of 2.0 µCi as a tritium labelled molecule 45 minutes before the mice were decapitated. Selected areas of the mice brains were dissected and the amount of radioactivity per mg tissue was determined. Thus, the inhibition of the in vivo binding of drug X and metabolite Y by substance Z was determined. Overall, 197 plasma concentrations (65 drug X, 132 metabolite Y) and 132 PD measurements, from 132 mice, were available for developing the PK/PD model. The analyses were performed using the FO estimation method supplied by NONMEM version V, combined with graphical visualisation methods. Model development was performed in a sequential way, starting with a PK model for the metabolite after intravenous administration. Next, PK data from other administrations were added and the respective PK/PD models were built. The final model was to describe the complete PK/PD data of the 132 mice treated with drug X or Y.

Results: Plasma concentration-time profiles of drug X and metabolite Y were best described by one compartment models with saturable Michaelis-Menten (MM) elimination kinetics. Absorption of drug X after oral administration was best described by a first-order process combined with a MM process accounting for the first-pass metabolism. Absorption of Y could be modelled using a first-order absorption process. Metabolic formation of Y out of X was accounted for by a MM metabolism step. Volumes of distribution were found to be large with 17.7 L/kg (X) and 13.6 L/kg (Y) suggesting an extensive distribution into tissues. Within the linear PK range of X and Y, the parameters clearance and half-life could be derived from the estimated MM parameters. Clearances were found to be high with 5.3 L/h/kg (X) and 1.9 L/h/kg (Y) which resulted in half-lives of 2.3 h (X) and 4.9 h (Y), respectively.
The PD effect was best described by an extended Emax model which accounted for the competitive interaction of drug X and its metabolite Y. It was assumed that the efficacy (Emax) was equal for both compounds and that the maximum effect achievable by X and Y was a 100% inhibition of the neurotransmitter W re-uptake transporter. To account for the time delay in the PD, effect compartments were introduced in the model. KEO values were estimated to be 0.555 1/h for drug X and 0.878 1/h for the metabolite Y. EC50 values estimates were 72.3 nM for drug X and 363.1 nM for the metabolite Y.

Conclusion: A PK/PD model was successfully developed describing the plasma concentration-time profiles of the parent compound X, its metabolite Y and the inhibition of the neurotransmitter W re-uptake transporter simultaneously. Pharmacokinetics of drug X and its metabolite Y exhibited non-linearity which had never been noticed before in any species treated. Simulations performed with parameters obtained from this data analysis showed that MM kinetics have only an impact on high concentrations caused by high doses administered in this trial. However, non-linearity in human PK has not been observed so far and is not expected to occur within the effective plasma concentration range.
Pharmacodynamic investigations revealed a 4.1 - 5.0 fold higher in vivo potency of drug X in comparison to metabolite Y regarding the inhibition of the neurotransmitter W re-uptake transporter in mice. Comparison of EC50 values of iv data and iv plus po data indicated that no additional active metabolites were built during the first-pass metabolism of drug X. Since under steady state conditions in humans plasma concentrations of the metabolite Y were approximately 3 fold lower than that of the parent compound X, and since the in vivo potency of Y is 5 fold lower the contribution of the active metabolite Y to the overall efficacy might be low.